What Science Knows about Cancer: Course Guidebook

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What Science Knows about Cancer

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Professor David Sadava is Adjunct Professor of Cancer Cell Biology at the City of Hope Medical Center. He also is the Pritzker Family Foundation Professor of Biology, Emeritus, at Claremont McKenna, Pitzer, and Scripps, three of The Claremont Colleges. At Claremont, he has twice won the Huntoon Award for superior teaching. Professor Sadava is the author or coauthor of more than 55 peer-reviewed scientific research papers and five books, including two recent biology textbooks. He received his Ph.D. in Biology from the University of California, San Diego.

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Guidebook

THE GREAT COURSES ® Corporate Headquarters 4840 Westfields Boulevard, Suite 500 Chantilly, VA 20151-2299 USA Phone: 1-800-832-2412 www.thegreatcourses.com

Subtopic Health & Wellness

What Science Knows about Cancer Course Guidebook Professor David Sadava City of Hope Medical Center and The Claremont Colleges

PUBLISHED BY: THE GREAT COURSES Corporate Headquarters 4840 Westfields Boulevard, Suite 500 Chantilly, Virginia 20151-2299 Phone: 1-800-832-2412 Fax: 703-378-3819 www.thegreatcourses.com

Copyright © The Teaching Company, 2013

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David Sadava, Ph.D. Adjunct Professor of Cancer Cell Biology and Pritzker Family Foundation Professor of Biology, Emeritus City of Hope Medical Center and The Claremont Colleges

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rofessor David Sadava is Adjunct Professor of Cancer Cell Biology at the City of Hope Medical Center. He also is the Pritzker Family Foundation Professor of Biology, Emeritus, at Claremont McKenna, Pitzer, and Scripps, three of The Claremont Colleges. Professor Sadava graduated from Carleton University as the science medalist, earning a B.Sc. with first-class honors in Biology and Chemistry. A Woodrow Wilson Fellow, he received a Ph.D. in Biology from the University of California, San Diego. Following postdoctoral research at the Scripps Institution of Oceanography, Professor Sadava joined the faculty at Claremont, where he twice won the Huntoon Award for superior teaching, in addition to receiving numerous other faculty honors. He has taught undergraduate courses in general biology and biotechnology and one of the first advanced undergraduate courses in cancer biology. He also has been a visiting professor at the University of Colorado and at the California Institute of Technology. Professor Sadava has held numerous research grants and has written more than 55 peer-reviewed scientific research papers, many with his undergraduate students as coauthors. A laboratory scientist, his research concerns resistance to chemotherapy in human lung cancer, with a view to developing new plant-based medicines to treat this disease. He is the author or coauthor of five books, including the recently published ninth edition of a leading biology textbook, Life: The Science of Biology, as well as a new biology textbook, Principles of Life.

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Professor Sadava also has produced Understanding Genetics: DNA, Genes, and Their Real-World Applications with The Great Courses. ■

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Table of Contents

INTRODUCTION Professor Biography ............................................................................i Course Scope .....................................................................................1 LECTURE GUIDES LECTURE 1 Cancer Is an Ongoing Challenge .......................................................5 LECTURE 2 Cancer Is a Major Burden to Society ................................................12 LECTURE 3 Discovering Causes of Cancer in Populations .................................18 LECTURE 4 Some Causes of Cancer in Populations ...........................................25 LECTURE 5 DNA Is the Key to Understanding Cancer ........................................31 LECTURE 6 How Does DNA Change to Initiate Cancer? .....................................38 LECTURE 7 How Do We Know If Something Causes Cancer? ...........................44 LECTURE 8 How Do Normal Cells Function? ......................................................50 LECTURE 9 What Is Different about Cancer Cells? .............................................56 LECTURE 10 How Do Tumors Grow? ....................................................................63 iii

Table of Contents LECTURE 11 How Tumors Spread and Thrive .......................................................69 LECTURE 12 What Are Tumor Viruses?.................................................................75 LECTURE 13 How Do Tumor Viruses Cause Cancer?...........................................81 LECTURE 14 How Do Cancer-Causing Genes Work? ...........................................87 LECTURE 15 Can Cancer Be Inherited? ................................................................93 LECTURE 16 How Do Normal Genes Suppress Tumors? .....................................99 LECTURE 17 How Do Genetic Changes Result in Cancer? ................................105 LECTURE 18 Treating Cancer with Surgery ......................................................... 111 LECTURE 19 Treating Cancer with Radiation ...................................................... 117 LECTURE 20 Treating Cancer with Drugs ............................................................123 LECTURE 21 How Do Drugs Attack Cancer? .......................................................129 LECTURE 22 Frontiers of Cancer Treatment........................................................135 LECTURE 23 Can Screening for Cancer Be Useful? ...........................................141 iv

Table of Contents LECTURE 24 Can Cancer Be Prevented?............................................................147 SUPPLEMENTAL MATERIAL Glossary .........................................................................................153 Bibliography ....................................................................................163

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What Science Knows about Cancer Scope:

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here are few words in any language that strike as much fear as the word “cancer.” One person in three develops malignant cancer in his or her lifetime, and one out of four dies from it. The aim of this course is to explain the science that underlies this disease. As you learn about how cancer works to subvert the body’s normal functioning, you will see how cancer can be treated and even prevented. The first part of the course sets the stage, describing the challenge that cancer poses to humanity. Lectures 1 and 2 outline where we have been and where we are. Because cancer typically strikes older people, it was relatively rare until the past century. People thought—and many still think—that cancer was caused by an imbalance of bodily fluids or was a punishment by a deity. More recently, explanations of cancer based on the chemistry and physics of cells in the body have taken hold. The U.S. government optimistically declared a 10-year “war on cancer” in 1972. Clearly, it failed and has turned into a war of attrition. After heart disease, cancer is still the second leading cause of death, with lung cancer leading the way. Lectures 3 and 4 deal with epidemiology, the study of diseases in populations. It seems that every day, the results of long-term studies of groups of people point to new links between diet, environmental exposure, or lifestyle and cancer. The most obvious of these culprits is tobacco smoking, which is implicated in about one-third of all cancer. Less clear are the effects of various aspects of diet, where data are often conflicting. Even less clear is the link between personality and cancer. More direct information on the causes of cancer is revealed in the second part of the course. In Lecture 5, we enter the cell and focus on its genetic material, DNA. This is where a lot of cancer begins. The human genome has several billion chemical “beads” making up long chains of DNA in every one of the trillions of cells in the body. Many of the instructions in DNA are expressed as proteins. Mutations are changes in the DNA “beads.” Every day, thousands of these changes occur spontaneously in many cells, and they 1

can result in altered proteins with changes in cell functions. As Lecture 6 points out, most cancer-causing agents (carcinogens) cause mutations in DNA. We are exposed to thousands of these agents all the time, ranging from ultraviolet radiation from the Sun, to naturally occurring chemicals in the bodies of plants and animals that we eat, to industrial pollutants. Cells have ways to repair the DNA mutations before cancer starts. But too often, the damage overwhelms the repair systems, and the mutations are permanent. Lecture 7 describes how scientists have developed lab tests on simple organisms to try to sort out cancer-causing agents from harmless ones. Unfortunately, the results of these tests are often unclear and may not apply to humans—so people and governments apply risk analysis, where costs and benefits of exposure are weighed and decisions are made.

Scope

The third part of the course describes the features of cancer as a disease of cells. In Lectures 8 and 9, cells in general and cancer cells in particular are introduced. All cells in the body—whether on the skin or inside the heart—have basically the same overall structure, with the entire DNA genome enclosed in a nucleus. When a cell’s DNA is changed, its functions can change, and cancer can be initiated. This results in cell changes such as constant cell reproduction (so that the tumor grows); changes in the cell surface (so that cancer cells are less “sticky”); and a general dedifferentiation, or loss of specialized appearance and function. While a tumor with billions of cells may arise from a single cell, the cells keep on changing so that only some of the cells may retain the ability to keep growing. These are called cancer stem cells. In Lectures 10 and 11, the growth and spread of cancer are described in cellular terms. Tumors can be benign or malignant. Benign tumors grow to a limited size and typically stop as a ball of cells; they do not spread but can cause significant illness when they grow inside an organ such as the brain. Malignant tumors can metastasize, or spread by breaking off some cells and sending them throughout the body via the blood or lymphatic systems. Tumors send chemical signals to nearby blood vessels to sprout branches to nourish the tumor, a process called angiogenesis. As a tumor grows and spreads unchecked, it places an increasing burden on the body’s functions, leading to serious illness and death. The fourth part of the course describes the scientific discoveries about cancer deep inside cells. Some of these have come from cancer viruses and 2

others from inherited cancers. About 10 percent of cancer is caused by viral infections, and the details of these are described in Lecture 12. These viruses picked up their cancer-causing oncogene DNA from normal cells, and the role of these proto-oncogenes is outlined in Lectures 13 and 14. In the many cancers not caused by viruses, the normal cell’s proto-oncogenes get changed by mutation. These changes turn on the expression of the genes, setting in motion a series of events that result in uncontrolled cell reproduction. About 10 percent of cancers result from DNA mutations in genes that are passed on from parent to child, and these tumors and their inheritance patterns are striking, as shown in Lecture 15. In Lecture 16, the genes mutated in hereditary cancer are identified as tumor suppressors, encoding proteins that normally act as “brakes” to block cell reproduction. When the genes are mutated, the brakes are off. Other inherited cancers involve the inactivation of genes involved in DNA repair, so mutations pile up unchecked. Lecture 17 puts these cellular details of genes and mutations together. We now have an amazingly detailed view of the sequence of events occurring inside a cancer cell as a tumor develops. For example, at least six separate events, beginning with DNA changes, are involved in the development of colon cancer. There are now tests for early DNA changes in cancer, with a goal of cutting the cancer off before it grows to become a clinical problem. What does all of this knowledge about the science of cancer mean in terms of treatment? The fifth part of the course describes how surgery, radiation therapy, and chemotherapy (drugs) are used to treat this disease. In Lecture 18, surgery is noted as the mainstay of cancer treatment, with a cure possible in localized tumors. As scientists have learned about the events of tumor growth and spread, surgeons have changed their operations on tumors to be less invasive and disfiguring. This is especially notable in breast cancer surgery. Cancer can even be prevented by surgery in people who are especially susceptible to getting a specific type. Radiation, which can cause cancer, can also treat it (Lecture 19). Focused beams of X-rays or other kinds of radiation can damage tumors while minimizing damage to adjacent normal tissues. If a tumor has spread to other locations in the body, chemotherapy must be used to deliver treatment via the blood system (Lectures 20 and 21). Unfortunately, this wide distribution has a downside: The drugs also enter normal cells, causing damage collectively known as side effects. The therapeutic index, comparing cancer damage and normal tissue damage at 3

a specific dose of drug, is the key to a drug’s success. Many cancer drugs are natural products, and they attack general mechanisms in the cancer (and normal) cells, such as DNA. New, targeted therapies are being developed that attack specific steps in cancer development, such as the proteins encoded by proto-oncogenes, tumor suppressor genes, metastasis, and angiogenesis. But a challenge remains as cancer cells develop resistance to medications. The frontiers of cancer treatment include harnessing the immune system and adding new genes (gene therapy). As Lecture 22 describes, these show promise, but are not yet widely used.

Scope

The sixth part of the course circles back to the beginning of the course, where cancer in populations was presented, describing cancer screening and prevention. As Lecture 23 shows, cancer screening uses samples of cells (e.g., the Pap smear for cervical cancer), X-rays (mammograms for breast cancer), and blood tests (the PSA test for prostate cancer) to try to detect cancer early enough so that surgery can remove it before it causes harm. Some of these screening programs have been very successful at reducing cancer deaths (e.g., Pap smear) while others have been somewhat less successful (mammograms), and still others remain controversial (PSA test). Knowledge of the science of cancer causation and development can be used to prevent this disease from starting or growing (Lecture 24). Cancer prevention by reducing cigarette smoking is already showing results, and the good news will accelerate. Vaccines against known cancer-causing viruses are already in use. On the other hand, dietary manipulations are clouded in ambiguity. Eating a healthy diet may not really prevent cancer if we do not know what a healthy diet really is. Progress in understanding each individual’s genetic makeup and each tumor’s DNA changes will make cancer prevention and treatment more effective. ■

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Cancer Is an Ongoing Challenge Lecture 1

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alignant, potentially deadly cancer affects one person in three in North America, Europe, and Australia and kills one person in four. The conventional approach to cancer has been to find out what is wrong at the tissue and cell levels and treat the symptoms (dividing cells). The molecular approach is to find out exactly what is wrong inside the cell at the chemical level and more effectively treat or even cure the disease. The aim of this course is to explain the science that underlies cancer, the amazing stories about how it works to subvert the body’s normal functioning, and, with our understanding, how we can treat it. A Case Study: Kareem Abdul-Jabbar  The great NBA basketball player Kareem Abdul-Jabbar was diagnosed in 2008 with leukemia. If he had contracted the disease even 10 years earlier, with the best treatment known at that time, he might have expected to live another five years. Today, he is cancerfree, thanks to molecular medicine. 

During his career in the NBA, Kareem Abdul-Jabbar was one of the most talented players. Everywhere he played, he set records, most of which still stand. He retired in 1989. All of his athletic ability did not insulate him from cancer. In late 2008, he experienced symptoms including hot flashes and night sweats. A physical exam showed an enlarged spleen. An examination of his blood showed that his white blood cell count was about 200,000/ml, while a normal count is about 5,000/ml.

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Kareem Abdul-Jabbar’s diagnosis was chronic myelogenous leukemia (CML). In CML, two chromosomes swap ends as the result of a mutation. He had many white blood cells called “blast cells” that crowd out red blood cells. When they do that, these leukemia cells prevent red blood cells from carrying oxygen, resulting in anemia. They crowd out the platelets, the blood5

Lecture 1: Cancer Is an Ongoing Challenge

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In terms of treatment, the drug Gleevec is targeted to the molecule that results from the mutation of the chromosomes, and it blocks the division of these cancer cells. This kind of targeted medical treatment, referred to as targeted chemotherapy, which is based on scientific understanding at a molecular level, is the new frontier of cancer research. In addition, chemotherapy involves the use of drugs to stop cancer cells from growing. A bone marrow transplant improves the effectiveness of the drug dose. As a result of these three approaches, survival increased to almost 10 years from In normal blood, typically there are 5,000 about two years. white blood cells per milliliter, which is about a teaspoon of blood.

Kareem Abdul-Jabbar received his CML diagnosis in 2008, and he was cancer-free two years later. This happened as a triumph of science: understanding the problem in CML and attacking it. The triumph of science is a deeper understanding of what’s going on with disease. In conventional medicine, the idea is to see what happened and to try to treat the symptoms. In molecular medicine, the new medicine that’s coming from molecular biology, the idea is to find exactly what’s wrong deep inside the cell at the chemical level and then cure the disease. This is what’s called targeted therapy; this is what happened with Kareem Abdul-Jabbar.

© Purestock/Thinkstock.

clotting cells, resulting in bleeding as well. They crowd out white blood cells involved in immunity, resulting in infections. Kareem Abdul-Jabbar had a moderate number of blast cells, so he was in the “chronic” phase.

The History of Cancer  DNA is a chemical; it’s an information system, and it’s inherited. Every cell in the body has six feet worth of DNA crammed like spaghetti into things you can’t see, called chromosomes. There are 60 trillion cells in the body. DNA encodes cell functions, and cell functions are mainly expressed as proteins. These are the proteins that essentially are the functional aspect of DNA. All cells have the entire inherited DNA, but they make only certain proteins. The chromosomes in humans happen to be in 23 volumes. We have one volume of each chromosome from our parents: one from our mother and one from our father. 

For cancer, history may improve our concepts of the causes, treatment, and prevention. Cancer history is studied in two ways: by actual specimens and by written materials. There are two types of specimens that we can study. First are fossil bones because the soft parts of the body usually are not preserved over time. Secondly, we can look at mummies.

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The second way we can study cancer is through written materials. There are plenty of articles handed down, dated from 1000 B.C., from China associating cancer with diet. If you look through history and all the writings about cancer, we come up with about three ideas for the causes of cancer: that it is a punishment by God, a religious idea; that it is caused by an imbalance of chemicals, or something in the body called humors; and that it is the disease of cells and chemicals inside of cells.

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Biological science has three major ideas: mechanism, cell theory, and evolution by natural selection. Mechanism in life science says that cancer, like all life, has a chemical, physical basis. They are not humors that are balancing, but chemicals that we can identify. Cell theory says that cancer is a disease of cells, those building blocks in humans. Those cells divide and cause a tumor. Evolution applies to cancer because as tumors grow and develop, they change. Mutations happen, and a tumor becomes more difficult to treat. The cancer that ends up growing very large is very different sometimes 7

Lecture 1: Cancer Is an Ongoing Challenge

than the cancer that began. The idea that cancer is a mechanistic cellular disease persists today with most scientists and physicians.

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In 1971, on December 23, President Richard Nixon signed the National Cancer Act to coordinate U.S. efforts. He declared war on cancer with a stated aim to eliminate the disease within the decade of the 1970s. Obviously, it didn’t work because cancer still exists. There are two events that happened in the 20th century with cancer that lead to this optimism: the invention of chemotherapy and its effectiveness and the idea of cancer viruses.

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The first 60 years of the 20th century in life science was the era of biochemistry—that is, looking at all the little chemicals inside the cell and seeing how they were transformed, what they did, and how they were controlled by proteins. In the case of cancer, each chemical is catalyzed by an enzyme, usually a protein, encoded for by DNA. The idea that DNA is necessary for cancer growth and that proteins and chemical changes happen led to major advances in chemotherapy up until 1970.

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Charles Huggins won the Nobel Prize in 1939. He proposed that prostate cancer is stimulated to grow by a hormone, the male sex hormone testosterone. He said that the way we could treat it is by eliminating the male hormone testosterone. There are two ways to do that: the surgical way (castration) or to design an antihormone drug, an antitestosterone, which he did. His antitestosterone drug alleviated the symptoms and growth of prostate cancer. This began, before WWII, the era of modern chemotherapy.

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In the 1940s, Sidney Farber, working at Harvard medical school, found that a vitamin called folic acid was necessary for bone marrow cell production. At the chemical level, they found the biochemical pathway involved where folic was needed. Farber reasoned that if folic is necessary for bone marrow to make white blood cells, then perhaps an antifolate, something that would block folic acid, would be able to treat leukemia. The drug was called methotrexate; it was very successful with children.

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In the 1950s, two scientists—George Hitchings and Gertrude Elion (who also won the Nobel Prize)—realized that DNA is necessary for cancer because DNA has to reproduce for cells to divide, so they made the first DNA antimolecules. These were successful as well.

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In the 1960s, scientists realized that cancers are not homogeneous. All the cells of a leukemia may not be the same as they are for some cancers, so they developed combination therapies of different drugs. In the case of Hodgkin’s disease in children, which was normally lethal, people were cured and lived. There was great optimism with these new drugs.

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Another idea was that cancer is an infectious disease. In the 19th and 20th centuries, there was a great development in medicine called the germ theory by Louis Pasteur. Robert Koch, and other great microbiologists, found that diseases—the scourges of humanity like tuberculosis and small pox—were caused by bacteria and viruses. We could treat them with antibiotics or even prevent it with vaccines in some cases.

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In 1910, a virus was discovered to cause cancer in chickens, and by the 1960s, there were many tumor viruses in animals that had been identified, especially in rodents. Some of these viruses had unusual ways to reproduce—RNA was one, rather than DNA. There was great excitement that cancer might be a virus, and in that case, you could treat it with a vaccine or prevention. This led a woman named Mary Lasker to lobby for the National Cancer Act in the late 1960s, and it was passed. There was great optimism in the 1970s, but we really haven’t made much of a dent; one in four people in our society still die of cancer.

Important Terms cell: The basic unit of biological structure, function, and continuity. It contains the genome as well as the chemical components for biochemistry.

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chemotherapy: The use of drugs to treat a disease; used most commonly with cancer and some infectious diseases. chromosome: A DNA molecule containing all or part of the genome of an organism and that has the ability to replicate. DNA: Deoxyribonucleic acid, a polymer of nucleotide building blocks (A, T, G, and C) that acts as the genetic material in most living things. enzyme: A biological catalyst that speeds up a biochemical transformation without emerging changed by the process; most enzymes are proteins, although some are RNAs. mutation: A change in the genetic material that is passed on to both daughter cells after cell division. If the cell is a germ line cell, then the change can be passed on to offspring and is inherited. If the change is in a somatic cell, then it is passed on only to the cells deriving from the original changed cell.

Lecture 1: Cancer Is an Ongoing Challenge

protein: A large molecule composed of amino acid building blocks linked together. RNA: Ribonucleic acid, a polymer of the nucleotides A, G, C, and U. There are several types of RNA in the cell, such as transfer RNA and messenger RNA. They are mostly involved in gene expression. targeted chemotherapy: Use of a drug that has a rather specific target molecule in a diseased cell. This is done to minimize side effects of treatment. It is a frontier of cancer treatment. vaccine: A harmless formulation of a disease agent foreign to the body that provokes an immune response that protects the body from infection by the intact disease agent. Vaccines against certain viruses that cause cancer can be used to prevent those cancers. Vaccines can also be made against tumors after they develop. virus: An infectious particle usually composed of DNA and protein that requires a host cell to replicate. 10

Suggested Reading DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. James, Cancer. Mukherjee, The Emperor of All Maladies. Rettig, Cancer Crusade. Sontag, Illness as Metaphor.

Questions to Consider 1. An individual with cancer is often described as “battling” the disease. What are the implications of this metaphor for the individual, for those around the person (including medical personnel), and for the belief systems of society?

2. Two ideas about cancer that are commonly believed by the general population are that it is largely inherited (“runs in families”) and/or caused by a virus (infectious). As the course begins, do you believe these ideas?

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Cancer Is a Major Burden to Society Lecture 2

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Lecture 2: Cancer Is a Major Burden to Society

ancer is a challenge for humanity. One person in three still gets malignant cancer, and one person in four dies of cancer. In this lecture, you will learn that cancer is a burden on society—not only a burden of suffering of people, of individuals and the individuals around them, but also an economic and social burden. You will also learn that cancer is an increased medical problem in this century; statistical information on cancer offers some suppositions as to what might be going on. Finally, you will learn that cancer is a global challenge. Cancer as a Burden on Society  Astonishingly, 13.5 million Americans have malignant cancer— cancer that has the capability of spreading elsewhere in the body— excluding nonmelanoma skin cancer. Of the 13.5 million Americans with cancer, about a third of them were diagnosed less than five years ago. Statistics show that cancer is a disease of older people. This idea primarily reflects multiple chemical changes to cells that give rise to malignancy.

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Cancer is most common in some organs. The most common cancer in males is prostate cancer. The second and third most common cancers, respectively, are lung and colorectal cancers. For females, the most common cancer is breast cancer, followed by lung cancer, followed by colorectal cancer. This may reflect the uses of these organs—rapid wear and tear.

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Different cancers have different medical costs that may reflect when the cancer is diagnosed. For example, lung cancer is diagnosed late, when patients are sicker, so they need more care. New drugs, such as Gleevec for chronic myelogenous leukemia, are very expensive. New targeted therapies typically cost $250 per day, every day, for life sometimes.

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The financial cost of cancer varies from year to year. An initial year of diagnosis is very expensive. The last year of life is quite expensive, but the intermediate years are not very expensive. The current direct costs in the United States for cancer are about $124 billion. Cancer makes up a few percent of total healthcare costs, which are about $2.5 trillion. There are additional costs due to cancer called indirect costs, which include things like the loss of economic productivity of a person due to cancer. Together, the direct and indirect costs of cancer are about $274 billion per year, which is a few percent of the total gross domestic product.

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Cancer is the second leading cause of death. For cancer, the mortality rate is going down somewhat, which is good news. For heart disease, the decline has been absolutely spectacular. People are eating a lot better, eating less, and exercising, but there is still a lot of obesity. Treatment has had major contributions to the reduction of deaths due to heart disease. For example, surgery (such as implanting valves in the heart and bypass surgery) and drugs (such as anticholesterol drugs, antihypertensive drugs, and anti–congestive heart failure drugs) have made spectacular improvements in the treatment of this disease.

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For cancer, we have not had this spectacular improvement yet, but the lesson of heart disease tells us that if we get the right information, we could get there as well for cancer. An interesting way of looking at this is to look at the life expectancy of a newborn baby. In 1970, the life expectancy of a baby born in 1960 was 70 years. In 2000, the life expectancy was 77 years, so from 1960 to 2000 life expectancy in the United States of a newborn baby increased by seven years.

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Of the seven years, 4.9 years of improvement was due to reduction in deaths from cardiovascular disease, and 1.4 years of improvement was due to reduction in deaths in the neonatal period. The reduction of deaths due to cancer was 0.2 years from 1960 to 2000, or 10 weeks. That is what all of the war on cancer got us in

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terms of improvement of lifespan. We have a long way to go, and we have the means to get there. 

Cancer is a disease of older people. For the first 20 years of life, the leading causes of death are accidents and assaults, and cancer is the third. For the next 20 years, ages 20 to 39, accident and suicide are the top causes of death, with heart disease and cancer next. After age 40, cancer and heart disease are the major causes of death, and after age 80, heart disease is the major cause. The cancer that is most lethal in males is lung cancer. For females, the most lethal cancer is also lung cancer, and breast cancer is second while colorectal cancer is third.

Lecture 2: Cancer Is a Major Burden to Society

Cancer as a Medical Problem  Before 1900, cancer was a rare disease. Most people seemed to die of infectious disease. The lifespan was a lot lower than it is now because there was not good public health. For example, in the year 1900, the typical lifespan of a newborn in England was 45 years, and it was similar in the United States—most Americans died in their 40s.

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Now, of course, we have improved public health, improved explanations of disease, and improved sanitation. More people seem to be living longer. If you live longer, you can develop cancer. Remember, cancer is a disease of older people. If we look at countries that are not as developed as America and Britain, as these countries become more developed (more affluent), they live longer, and if a person lives longer, he or she is more susceptible to cancer.

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There has been a modest improvement in survival of cancer. However, if we look at incidence, we see something rather surprising: that the incidence of cancer has increased. The two possible explanations of this are that there is more actual cancer (an epidemic) or that we are getting better at finding it. If we look at individual types of cancer and see what each type was doing during this period of time, maybe one of the cancers was spiking, and that could give us an idea of what was causing this epidemiologic increase.

From 1975 to 2005, we see a modest increase in breast cancer in females over time. For males, lung cancer decreased slightly in incidence while colorectal cancer decreased modestly. Urinary bladder stayed about the same. Liver cancer increased slightly, but there was a huge increase in prostate cancer. The reason for this increase in prostate cancer was due to the inventions of the digital rectal exam and a blood test called the PSA test.

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Over the past century, starting in 1930, stomach cancer decreased to a low level in both males and females. Stomach cancer in the United States used to be the most lethal form of cancer up until the 20th century, and it still is among the most lethal forms of cancer in Asia. We can make some guesses as to why stomach cancer decreased, and one of those guesses is smoked meat and fish.

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Not surprisingly, the most common cancer for women is breast cancer.

Before the invention of refrigeration to preserve meat and fish, people would salt the meat or fish, dry it out a little bit, and preserve it in salt. In the acidic environment of the stomach, there is a chemical reaction that happens with the salt and the breakdown of the proteins in the stomach of the meat, and it forms a very potent cancer-causing chemical, which then causes stomach cancer. The invention of the refrigerator obviated the need for salted meat and fish, and the rate of stomach cancer decreased.

Cancer as a Global Challenge  Cancer is not just a local disease; it is a global disease. The Global Burden of Diseases (GBD) Study is a collaboration between the World Health Organization and the Harvard School of Medicine. 15

Lecture 2: Cancer Is a Major Burden to Society

It is a time-based study combining years of life lost because of premature mortality and years of productive life lost if you are living in a state of less-than-full health—that is, it combines morbidity and mortality. 

The GBD Study has very interesting data. The most important disease in 2004 worldwide for humanity was lower respiratory infections, followed by diarrheal diseases, unipolar depression, and heart disease. Cancer is not on that list. For 2030, there will be an estimated shift in some of these diseases. HIV, for example, is going to decrease dramatically as a cause of morbidity and mortality. By 2030, the most important disease affecting humanity is going to be unipolar depression. Four of the top 10 drugs sold in this country are for depressive illnesses, and depression is a very common and very difficult thing to deal with in our society.

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When we look at the causes of death worldwide, we see that the only cancer in the top eight is lung cancer. The top disease is coronary, followed by stroke and respiratory infections. For lowincome countries, cancer is not on the list at all. Maybe there is a lifespan issue, but there could be other issues as well. For highincome countries, there are two cancers on the list: lung cancer and colon cancer.

Important Term incidence: Frequency of a disease in a population per unit of time. For cancer, incidence is typically expressed as the number of new cases per 100,000 per year.

Suggested Reading DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. James, Cancer. 16

Mukherjee, The Emperor of All Maladies. Sontag, Illness as Metaphor.

Questions to Consider 1. The death rate due to cardiovascular diseases has declined significantly in the past three decades, but although there has been some decline in the cancer death rate, it has been modest in comparison. What do you think are reasons for the difference?

2. A major issue in health care costs has been the rise in cancer care, especially new drugs that can cost at least $60,000 per year. For a patient with lung cancer caused by smoking, should society (e.g., Medicare) pay these high treatment costs?

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Discovering Causes of Cancer in Populations Lecture 3

T

Lecture 3: Discovering Causes of Cancer in Populations

his lecture discusses links between cancer and the environment and tries to identify causes. Hopefully, once we know about the causes of cancer, we can work toward eliminating those causes in the environment. In this lecture, you will learn about the science of epidemiology. You will also learn how population studies can indicate causes of cancer. Then, you will learn how epidemiological studies of individuals—including case-control studies and cohort studies—are conducted and how this type of evidence can be evaluated. Epidemiology  Epidemiology is the study of the distribution and determination of states of health in a human population. The goals of epidemiology are the prevention, surveillance, and control of health disorders in the population. In the United States, epidemiology is largely a function of an organization called the Centers for Disease Control and Prevention (CDC).

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The aims of epidemiology are several. Epidemiology assumes that human disease may be related to the environment. The ultimate aims of epidemiology are to establish a cause-and-effect relationship. This is hard to do because most diseases involve three different aspects: the agent (the thing that might cause the disease, which could be inside the body or something from the outside), the host (the person), and the environment.



For example, the influenza, or flu, agent is either a virus or, in some cases, a bacteria. If the host is exposed to the virus that causes the typical flu, his or her immune system may fight it, but another person’s immune system might not because he or she didn’t get the vaccine. Alternatively, the host may be immunocompromised, which means that his or her immune system is not working well. In terms of the environment, you are not going to catch the flu if you

do not interact with people very much. On the other hand, crowding and malnutrition spread the disease. 

For cancer, one of the best sources of data might be death certificates. Generally, on a death certificate, by law, there is demographic data, including age, address, occupation, and spouse information. The problem is that the accuracy of death certificates relies on individual physicians. For example, in the 1940s, if a person had multiple diseases and died and diabetes was one of them, diabetes went to the top as the cause of death—even if they may have died of something else.

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There is population-based data on cancer incidence. In a number of regions of the country, when a physician makes a diagnosis of cancer, he or she has to report the disease to a central public health agency that then puts it into a database. That is what a reportable disease is. There is a huge reportable disease database for cancer called surveillance epidemiology end result (SEER) that is run by the National Cancer Institute in America and by the CDC. The database has several million cases and well over 100,000 new cases every year.

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A second source of information is the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which has been going on since the early 1990s. It has enrolled about half a million people from all over Europe and studies diet and other habits that people have as well as cancer. It’s a prospective study because the people that are enrolled do not necessarily have cancer; they are going to be followed for a long time, and blood samples will be taken periodically and stored.

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A third source of information on cancer is the Nurses’ Health Study, which started in the United States in 1976. It is a prospective study that follows people over time. Nurses from 11 of the most populous states are being followed. There are over 100,000 nurses that have questionnaires they are filling out every two to four years on their

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health, diet, and existence of disease. They take blood samples every two years well.

Lecture 3: Discovering Causes of Cancer in Populations



A causative risk factor is the actual cause of the disease. A descriptive risk factor distinguishes people who are at increased risk, but it is not the actual cause. The risk is the individual’s chance of getting the disease. Relative risk is the number of times higher the risk is of getting the disease in those who have the same risk factor as compared to those without the factor.

Studies of Epidemiology: Populations and Individuals  One way to study epidemiology is by looking at international comparisons. Specifically, immigrant studies involve watching what happens when people in an area that has a certain rate of cancer move to an area with a different rate of cancer. It takes many, many generations to see significant genetic change in populations of humans. Studies of Japanese and first- and second-generation Japanese Americans show significant decreases in the incidence of stomach and liver cancer and an increase in colon cancer.

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In addition to doing immigrant studies, researchers can study a population that is in the same place but is exposed to something new. In a descriptive epidemiological study, researchers discovered that endometrial cancer—a cancer of the endometrium, which lines the uterus in women—increased significantly in large city populations (but not in rural areas) after the introduction of estrogen for postmenopausal use.

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Epidemiological population studies can point out trends and raise questions, but studies of individuals must pinpoint the cause. There are two types of studies on individuals for cancer causes: casecontrol studies and cohort studies.

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Case-control studies compare people with cancer (cases) and people without cancer (controls) to calculate relative risk of exposure to a carcinogen or other condition. Cohort studies compare people who were exposed to a risk factor with people who were not exposed,

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The problem with epidemiology is that there are many, many small studies that show small relative risks, present conflicting data, and confuse the public—leading to what a great physician once called an epidemic of anxiety. In other words, everybody is worried about things that are going to cause cancer. A typical small relative risk is less than two or three. For example, your risk of getting a certain type of cancer is one to 1,000, and that is pretty high for some cancers. Now, it’s going up to two to 1,000. It’s very hard to measure that reliably, and you end up with conflicting data.

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Two major challenges limit epidemiological studies: confounding variables, which are things that are hidden in a study (for example, not taking past smoking into account in a particular study); and biases in study design, which involves choosing the right controls (for example, random phone calls to select a control group tend to favor the wealthy because poor people are less likely to be home during the day to answer the phone, less likely to volunteer to take part in a study, and less likely to call researchers back).

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There was a case-control study on coffee drinking and pancreatic cancer that made headlines. It found a relative risk of two, so there was a twofold risk of getting pancreatic cancer if you were a coffee drinker. In the two groups—the cases and controls— researchers corrected for smoking. Both groups had equal numbers of smokers, but researchers did not interview In one study, coffee drinking was linked participants about past to pancreatic cancer, but this conclusion smoking. When they was not valid. 21

© Stockbyte/Thinkstock.

and both groups are followed on a long-term basis to see who gets cancer.

corrected for people who had smoked in the past, the relative risk went down to one. The conclusion was not valid because of this confounding variable.

Lecture 3: Discovering Causes of Cancer in Populations



Evaluating epidemiology evidence has to be done, and there are six main ways to evaluate them. o Are results of different designs of the investigations consistent? Do case-control studies and cohort studies give the same relative risk? o

Have different studies using the same design given the same result? In other words, does a case-control study in one place and another place give the same result?

o

Are the relative risks large—not 10 percent more, but 300 percent or 500 percent more?

o

Is the agent, the suspected thing that causes cancer, for example, specific for one type of cancer because different cancers are susceptible to different agents?

o

Is there a dose-response relationship? That is, in an epidemiology study, if you are exposed to one unit versus 10 units, you should get more cancer—in fact, tenfold more cancer—than if you are just exposed to one unit of the agent.

o

Is it biologically reasonable? For example, is it biologically reasonable that estrogens might be related to endometrial cancer?

Important Terms carcinogen: A substance or physical entity that causes damage to a cell, leading to cancer. Most carcinogens are mutagens that damage DNA.

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case-control study: Epidemiological analysis comparing two populations— one group with a cancer and one group without—and examining the proportion of people exposed to a suspected cancer-causing agent in each group. For example, lung cancer patients versus people without the cancer would be compared for smoking status. cohort study: Epidemiological analysis comparing two populations—one exposed to a suspected cancer-causing agent and the other not exposed—and examining the proportion of diseased people in each group. For example, smokers and nonsmokers would be compared with respect to lung cancer. epidemiology: The science of the incidence, course, and determinants of disease in populations. Cancer epidemiology has been useful at pointing to possible causes. immune system: Body functions that recognize and defend against substances foreign to the body, most notably infectious diseases. The immune system often recognizes cancer cells as foreign due to their genetic changes and kills the tumor. risk factor: Genetic or environmental condition that makes it more likely that an individual will get a disease. In cancer, there are causative risk factors (if removed, a person does not get cancer) and descriptive risk factors (put people at risk but are not causes).

Suggested Reading DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. James, Cancer. Rothman, Epidemiology.

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Questions to Consider 1. Every day, the media reports new epidemiological information linking something to cancer. What was in the news today? How can you evaluate this information?

2. Epidemiology is difficult. The incidence of thyroid cancer in Japan is

Lecture 3: Discovering Causes of Cancer in Populations

about one new case in 50,000 people per year and ranges from one in 30,000 to one in 100,000. Exposure to radiation is a risk factor for this cancer, which may take a decade to develop. How would you design an epidemiological study to link radiation exposure from the tsunamirelated nuclear power plant accident in 2011 with thyroid cancer?

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Some Causes of Cancer in Populations Lecture 4

T

his lecture will outline some of the environmental causes of cancer. In this lecture, you will learn that there are two overwhelmingly important causes of cancer in terms of epidemiologic studies: tobacco and diet. Then, you will learn about estrogen and reproductive status in women; medications, pesticides, and radiation as each relates to cancer; and personality and cancer. You will also learn about causative factors acting in combination when it comes to cancer. Tobacco and Diet  Tobacco is the single most important cause of cancer. If you look at smoking and global mortality, cigarette smoking is involved in 80 percent of all lung cancer, laryngeal cancer, oral cancer, and esophageal cancer and 30 to 45 percent of bladder cancer, kidney cancer, cervical cancer, and pancreatic cancer. Smoking is also involved in respiratory diseases and cardiovascular diseases. 

In China, cohort studies are being done that follow smokers for a period of time because smoking has increased a great deal in China. They have taken groups of factory workers who are smokers and nonsmokers, and they’re looking for the incidence of lung cancer. What they are finding is that 12 years out, the relative risk is 5; it has increased quite a bit after 12 years of smoking.

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In 1964, the U.S. surgeon general’s report on smoking and health began a real awareness of public health in the United States and many other Western countries. In addition, in the 1980s, a nonsmokers’ rights movement began, and smoking declined significantly during this time.

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The relative risk for smokers is typically between 10 and 20; it’s huge if you smoke for a long period of time. There have been over 50 studies on passive smoking. Typically, it involves exposure of 25



Many, many studies have been done on diet and cancer—in terms of both preventing cancer and seeing whether people who eat certain things can be cured of cancer or get better. The best studies have to be long-term studies, but this is very difficult. Imagine taking a group of people— not laboratory animals— and feeding them a certain diet and asking them questions about what they are eating.

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Studies of populations smoking is involved in 80 showed a correlation Cigarette percent of all lung cancer, laryngeal between dietary fat and cancer, oral cancer, and esophageal breast cancer, but in cancer. individual studies, this link does not hold up. (A high-fat diet does, however, lead to increased colon cancer and heart disease.) Colon cancer increases with a lowfiber, red meat, and processed meat diet. No preventive effect of a diet high in fruits and vegetables on breast or prostate cancer has yet been shown.

Reproductive Status in Women  More estrogen leads to more endometrial cancer in all of the epidemiologic studies that have been conducted of women. The reason estrogen causes cancer is that cells of the endometrium have a substance inside them called a receptor, which receives the hormone, and it binds to the cell surface on the receptor, gets inside the cell, and causes the cell to divide. 26

© Stockbyte/Thinkstock.

Lecture 4: Some Causes of Cancer in Populations

nonsmokers to smoke from their environment, either at work or in the household. Passive smoking increases the risk for lung cancer by between 1.3 and 1.4. This is significant, but it is not as much as you might believe, based on some of the advertising that exists.

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If you look at the incidence of breast cancer and exposure to estrogens, it increases. There have been many, many case-control and cohort studies, such as the Nurses’ Health Study, that show why in a lifetime a woman would be exposed to more estrogen in several natural situations. For example, if menarche, which is when a woman starts getting her monthly cycling, starts at a younger age, then there are more years of estrogen made by the ovary during that cycle. If there are more years, there might be more breast cancer, if that indeed is the case. On the other hand, if a woman starts cycling late—at age 13 or 14 rather than age 11—there is less estrogen during the lifetime.

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When a woman has a child, she stops cycling for a while, which means less estrogen exposure to the breast cells, and if that is true, then more children might be related to less breast cancer—and that indeed is the case. Menopause is the stopping of cycling. If that happens later on in life for a woman, then there were more years of estrogen, and that may lead to more cancer.

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Breast and endometrial cancers show a link with reproductive status in women. Early menarche, younger maternal age at births of children, and late menopause are risk factors for these cancers, probably due to increased exposure to estrogen.

Medications, Pesticides, and Radiation  One of the strongest medications you can take is cancer-fighting drugs, which stop cell division and damage DNA. Damaging genetic material can lead to cancer, so many people who get chemotherapy are at greatly increased risk for later cancers in other organs. Therefore, medications themselves may be carcinogens, because they damage DNA. 

Postmenopausal estrogen is another medication that could cause cancer. In the 1960s and 1970s, hormone replacement therapy started, and it involved a combination of estrogen and another hormone called progesterone. It was developed for many reasons,

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Lecture 4: Some Causes of Cancer in Populations

and the idea was to reduce hot flashes and bone fractures and some aspects of heart attacks in women who were postmenopausal.

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In the 1990s, a study was done called the Women’s Health Initiative—a cohort study for a large group of women who were taking postmenopausal estrogen and a group of women who were not—and it investigated what was going on in terms of cancer and other things with these women. The study found that hormone replacement therapy in postmenopausal women decreases the incidence of colon cancer and hip fractures but increases breast cancer, blood clots, and stroke.

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Aspirin and some other anti-inflammatory drugs reduce the incidence of colon cancer. The Nurses’ Health Study, a cohort study, discovered that women who were taking aspirin as an anticlotting agent for heart disease—specifically, coronary artery disease— were getting less colorectal cancer. In fact, there is a dose-response relationship between aspirin and colorectal cancer. In other words, if you take more tablets per week of aspirin, you get less cancer. It turns out that aspirin blocks the synthesis in the body of a molecule called a prostaglandin, which stimulates the cell division of cells in the colon.

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You might hear a lot about pesticides and the possibility of them causing cancer. Primarily, the data come from occupational studies of farm workers using pesticides. Many studies have been done on the environmental effects of pesticides, but few epidemiological analyses show an increased risk for cancer.

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Radiation causes cancer—especially in exposed parts of the body: skin, thyroid, bladder, breast, and blood cells. Another exposure to radioactivity that is quite serious is medical exposure. Medical procedures expose people to a large amount of radioactivity; different procedures expose people to different amounts.

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There are two main types of radiation: ionizing radiation, which comes from things that are radioactive, including bombs; and

ultraviolet radiation, which comes from the Sun. Ultraviolet radiation from sunlight is definitely linked to skin cancer, though usually of nonlethal, easily cured kinds. Careful studies of radon, a naturally occurring source of radiation, do not show an increased relative risk for cancer. 

The danger of the electromagnetic fields of power lines made big news, but epidemiology showed no link with any cancer. In fact, the radiation that comes from power lines is extremely low-energy radiation. In addition, studies on cell phones have shown no likely connection with brain cancer.

Personality as a Cancer Risk  There is a persistent belief that people’s personality can predispose them to cancer, or help in its treatment, but epidemiological studies have shown no increased related risk associated with character traits of introversion or extroversion, positive or negative attitude, or other personality characteristics. 

For example, a case-control study in the 1960s found that hospital patients with lung cancer were more extroverted, as defined at that time, than controls. However, it is not clear whether this was the result of their being in a hospital or their being naturally extroverted.

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Many anecdotes suggest that the clinical course of cancer has an effect on personality, but trying to see whether personality or valor has anything to do with the outcome is very difficult because it may not be clear whether their recovery was due to their following clinical advice. So far, the best epidemiology studies show no impact of personality on cancer.

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A single event is not enough to cause cancer. Not surprisingly, much epidemiology shows a synergism of factors. In other words, combinations of factors, which are much greater than the sum of the individual effects, can cause cancer.

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Suggested Reading DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. James, Cancer. Rothman, Epidemiology.

Questions to Consider 1. Women are starting menstruation at a younger age and are having fewer children later in life. What do these factors mean for future rates of breast and endometrial cancers?

2. Two persistent beliefs are that cancer is caused primarily by pollution

Lecture 4: Some Causes of Cancer in Populations

and that some people are predisposed to cancer because of personality traits. Why do people have these beliefs?

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DNA Is the Key to Understanding Cancer Lecture 5

I

n this lecture, you will explore DNA and how it changes to initiate cancer. You will learn that DNA is the genetic material for life. You will also learn how DNA is expressed in an outward way and duplicated in precise ways—and how these processes can go wrong. In going wrong, these changes can be spontaneous or induced from external agents. Changes in DNA underlie the stepwise development of cancer. Radiation and DNA  In the late-19th and early-20th centuries, X-rays and radium were discovered. X-rays were so high in energy that they allowed people to look right through the body to the skeleton, which was very useful for medicine and diagnostics. Marie Curie and her husband Pierre shared a Nobel Prize for the discovery of the element radium, a source of natural radiation. 

Radium has a lot of energy. In fact, it has so much energy that it glowed blue in the dark. If you look at the radium atom, it has a nucleus that has positively charged protons, neutrons, and a whole lot of electrons whizzing around it. Radium is unstable. It releases some protons and neutrons as a particle and, in the process, releases a terrific amount of energy.

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Later on, energy from radiation was used to treat cancer, but in the early 1900s, another use came up: Because radium glowed so well, a chemist got the idea that some of the energy that is in radium could be harnessed to cause other things to glow even better. He coated a watch dial with a mixture of radium and another chemical, and the watch glowed in the dark. The chemist did not patent his discovery, but the jeweler Tiffany’s did and made a lot of money doing it. It became the rage in Europe to have a watch or clock that would glow in the dark.

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Lecture 5: DNA Is the Key to Understanding Cancer 32



“Radium girls” painted radium onto watch dials so that the dials could be read in the dark; later, those girls got oral cancer and radiation poisoning and died. The radium industry fought court cases, so radium was not banned from watches until the 1970s. Radium causing cancer is an example of an occupational cancer caused by a specific cause.

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Japanese people exposed to radiation from the atomic bomb in World War II also developed cancers and had offspring with mutated genes because the reproductive cells as well as somatic, or nonreproductive, cells throughout the body were exposed to radiation.

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How exactly did radium cause cancer? The answer came from genetics, the science of heredity. In the first half of the 20th century, many scientists worked on model organisms (that is, simple organisms that can be manipulated in the lab) to discover the laws of genetics—how genes assort and how genes are transmitted from one generation to another. One of the most popular organisms is the fruit fly for genetic studies.

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In the 1950s, DNA was first identified as genetic material. The implication is that if radiation causes mutations and DNA is a genetic material, then radiation must damage DNA. In 1984, it was proposed that the only way we can figure out how much damage to genetic material happened in people who were exposed to radiation (and how much damage their offspring and grandchildren inherited) is to essentially get the entire sequence of all the DNA (building blocks) of a human. This led to the Human Genome Project.

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The Human Genome Project, which sequenced the entire chain of human DNA, can help us pinpoint how DNA is damaged in mutations and in cancer. The Human Genome Project was completed in the year 2000. The first draft of the human genome was published in 2000, and the final first genome was published in 2003. Since then, a lot more genomes have been sequenced, and there are many people and tumors that have been sequenced as well.

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The building blocks of DNA are called cytosine, guanine, adenine, and thymine. Just as there are 26 letters in the English alphabet, there are four letters in the alphabet of DNA: G, C, T, and A. It turns DNA has a very distinct doublehelix structure that shows its two out that in the double-stranded strands held together by DNA’s molecule of DNA, the rungs building blocks. are these bases called G, C, T, and A, and they fit together nicely. It turns out that A fits with T, and G fits with C, so if you write one strand of DNA, you have written the other.

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DNA molecules are very, very long and extremely, extremely thin. In every one of the 60 trillion cells you have, there are six feet (two meters) of DNA, with 2.3 billion base pairs from 23 different molecules, for an average of 100 million “beads” on the chain.

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A genome is the complete sequence of DNA—either from an organism, a human, or a tissue (for example, a tumor). All humans share 99 percent of the complete sequence of the genome. If we are 99 percent the same and only one percent different and we have three billion of these things, then there are still millions of differences in DNA between us. Those differences in DNA are mutations. 33

© iStockphoto/Thinkstock.

DNA as Genetic Material  There is a lot of circumstantial evidence that DNA is genetic material. The structure of DNA, the double helix, is very famous and was first unveiled by two scientists named Watson and Crick in 1953. Structurally, DNA has two strands, and the strands are held together by the building blocks of DNA. There are millions of these building blocks in a DNA molecule.

Lecture 5: DNA Is the Key to Understanding Cancer



DNA can undergo spontaneous mutations (because DNA is a chemical that is unstable) or induced mutations (from radiation or other carcinogens). Mutations are scattered all over our genome, and if those mutations are in genes or genetic determinants that are involved in the control of cell division, you can envision that they might involve cancer. We are now talking about cancer as a series of genetic mutations.

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Humans have two copies of each chromosome encoded in DNA— 46 in all, with 23 from each parent. The process of cell division begins with a cell nucleus, and then the chromosomes get doubled because one copy goes into each of the new cells. Then, the chromosomes line up. Then, they separate, and the result is two new cells. This is an amazing process.

DNA Expression and Duplication  Genes are expressed as a phenotype at many levels: For example, a person may be tall or short, a heart may be large or small, a tissue may be muscle or bone, and a cell may be normal or cancerous. Phenotypes are determined largely by proteins, and the genetic program in DNA determines which proteins are expressed. When a mutation alters a gene, the protein it encodes may be changed, and the result can be cancer. For example, if the protein is involved in growth or cell division, cells may reproduce in an uncontrolled way, resulting in a tumor.

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Damaged DNA is usually detected and repaired by proteins specially assigned to that task, but if something interferes with those proteins, the mutation may be duplicated and passed on when a cell divides (reproduces) to form two new cells.

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Spontaneous DNA changes are always occurring in cells; mutations are always with us. They are important in evolution, because they create diversity of phenotypes for natural selection. Most changes are insignificant; many are caught and repaired. A very few provide an evolutionary advantage; some result in cancer.

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Induced DNA changes happen when an outside agent—such as tobacco smoke, radiation, or sunlight—changes the chemistry of DNA, either directly or indirectly. Epidemiology tries to identify such agents so that they can be avoided or eliminated.

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Two types of genes important to cancer are affected by carcinogens: oncogenes, which speed up cell division (the gas pedal), and tumor suppressor genes, which slow down or prevent cell division (the brakes). In order to get the car to go forward, you have to release the brakes, so there are mutations in these genes that normally stop the cell from dividing and then they allow cells to divide.

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A single mutation does not cause cancer. Usually, several events are involved in the growth and spread of a tumor. Scientists are now learning to identify the precise DNA changes that can occur and finding ways to intervene at various steps in the process.

Important Terms base pairs (nucleotides): Chemical interactions between nucleotides in the same or opposite strands of nucleic acids. A pairs with T or U; G pairs with C. gene: The unit of heredity; a sequence of nucleotides on a chromosome that is expressed as a product that is part of the phenotype. genome: A complete genetic sequence of an organism or cell. The Cancer Genome Anatomy Project seeks to describe the genomes of tumor types. induced mutation: Inherited DNA change caused by an external agent, such as a chemical or radiation. If this occurs in an oncogene or a tumor suppressor gene, it can contribute to the development of cancer. Many carcinogens cause induced mutations. oncogene: A gene carried by a virus that, when activated, forms a product that acts as a “gas pedal” to stimulate cell division, leading to cancer. Some

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oncogenes form growth factors; others form receptors for growth stimulators. Still others form molecules that block cell death. phenotype: The outward appearance resulting from the expression of a gene. It can be influenced by the environment. spontaneous mutation: Permanent, inherited change in DNA caused by the internal chemistry of the cell, commonly due to errors in DNA replication. Cancers without a known cause probably develop by spontaneous mutation. tumor suppressor gene: A gene in a cell whose product normally inhibits cell division, leading to cancer. Some tumor suppressor genes form molecules that inhibits progress through the cell division cycle, and others form molecules that are involved in the repair of DNA damage.

Suggested Reading

Lecture 5: DNA Is the Key to Understanding Cancer

Almeida and Barry, Cancer. Clark and Russell, Molecular Biology Made Simple and Fun. Collins, The Language of Life. DeVita, Lawrence, and Rosenberg, Cancer. Goodsell, The Machinery of Life. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. LaFond, Cancer. Mullner, Deadly Glow. Ridley, Genome. Sadava, Hillis, Heller, and Berenbaum, Life. Scotting, Cancer.

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Questions to Consider 1. Is the way that DNA is duplicated similar to a copy machine? Is it possible that you still have some of the same atoms of your parents’ DNA?

2. How is it that even if we eliminate all the environmental causes of cancer at the DNA level, cancer will still occur?

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How Does DNA Change to Initiate Cancer? Lecture 6

I

n this lecture, you will learn about things that damage DNA and also cause cancer—carcinogens. You will also learn about some carcinogens that don’t damage DNA but still cause cancer. This lecture will also discuss some DNA changes that are not inherited, called epigenetic changes, that are involved in the expression of genes and also underlie cancer. Epigenetic changes in the expression of DNA are being targeted by drugs. The new field that deals with these changes is called epigenetics.

Lecture 6: How Does DNA Change to Initiate Cancer?

Damaging Carcinogens  Cancer occurs when DNA is damaged—mutated—in certain ways. Mutations occur all the time in DNA. A repair mechanism scans along the DNA for mispaired or altered bases (building blocks), removes them, and replaces them with the correct base.

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In some cancers, the repair system is defective, and over time, mutations pile up—some in key genes that regulate cell division. In other cancers, the mutation rate overwhelms the repair system; the cells are dividing too fast for repair to keep up. This is usually due to induced mutagens. Such mutagens, or carcinogens, come from either chemicals or radiation in the environment.

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We are exposed to tens of thousands of chemicals in the environment, both natural and synthetic. Some of these chemicals are transformed in the liver to a water-soluble and more chemically reactive form that can bind to DNA if it is not excreted quickly enough by the kidneys. Some chemicals are not water-soluble (estrogen) and are stored in fat cells, where they can accumulate until the dose becomes toxic and begins to alter the DNA.

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Aflatoxin, made by a fungus on corn or peanuts and associated with liver cancer, gets changed in the liver and binds to the G base of

DNA, coating it so that the DNA replication system can’t see it and replaces it at random. 

Nitrous acid, from the salt used to preserve meats and fish and associated with stomach cancer, causes a chemical change in the C base so that in DNA replication, it pairs with A instead of G. It takes a second DNA replication, pairing a new base with the incorrectly substituted one, for the mutation to become permanent, so rapidly dividing cells (like those in the liver and lining of the stomach) are the most prone to cancer.

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Many natural and synthetic chemicals are tested for carcinogenesis, but the process is expensive and time consuming, and there are thousands of chemicals to test. There is not enough time to test all of these molecules for cancer for DNA damage. However, shortterm tests have been developed.

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When ultraviolet light hits DNA, it causes two adjacent T bases to bind with each other so that random bases are inserted opposite them on the DNA chain instead of the appropriate A bases. This is disastrous in terms of DNA because the mutation becomes permanent. Repair will remove the T-T bond and replace it with T and T, but if the repair is defective, or if there is too much ultraviolet light, skin cancer can result.

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Squamous and basal cell cancers can nearly always be cured, but melanoma is highly malignant and often lethal. A rare genetic disorder occurs in people who lack an ultraviolet-damage repair system, and they are highly prone to skin cancer at an early age.

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Radiation from atomic bombs and nuclear-plant disasters, called ionizing radiation, can cause severe DNA damage, including free radicals, DNA strand breaks, and rearranged chromosomes. Even radiation therapy to cure cancer can cause a different cancer later on.

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Radiation causes two types of damages in terms of chromosomes and cancer: the formation of a fusion gene (half of one gene and 39

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Lecture 6: How Does DNA Change to Initiate Cancer?

A chemical that reaches a cell in the body after being exposed to the environment is not usually the same as the chemical in the environment because the chemical is transformed by the liver.

half of another results because the genes were shuffled and the chromosomes broke and resealed) and the translocation of a gene to an active site in the genome that causes it to be turned on (the gene itself is all of a sudden in a new environment and becomes very active). Nondamaging Carcinogens  Some chemicals cause cancer without actually damaging the DNA; instead, they act via the receptor system. Examples of nondamaging carcinogens include estrogen, asbestos, and a bacterial infection called Helicobacter pylori (H. pylori). 

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Estrogen, which is associated with breast, ovarian, and endometrial cancer, binds to a receptor on the outside of the cell, triggering a change in DNA expression and cell division within the cell. This happens every month in the uterine lining of the ovarian cycle. Treatment involves manipulating the estrogen receptor system to try to reduce estrogen binding and stimulating cell division.

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Minerals, such as asbestos in buildings and pipes, can be inhaled and cause cancer after long latency by scarring the lungs and causing cell division. Asbestos causes a specific type of cancer called mesothelioma, which is considered a signal cancer for this type of damage by asbestos because this type of cancer doesn’t result from other carcinogens.

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Infections are not directly damaging to DNA. The H. pylori bacteria live in the acidic environment of the stomach and irritate the stomach lining, causing ulcers and stomach cancer. We now have a very precise molecular description of the events involving the bacterium sending out signals that stimulate the cells just like estrogen does. People used to think that ulcers were caused by stress or bad eating, but it turns out that they are caused by a simple infection with a bacterium.

Epigenetic Changes in DNA  Epigenetics is possibly inherited, but changes in DNA are not necessarily inherited and can contribute to cancer by changing the expression of DNA. Recall that DNA sits inside of a cell and doesn’t do anything unless it’s expressed in some way. 

Although we once thought that an individual’s genome was set at birth, we have recently discovered that it can change over a lifetime due to DNA methylation and DNA packaging. These processes affect the oncogenes, which stimulate cell division, and the tumor suppressor genes, which block cell division. These are semipermanent changes in DNA for its expression only; they do not change the bases of DNA at all—it’s just a small change.

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DNA methylation turns genes off. There are two types of DNA methylation. If you reduce the expression of a gene that normally stimulates cell division, then the cell is not going to divide, which results in less cancer. If you reduce the expression of a gene that normally blocks cell division, then cells will be allowed to divide.

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Lecture 6: How Does DNA Change to Initiate Cancer?

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DNA packaging turns genes on. If we increase the expression of genes that stimulate division, stopping it from being blocked, then the result is more cancer. If we stimulate genes that block cell division, the result is less cancer. There are reciprocal things going on with both DNA methylation and DNA packaging.

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DNA methylation reduces the expression of both oncogenes and tumor suppressor genes. If it reduces the expression of tumor suppressor genes, then cancer can result. Cancers where DNA methylation is involved have a poor prognosis and must be treated aggressively.

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DNA packaging opens up (“unpacks”) the DNA chain, exposing the DNA to the expression machinery, increasing the expression of these genes. (DNA is usually packed tightly by proteins, and if you change those proteins, you can change the expression of DNA.) If DNA packaging increases the expression of the oncogenes, cancer can result.

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There is a drug called Vorinostat that has been developed that targets the DNA packaging mechanism. It does this by causing the DNA packaging to loosen up so that the genes that inhibit cell division will be expressed. The idea is to open up the DNA of inhibitory genes, genes that normally block cell division. Vorinostat has been used with some success in such cases.

Important Terms epigenetics: Changes in DNA or its expression that can be passed on to daughter cells but do not basically change the genetic capacities of the nucleotides in DNA. These changes include adding methyl groups of C in DNA or altering the proteins that bind to DNA and occur in many cancers. mutagen: A substance that damages DNA, leading to permanent genetic changes in the affected cell and its descendants. Most cancer-causing entities in the environment are mutagens.

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radiation therapy: The use of radiation-emitting isotopes of chemical elements to treat cancer. Radiation is typically given in small doses over several weeks to avoid extensive damage to normal tissues. translocation: Transfer of part of one chromosome onto another. This shuffling of genes usually results in alteration of gene expression and cell function. Translocations are common in blood cancers and solid tumors.

Suggested Reading Almeida and Barry, Cancer. Clark and Russell, Molecular Biology Made Simple and Fun. Collins, The Language of Life. DeVita, Lawrence, and Rosenberg, Cancer. Goodsell, The Machinery of Life. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. LaFond, Cancer. Mullner, Deadly Glow. Ridley, Genome. Sadava, Hillis, Heller, and Berenbaum, Life. Scotting, Cancer.

Questions to Consider 1. Do all cancer-causing agents actually change DNA? What are the differences between a carcinogen that changes the chemistry of DNA and one that does not?

2. How does epigenetics present a challenge to the Darwinian view of the biological world?

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How Do We Know If Something Causes Cancer? Lecture 7

W Lecture 7: How Do We Know If Something Causes Cancer?

e are exposed to thousands of chemicals and substances every day, and we can’t test them all by long-term epidemiology or studies on carcinogens to determine whether they cause cancer. In terms of public policy, what do we do about this? This lecture focuses on how to deal with this issue of overwhelming cancer-causing agents in the environment and which experiments we can do to figure out whether something causes cancer. In this lecture, you will learn about rapid testing for carcinogens that uses model organisms and cells, and you will also learn about the concept of risk analysis. Testing for Carcinogens  For decades, we have known that there is a link between tobacco smoke and cancer, but as long as the exact biochemical mechanism was unknown, tobacco companies could claim it was air pollution or diet or something else. Tobacco smoke has over 3,500 chemicals in it, and at least 60 of those chemicals have been shown to cause cancer in lab tests and in animal tests. The challenge was to link a specific chemical in tobacco to human lung cancer. Which one (or ones) was (or were) the culprit, and how did it (or they) work?

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Only in the 1990s did Gerd Pfeifer finally solve this mystery: Benzpyrene binds to DNA at the G base, resulting in a mutation to T, which causes lung cancer. His experiments found that a specific carcinogen, benzpyrene, from tobacco binds to a specific gene, p53, and causes a specific mutation, which leads to an inactive protein, which leads to genetic damages, which leads to cancer.

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This scientific finding—linking a specific carcinogen to DNA damage in lung cancer—led to the successful prosecution of tobacco companies, and no tobacco company now argues that cigarette smoke is not connected to cancer.

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There are thousands of chemicals in every food we eat (even organic foods), and we are exposed to thousands of others every day. To find out which ones cause cancer, we need rapid tests for carcinogens. Testing for carcinogens uses model organisms or cells because we want a quick result. We can’t afford to do 30 years of epidemiology on thousands of molecules and then do laboratory tests and zero in on a certain gene.

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The logical assumption is that carcinogens damage DNA and then cause mutations in DNA damage, so the carcinogens that damage DNA could end up causing cancer as well. The second assumption is that simple organisms can act as stand-ins for humans because the basic mechanisms of biology are the same in all organisms. The third assumption, of course, is that we want these tests to be cheap and rapid.

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Bacteria are a frontline screen for carcinogens because they are easy to grow in the lab, and they form colonies with millions of cells. Because the liver often changes a stable chemical into a more active form, liver extract can be added to the bacteria to simulate what happens in the body.

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Human cells can also be grown in the lab and may give a more realistic test of what happens in the human body. A potential carcinogen is added to the cells and the cell colony is observed for growth of cancer cells.

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Another type of analysis of human cells is to look for DNA changes indirectly. When chromosomes are duplicated during the time when the cell is about to divide, the two new DNA molecules lay side by side, and you can actually have different dyes to stain them so that you can tell them apart. Normally, these would separate during cell division—where one cell will get one of them and the other cell will get the other—but before cell division starts, we can look for changes in the chromosomes, or genetic damage.

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Lecture 7: How Do We Know If Something Causes Cancer? 46

Human cell tests, if positive, are often followed up with animal tests. Obviously, these are going to be animals we can use in a laboratory that are somewhat similar to humans. Typically, they’re going to be rodents, such as rats and mice.

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Scientists can either expose some cells in a laboratory dish to the possible cancercausing agent and then Bacteria are very easy to grow in the laboratory; millions of them grow in a very implant the cells into short amount of time. an animal and watch to see if a tumor grows, or they can actually take the animal itself and expose the animal to the possible cancer-causing agent and see if the animal gets cancer. You have a control group that is untreated and an experimental group that is treated, for example, with benzpyrene, and you see whether the animals end up with tumors.

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Are mammals similar enough to humans? Testing on these animals is quite expensive, and it costs between $10,000 and $20,000 because of all the animals and time. You need a lot of animals if there are thousands of chemicals to test.

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Bacteria and even human cells are not human. These rapid tests reliably identify carcinogens about 60 percent of the time, so animal tests with mice and even monkeys are necessary.

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Carcinogens are both natural and human-made. There is a general feeling that natural things are better and safer than artificial things— such as food additives and artificial sweeteners—but in fact, many carcinogens come from plants, which use them as chemical defense mechanisms. There are hundreds of such chemicals in any plant we eat that test positive for carcinogens. In other words,

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many of these chemicals cause DNA damage and cause cancer in laboratory animals. 

Nicotine is a neurotoxin; it affects the nervous system, and it is made by tobacco. A tobacco hornworm, an immature form of an insect, is a pest that chews up tobacco leaves. If the nicotine level in a plant is very high, all of the worms will die because nicotine is poisonous to the nervous system of the worm. This is an example of a plant that uses a carcinogen as a chemical defense mechanism.

Risk Analysis and Carcinogens  Nearly 35 percent of the risk factors for cancer come from our diet, though it’s not at all certain which of these chemicals do what to our DNA. Risk analysis is a matter of public policy where people in government consult with people of the overall population, including experts in medicine and science, and determine how to analyze the risk of something that we’re going to be exposed to— for example, the risk of getting cancer. 

Nearly everything we do in life—even just sitting perfectly still—entails some risk. We are constantly, even unconsciously, performing informal risk analyses all the time. For example, every day, approximately 40,000 people in the United States are killed in motor vehicle accidents. There are 280 million Americans, so on a statistical basis, your chances of getting killed in a motor vehicle accident if you drive for one year is one is 7,000. You can do many things to minimize your risk by being a good driver, but you are still taking a risk. The main question is whether the benefits outweigh the risk.

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Risk analysis includes the following components as they apply to carcinogens. o Hazard assessment: Does it cause cancer? o

Dose-response assessment: How much cancer does it cause at what dose?

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Exposure assessment: How much of it gets into people?

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Risk characterization: Is the exposure worth the benefits?

Public policy is often motivated more by public opinion, media rumors, or scare tactics than by science. Perhaps the moral of the story is that politicians should take a science course. If animal tests are used as an index of carcinogenic potency, human exposures indicate more of a risk from natural substances, and even such common things as exposure to air inside a home than typical exposures to synthetic pesticides and food additives.

Lecture 7: How Do We Know If Something Causes Cancer?

Important Term risk analysis: Evaluation of both biological and social aspects of an activity in relation to disease. In cancer, risk analysis involves a quantitative estimation of the hazard of exposure to a carcinogen and cost-benefit analysis of its value to the individual.

Suggested Reading Almeida and Barry, Cancer. Collins, The Language of Life. DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. LaFond, Cancer. Sadava, Hillis, Heller, and Berenbaum, Life.

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Questions to Consider 1. Is it surprising that a lot of cancer is caused by naturally occurring agents, as opposed to factors made by humans? Does this change your view of laws concerning environmental regulation?

2. Think of a potentially carcinogenic activity that you engage in (e.g., smoking or eating cancer-causing food). Do a risk analysis for the activity. Does the analysis change your view of the activity?

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How Do Normal Cells Function? Lecture 8

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arcinogens initiate transformation from a normal cell to a cancer cell. This lecture dives into the cell to see exactly what happens. In this lecture, you will learn that cells are the basic structures of living things. You will also learn that human cells have internal structures to carry out various functions and that human cells can become specialized or cancerous, but in both cases, they retain the entire genome—all of the DNA—in the nucleus.

Lecture 8: How Do Normal Cells Function?

Cell Reproduction and Protein Kinase  How does cancer develop? So far, we have looked at three main ideas: mechanism (cancer acts at the level of DNA); cells (cancer is a cellular disease); and natural selection (cancer evolves through advantageous mutations and drug resistance). Therefore, knowing what goes on inside of cells is important to controlling cancer.

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Cell reproduction involves a complex series of events in which chromosomes line up and are duplicated and then are separated into two new cells. It’s really like a symphony. Just like a symphony, cell reproduction has a conductor. Two scientist teams, working independently on different organisms, came to the same conclusion about the conductor of events in the cell cycle.

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Leland Hartwell asked the question: What can we learn about normal cell division from cells that have a genetic mutation in the cell division cycle? In using this approach, you could compare the mutant organism with the normal organism and see what the mutant is missing if the cell stopped at a certain point.

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The cell that Hartwell used was yeast, which is one of the model organisms that biologists use to study biology. It undergoes cell division and has all of the cell parts that a human cell has—only it’s really easy to grow in the laboratory. Yeast reflects humans or other

organisms because of our assumptions in evolution that we all have a common ancestor and the same chemistry. We all have DNA, and we all express DNA in various similar ways. 

The reproduction of yeast cells follows a familiar pattern. The yeast cell forms a little bud as it begins to reproduce; a little lip comes off the yeast cell. The lip gets bigger and bigger, and in the meantime, the nucleus reproduces itself—it reproduces all of its DNA. Then, you have two nuclei, and one of the two nuclei migrates into the other bud.

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Hartwell isolated some mutants of yeast and found that one of the phenotypes (outward expression) of the mutants was stopped in the cell cycle. In other words, the mutant stopped right when it was about to divide. It should have been dividing, but instead, it just stopped. Hartwell and his colleagues went looking for what was missing in that mutant because that must be the thing that gets the cell to commit to duplicating its DNA.

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James Maller tried an experimental approach and used a different organism. The organism that he used—the frog—is a popular one in biochemistry studies. The frog has a life cycle that you may be familiar with: An egg is shed out into the water, and the egg makes a little pollywog or larva, which then forms a frog. The egg develops inside the frog.

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Maller studied the egg development of the frog. During development, the egg begins to grow, and then the frog forms multiple eggs. When the immature egg is just sitting there, a hormone that is made by the frog comes and knocks on the door of the egg cell. Then, some chemistry happens inside the egg cell, and the egg gets stimulated to go into cell division.

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In his experiment, Maller took an immature egg cell of the frog in a laboratory dish and stimulated it with the hormone. Of course, the immature egg cell then stimulated itself to divide. Then, he sucked out the contents of the stimulated cell and injected the contents into 51

Lecture 8: How Do Normal Cells Function?

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When Maller isolated this stimulus for cell division, he found a very unusual protein (for that time) called a protein kinase, which is a very important type of molecule in cells of many organisms. When the process known as mitosis, cell Hartwell looked back In division occurs, and the result is the at the yeast and asked formation of two new nuclei. what the mutant that didn’t go into cell division was missing, it was the protein kinase. It turned out that Maller and Hartwell were seeing the same thing: The mutated gene in yeast was one that normally encodes a protein kinase.

Cells as Basic Structures  In biology, cell theory states the following three things: Cells are the units of life; cells are units of structure and function; and cells are units of continuity, because our cells both create our offspring and survive in them.

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Humans reproduce and develop by cell division; an adult human being is made of about 60 trillion cells. A single fertilized egg gives rise to a complex human. Human cells have internal structures, and they carry out various functions.

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There are two types of cells in the living world: complex cells and simple cells. A prokaryotic cell is a simple cell like bacteria. It doesn’t have a nucleus or any special structures inside to speak of. Prokaryotic cells are highly successful. In fact, we have 100

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a cell that was not dividing. The cell had not seen a hormone at all, but when he added the stimulus to the interior of the other cell that was just sitting there, the other cell was stimulated to go into cell division, or mitosis.

times more bacteria in our bodies then we have human cells. The other type of cell is called a eukaryotic cell, which is much more complex than a prokaryotic cell. 

Each human cell contains a nucleus with DNA encoding the entire genome for that person, mitochondria to supply the cell with energy, RNA “factories” for producing proteins, a cytoskeleton for shape, and a cell membrane to protect the cell.

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Cells are held in place by two things: interaction with other cells and interaction with the coating. Almost all of the membrane functions are encoded by DNA because they are all properties of proteins. If you mutate DNA, as has happened in a cancer cell, you will make abnormal proteins, and the abnormal proteins might alter the properties of the membrane.

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Understanding both normal cell processes and what goes wrong in a cancer cell are critical to cancer research. A major way of diagnosing cancer is to look at cells. Cells are too small to see with the naked eye, so you need microscopes. One type of microscope that is used to see cells is a light microscope. It’s a familiar microscope that is used overwhelmingly in diagnosis and treatment of cancer. On the other hand, an electron microscope sees a lot more detail, requires a lot more preparation time, and is not used that much diagnostically. Instead, it is used in research.

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Cells can become specialized, or they can become cancerous; either way, they retain the entire genome—the entire DNA. The process of cell differentiation involves a cell, such as an egg cell, that gives rise to all the different tissues. An undifferentiated, ordinary cell in the embryo has the capability to ultimately form all the different tissues in the body, including nervous tissue, bone, muscle, epithelial coating of the skin, and blood tissue.

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An important aspect of these specialized cells is that most differentiated tissues do not divide. Instead, once they die, they are replaced by other cells that are undifferentiated that then become 53

differentiated. Differentiated cells are nondividing cells. This is important because if nondividing cells have its DNA damaged, there’s a lot of time to repair it before DNA duplication happens and the DNA damage becomes permanent. Typically, cancers arise in undifferentiated dividing cells much more often than in differentiated, specialized cells. 

Undifferentiated cells in the embryo—stem cells—become specialized tissues in an adult. Most differentiated cells (nerve, muscle, blood) stop dividing. Epithelial cells (skin and lining of organs) continue to divide and are the sites of the most common tumors. Cancer cells divide rapidly and are different from normal cells in other ways as well: They may have some DNA from the original genome either mutated or turned off.

Important Terms

Lecture 8: How Do Normal Cells Function?

cell cycle: The sequence of events by which a cell reproduces (divides). differentiated cell: A cell that has a specialized function, such as muscle. Usually, cells are irreversibly differentiated. Cancer cells are relatively less differentiated or undifferentiated. eukaryotic cell: A cell with a nucleus and other cell components that are each enclosed within membranes; these cells make up animals (including humans) and plants. mitosis: Division of the nucleus of a cell, separating two replicated sets of chromosomes. The presence of a large number of cells in mitosis is a hallmark of aggressive cancers. stem cells: Continuously dividing, undifferentiated cells in the body that replace cells that are lost due to wear and tear or programmed cell death. Cancers can develop from stem cells.

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Suggested Reading Almeida and Barry, Cancer. Collins, The Language of Life. DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. LaFond, Cancer. Sadava, Hillis, Heller, and Berenbaum, Life. Scotting, Cancer. Skloot, The Immortal Cells of Henrietta Lacks. Sompayrac, How Cancer Works.

Questions to Consider 1. In 1850, William Gladstone, the British minister of finance, asked the famous physicist Michael Faraday the practical value of his discoveries of electricity. Faraday responded, “One day, sir, you may tax it.” It is difficult to predict the social value of scientific research. How does this apply to the research on the control of the cell division cycle? Can you think of other current basic research that might seem esoteric but may have practical value later?

2. Cells in the body that are specialized (differentiated) generally do not divide. Does this mean that they have lost the potential to divide? What about the division potential of stem cells?

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What Is Different about Cancer Cells? Lecture 9

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Lecture 9: What Is Different about Cancer Cells?

n this lecture, you will learn about the unusual properties that cancer cells have. These properties are not present in all cancer cells, but many cancer cells have many of the properties that will be discussed. Two of these properties will be described in detail: One of them is that cancer cells divide without normal controls, which is very important for the growth of tumors, and the other one is that cancer cells do not die. Unusual Properties of Cancer Cells  Cancer cells have unusual properties; they have several properties that distinguish them from normal cells. Cancer cells can be studied in the laboratory in two ways: cells can be taken from biopsies of patients, and normal human cells can be taken in the laboratory environment and transformed by adding a cancer-causing agent so that they become cancer cells. In either case, we have to be cautious with any conclusions we come to.

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Generally, cells in a laboratory dish outside of the organism have more or less similar properties, but the context of these tumor cells is very different. In the body, the tumor is surrounded by other tissues, fluids, and hormones, but when people have looked at tumors in the body of an organism, they find most of these properties there.

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The first property of cancer cells is that they lose all constraints to growth (meaning reproduction). In the lab, cancer cells overgrow. In a tumor, cells detach in order to keep growing and to keep reproducing. They have to detach from the extracellular material that surrounds them. If there’s a mutation and the protein made by the membrane gets changed, the protein no longer attaches the cell to the glue that is outside of it, and that is exactly what happens as tumors develop.

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A second type of membrane protein binds one cell to another. If you change that program of proteins and binding so that it no longer makes a protein that will bind two cells together, then the individual cells are free to divide and move if they are metastatic—if they spread to other organs.

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The second property of cancer cells is that they alter cytoskeleton, or the fibers inside the cell. Alterations of these fibers inside the cell are important for the structure, or the shape, of the cell, but some of these alterations of the edge of the cell also allow the cell to kind of have projections so it can move. This is very important in cancer metastasis.

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The third property is that cancer cells have altered cell communication. There are cell-membrane proteins that make a hole between cells. Cells want holes in their membranes because it is a way of getting things rapidly from one cell to another. In normal cells, the pores are typically intact; they integrate the cell very well. In tumors, however, very often there are fewer pores between the cells, so the cells are not integrated. This has great importance in therapy. If the tumor cells don’t have these pores, then a drug is going to take a long time to get inside the tumor.

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The fourth property of cancer cells is that they can spread through other organs. This process is called metastasis. The fifth property is that cancer cells can recruit their own blood supply when they are near the blood. This is called angiogenesis.

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The sixth property is that cancer cells fail to differentiate, or specialize. Recall that stem cells are undifferentiated in many tissues and then become specialized. Stem cells are generally pluripotent; they have multiple capabilities. In cancer, very often cells do not differentiate. Cancer stem cells divide rapidly, so spontaneous or induced mutations accumulate because there is not enough time for repair.

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Lecture 9: What Is Different about Cancer Cells?

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The origin of cancer is the seventh notion of cancer cells. Tumors are clonal. A clone is a group of identical organisms; a clone of cells is a group of identical cells. The assumption in cancer is, and has been, that all cancers come from a single cell. In the multistep model of cancer, a single cell is assaulted in some way, and initiation happens. Then, more mutations happen, and what results is a tumor, which grows and is metastasized. Mutations pile up in a single cell and accumulate over the time of life.

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The problem in cancer treatment is that therapy continues to assume that all tumor cells are the same, or homogenous. This is a real challenge as we go onward in cancer research and treatment.

Cell Division and Death  The eighth difference between cancer and normal cells is that cancer cells divide without normal controls. In normal differentiated cells, the cell reproduction cycle is stopped at a restriction point. The protein that acts at the restriction point is called the RB protein, which is named after a tumor called retinoblastoma. The RB protein acts to block cells from passing the restriction point. The cell cannot pass the restriction point, so it just sits there. It’s going to be in this nuclear phase, doing cell things, but it’s not going to divide.

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In most differentiated cells, most of the time, the RB protein is active, blocking cells from passing through the restriction point to duplicate their DNA. It turns out that the RB protein blocks the expression of genes involved with cell division and DNA duplication. The RB protein is a tumor suppressor. As long as the RB mechanism is sticking onto DNA, then there are going to be problems.

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How does a kinase stimulate cell division? The kinase essentially modifies RB, adding phosphate to it, so that it opens up and allows the genes for cell division and DNA replication to be expressed. The kinase removes the RB block.

In some tumors, RB is mutated such that it doesn’t go into the nucleus. Instead, it just sits out there and does not block the expression of genes involved with cell division. The result is that genes for cell division are expressed, and the cells go into the cell cycle repeatedly without control. This uncontrolled growth results in a tumor.

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The ends of chromosomes turn out to be an interesting characteristic of the control of cell division. At the ends of chromosomes is a special sequence called the telomere, which keeps the chromosome intact. Chromosomes are huge molecules of DNA, with 100 million base pairs of DNA, but at the end, there are about 16,000 caps of telomeres, and they have proteins associated with them.

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Telomeres are kind of like the coating on the ends of huge molecules a shoelace. Every time a Chromosomes, of DNA, contain about 100 million cell divides and reproduces base pairs of DNA. its DNA, this coating gets shorter and shorter. After a certain number of cell divisions, the end of the chromosome is so “frayed” (like a shoelace) that the cell dies. The chromosomes in the cell are essentially so unstable that the cell dies.

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A typical cell in a laboratory dish will divide about 50 times and will stop because the telomeres get shorter and shorter. Cancer cells do not shorten their telomeres because they have a protein called telomerase, which keeps cancer cells from dying—it keeps the ends of the shoelaces intact. Stem cells are always dividing, and after a number of divisions, they don’t express telomerase, shorten their telomeres, and die. 59

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The ninth difference between cancer cells and normal cells is that cancer cells do not die. We want cancer cells to die; we’d like to block telomerase. In fact, there are a number of molecules under development for blocking telomerase, which will block the chromosome from shortening and keep these cells stable.

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Many normal cells have a programmed cell death, called apoptosis, but cancer cells do not die. They make a protein that blocks apoptosis. One approach to cancer, then, is to make drugs that inhibit the apoptosis blockers, thus leading to cancer cell death.

Important Terms

Lecture 9: What Is Different about Cancer Cells?

angiogenesis: Recruitment of a blood supply by a tumor. The tumor sends out a chemical signal to nearby blood vessels, which sprout branches that grow to the tumor. apoptosis: Genetically programmed series of events that results in the death of damaged cells. Cancer chemotherapy often reduces the size of a tumor by increasing apoptosis in tumor cells. biopsy: Removal of part or all of a tissue suspected of being diseased and laboratory analysis of that tissue to confirm the presence of the disease. Cancer diagnosis is made after biopsy. cancer stem cells: Cells within a tumor that can form the growing tumor. They may actually be only a small minority of the cells in a particular tumor. clone: Genetically identical cells or organisms that arise from a single cell. Although cancers are in general clonal, different cells of a tumor may contain different mutations. metastasis: The ability of a tumor to break off cells, which travel in the blood or lymphatic system to a new location in the body and grow to a satellite tumor.

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multistep model: Series of sequential events describing the development of a tumor—from initial damage of a cell to tumor metastasis. Each event is mediated by distinctive genetic and cellular changes. restriction point: Stage of the cell division cycle when a “decision” is made to proceed and replicate DNA, setting the stage for division. There is extensive regulation at this point, and cancer cells often lack proper regulation, leading to continuous cell reproduction. telomere: The two ends of a chromosome, where specific DNA sequences prevent DNA damage when it replicates.

Suggested Reading Almeida and Barry, Cancer. Collins, The Language of Life. DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. LaFond, Cancer. Sadava, Hillis, Heller, and Berenbaum, Life. Scotting, Cancer. Skloot, The Immortal Cells of Henrietta Lacks. Sompayrac, How Cancer Works.

Questions to Consider 1. With another person, try a role-playing exercise: One of you is a normal cell in the skin, and the other is a skin cancer cell. In some way, act out the differences. How do these differences arise? What do all of these differences mean for the number of DNA changes needed to transform a normal cell into a cancer cell? How does this relate to the fact that cancer occurs more frequently as we get older? 61

2. Scientists used to think that cancer is caused by “cells gone wild”

Lecture 9: What Is Different about Cancer Cells?

dividing too much and that treating cancer means preventing cell division. How do discoveries about apoptosis (programmed cell death) change this view?

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How Do Tumors Grow? Lecture 10

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n this lecture, you will be introduced to the process of tumor growth and development. You will also learn the difference between benign and malignant tumors. In addition, you will learn about the diagnosis, staging, and grading of tumors; how tumors are named; and how they are diagnosed—from signs and symptoms to diagnosis and tumor markers. This lecture will also discuss metastasis, angiogenesis, and the burden of tumor growth on the body. Tumor Discoveries and Types of Tumors  In an experiment conducted by Dr. Judah Folkman, mouse cancer cells were implanted into a live mouse. Typically, the mouse cancer cells will grow gradually into a tumor, but Folkman noticed that the cells didn’t start growing until after a few days—there was a lag time. In his second experiment, he took cancer cells and did the same experiment, but this time, he did it in a laboratory dish in some isolated tissue from an organ, the thyroid gland. He waited and waited, but a tumor didn’t grow. He coined the term “tumor dormancy” for both situations. 

Folkman developed a hypothesis, or proposal, which he was going to test with experiments. His hypothesis was that in order to grow, a tumor—like any organ in the body—needs a blood supply. Blood delivers oxygen through hemoglobin to tissues, for energy, and it removes waste like carbon dioxide. Every cell in the human body has to be pretty close to the blood supply, which is why we have capillaries. A typical cell in the body has to be, at the most, five cell layers away from a blood vessel. During the development of organs, the blood supply has to be recruited, and that process is called angiogenesis.

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Folkman’s discovery explained both the lag time for the tumor in the live mouse and the failure of the tumor to grow in the lab 63

Lecture 10: How Do Tumors Grow? 64

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The actual angiogenesis inhibitor from the natural system in mice, for example, that was sending out the inhibitor that blocked antiangiogenesis in mice for metastases didn’t turn out to be the answer. The answer turned out to be found by studying the natural system. Antiangiogenesis drugs are now a major discovery in the last decade in fighting cancer. The system has been well worked out, the tumor cell and the receptor in the capillaries have been characterized, and the signal has been characterized. Several drugs are now in clinic, widespread use to successfully induce tumor dormancy and In order to grow, a tumor—like any block angiogenesis. organ in the body—needs a

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Benign tumors slowly increase in size, and then kind of stop. Benign tumors do not invade other tissues; they do not form metastases. Benign tumors usually have a hard capsule of fibrous tissue that separates them from surrounding tissues. In benign tumors, the cells of the tumor very often resemble the parent. Some tumors that are benign make hormones, and that may cause physiological effects, so you have to remove the tumor in that case. A benign tumor may block an organ, in which case it should be removed as well.

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Malignant tumors have undifferentiated cells. Malignant tumors can invade metastases, as opposed to just sitting there. Malignant tumors don’t have a capsule that sort of defines the tumor edge; instead, they have a fuzzy edge because they keep growing.

blood supply.

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dish. Tumors can divert the body’s blood supply for their own use, and this is called angiogenesis. If scientists could come up with an antiangiogenesis drug, the tumor could not grow.

Malignant tumors lose all normal arrangement of a tissue, and they have variations of sizes and shapes. 

A typical tissue that lines an organ, on the very exterior, is epithelial. Below the epithelium is what is called mesenchyme, and in the mesenchyme are things like fat and blood vessels. Epithelial tumors, or carcinomas, make up 85 percent of all cancer. Mesenchyme tumors, or sarcomas, are solid tumors of primarily muscle and bone—and fat as well. They account for about five percent, at the most, of all tumors.

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Tumors of the blood, including leukemia and lymphoma of white blood cells, account for about nine percent of all tumors. Teratomas, tumors that differentiate and redifferentiate organs, account for one percent of tumors. Adenomas are tumors of the glandular epithelium. A melanoma is a tumor of the pigmented skin cells.

Diagnosis and Staging of Tumors  The first thing in diagnosis and staging, what brings a patient to the doctor, are signs and symptoms. The signs—physical manifestations—might include things like a lump that they feel, an ulcer that doesn’t heal, or blood loss that’s happening. Symptoms might include things like malaise (just not feeling right), fatigue (tired), unexplained weight loss, or any pain you can’t figure out. 

When a patient visits a doctor for any of these signs or symptoms, the first thing that the doctor does is a clinical exam of the patient, which might lead to imaging, a biopsy, or blood tests for tumor markers. In some cancers, you can begin a diagnosis just by observation. A doctor will do palpation to feel an organ—for example, the breast. Then, X-rays, MRIs, and CTs can help a doctor look for cancer. If the doctor suspects something to be cancer, then a pathologist examines the cells.

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Many diseases mimic cancer, so looking at the cells is a way to make sure that something is cancer. To get the cells, you can have surgery to biopsy the cancer. Laparoscopic surgery involves 65

Lecture 10: How Do Tumors Grow?

using just a small incision to remove a mass of cells. Exfoliative analysis involves sloughing off tumors that are easy to remove. The pathologist can look at the cells under a microscope, and at this point, in some cases, a diagnosis can actually be made.

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However, many cells kind of look normal, in many instances, in a biopsy. If the cell looks normal, you have to look inside the cell, which can sometimes be done with specific dyes, for markers in the cell. Other times, you have to look for other kinds of cell contents that the cells may have.

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Sometimes, as tumors grow, they release chemicals into the blood. Those chemicals, as tumors grow, might be tumor markers called biomarkers, which might be proteins or hormones that the tumor is making and sometimes can aid in a tumor diagnosis. Just looking at the tumor marker is, of course, not enough—it’s just an aid.

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More recently, people have started using molecular markers to look for the tumor. Doctors will do a biopsy, and then they’ll look inside the biopsy for certain things that are molecular—DNA changes. As we learn more about specific details of cancer, we’re learning more about tumor markers. The ultimate biomarker is DNA, and people are doing DNA sequences of entire tumors.

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Tumor staging is done after a diagnosis, and it tells how advanced the cancer is and defines normal tissue involvement. In the TNM system, T1 means that the tumor is localized, while T2 through T4 indicate increasing invasiveness. The stage helps to predict survival, and more advanced stages may require more aggressive therapies.

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A second type of analysis doctors do at this stage is tumor grading, which is used as a crude mark of aggressiveness of the tumor. Grade 1 is well differentiated with few cell divisions and a good prognosis. Grade 3 is poorly differentiated with lots of cell divisions and a poor prognosis.

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The early growth of tumors is very difficult to study, but we know that cervical, colon, and lung cancers grow very slowly over many years. (The problem here is that cancer therapy is primarily based on rapidly growing cells.) Melanoma and pancreatic cancers grow very quickly and may kill in a matter of weeks. Tumors are not even detectable by current methods until they have at least a billion cells.

Important Terms benign tumor: A tumor that is localized and does not spread to other sites in the body. Benign tumors usually grow to a limited size and are encapsulated by fibrous tissue. carcinoma: A tumor arising from epithelial cells that are at or near the surface of the body or linings of organs. Because epithelial cells commonly divide, they are quite susceptible to DNA damage and cancer. Most cancers are carcinomas. leukemia and lymphoma: Cancers of the white blood cell system, usually arising from immature, not fully differentiated cells. malignant tumor: A tumor that spreads from its site of origin to other sites in the body. The tumor spreads by cells migrating to the blood or lymphatic systems. sarcoma: A tumor originating in tissues, such as muscle, below the surface of the body or lining of organs. teratoma: Rare cancer in which there are multiple differentiation events within the tumor. For example, a teratoma in the abdomen may contain fragments of bone and kidney. tumor grade: Seen on biopsy, the fraction of cancer cells that are either dividing and do not resemble the cells of origin (high-grade tumor) or are not dividing and resemble the cells of origin (low-grade tumor). High-grade tumors have a worse prognosis than low-grade tumors.

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tumor marker: A substance either in a tumor cell or released by it to the blood that signals the presence of a tumor to a physician when it is identified. Tumor markers can be used in diagnosis or to monitor treatment. tumor stage: A graded series of evaluations at diagnosis of how far the tumor has invaded its organ of origin. Higher-stage tumors generally have a worse prognosis than lower-stage tumors on the surface of an organ.

Suggested Reading Almeida and Barry, Cancer. Collins, The Language of Life. DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. LaFond, Cancer. Sadava, Hillis, Heller, and Berenbaum, Life. Sompayrac, How Cancer Works.

Lecture 10: How Do Tumors Grow?

Questions to Consider 1. Most of us have had either a benign or malignant tumor—or both. Are they related? Does one cause the other? In your personal case, how did the tumor fit the characteristics of benign or malignant?

2. Why are the most common tumors carcinomas, arising from epithelial cells that line the organs? Why are the most aggressive tumors, with poor prognoses, ones that are poorly differentiated?

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How Tumors Spread and Thrive Lecture 11

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his lecture describes the spreading and thriving of tumors. In this lecture, you will learn about the most feared property of cancer: metastasis, which is the spread of tumors in the body. Then, you will learn about angiogenesis, which is how a tumor recruits its own blood supply. Metastasis and angiogenesis are to be feared. In both instances, science is leading to therapies that are being devised. You will also learn about the burden tumors have on the functioning of the human body. Metastasis: The Spread of Tumors  Metastasis, the spread of tumors to distant sites in the body, is the most feared aspect of cancer. Tumors can grow and maybe a surgeon will be able to take it out, but once a tumor spreads, it’s a very bad prognosis. About 60 percent of tumors have metastasized at the time of diagnosis. A tumor with metastases at the time of diagnosis is in most instances incurable. We can control it, but we can’t cure it. Metastasis is related to angiogenesis, the recruitment of a blood supply. 

The mystery of metastases was something that people had puzzled over for centuries, until the early 1800s. In 1829, a French physician, Jean Recamier, first showed in animals and in humans that metastases occur from a primary tumor breaking off small cells, which enter the bloodstream or other circulatory system and then seed themselves onto other organs. Before, it was thought that metastases were just new tumors—that they were arising spontaneously somehow.

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Metastasis occurs in a series of steps. In the first step, tumor cells grow toward a blood vessel. Tumors aren’t sitting by blood vessels all the time. They might be several cells away. There might be angiogenesis, which involves small capillaries, but tumors have to

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Lecture 11: How Tumors Spread and Thrive

grow toward a significantly sized blood vessel, so tumor cells will grow toward the blood vessel. 

In the second step, some tumor cells will enter the blood (or lymph) vessel. They will sneak their way in through the wall of the blood vessel. If it’s small, the blood vessel is called a capillary.

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Third, the tumor cells are carried in the blood (or lymph) circulation. Fourth, tumor cells adhere to the wall of the vessel near a target tissue and stop circulating. Fifth, the tumor cells leave the blood (or lymph) vessel, and then they grow in the target tissue. That is a metastasis.

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In the sixth step, the tumor grows in the target tissue. Instead of a big tumor creating a small piece of it, now it is a small cell that is going to grow into a big group of cells. The result is pretty sobering. A metastasis can be a disaster because it can horribly compromise the function of the organ.

Angiogenesis: The Recruitment of a Tumor’s Blood Supply  Angiogenesis is the recruitment of the blood supply at a metastasis or a primary tumor. A cell in the body has to be no more than five cells away from the blood in order to get a decent exchange of gasses and nutrients: Oxygen is being released from hemoglobin, and it enters a cell that is right by the blood capillary by a process called diffusion, which is a slow process. Therefore, the farther away a cell is from the source of oxygen, namely the blood, the less likely it is to get oxygen in a timely way. 

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In angiogenesis, the tumor sends a signal to a nearby blood vessel, which makes a branch. The signal will land on the cells of the blood vessel, and those cells are called endothelium, which is the lining of the capillary. The cells that line the blood vessel are stimulated to divide, resulting in more cells that line a capillary. The cells have to migrate up by digesting their way using MMPs, or proteases. They’re also going to migrate up because they can move; they have a cytoskeleton. They will form a blood vessel, which will then form

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There are a number of signals that come from a tumor to diffuse down to the nearby blood vessel, but the major one is called vascular endothelial growth factor (VEGF). Normally, the VEGF system is working all the time to restore oxygen supply to tissues when the blood circulation is not adequate through nourished tissues.

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For example, in an embryo, when new organs are forming, the new organ does not have enough oxygen because it is so far away from the blood. The lack of oxygen stimulates the Melanoma is a frequently recurring synthesis of VEGF, which cancer of skin cells that produce the then goes down to a receptor pigment melanin. protein, the VEGF receptor, which is on the endothelium lining of the blood vessel. A series of signaling events happens, leading to the molecular events of the blood capillary making a branch and cell division happening.

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If there is low VEGF expression, the tumor can’t recruit a blood supply well, which is good news in terms of tumor growth because a tumor may grow just to a limited size and will not be able to recruit a blood supply and grow any bigger. There is not much angiogenesis, and cell survival is better. Unfortunately, most tumors are really good at making VEGF. In fact, sometimes there is a mutation in the promoter, which is the region that promotes gene expression, that will make it more active and make more VEGF.

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the circulatory system for a growing metastasis (or tumor itself when a tumor begins).

Lecture 11: How Tumors Spread and Thrive

Tumors as Burdens on the Body  Tumors are burdens on the body. As tumors grow, they affect functions of the body, but at the same time, the body responds to the tumor. The body does everything it can to reject a tumor. The rejection of a tumor is done by a system called the immune system, which recognizes things that are foreign to the body, including an invading pathogen, a virus, or a cell that is different (like a cancer cell). Recognition, a major function of the immune system, is done by certain white blood cells.

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The second thing that happens is mobilization. Once the recognition event happens, the white blood cell labels the tumor as a foreigner and essentially sends a signal out to other white blood cells to assemble an army, which makes antibodies. Either these antibodies fight disease pathogens that can lead to the organism being killed, or they make cells called killer cells that can kill the target cell.

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Once the signal is sent and the white blood cells expand their numbers, these cells will then hone in on any tumor cell that has that marker and kill it. The problem is that tumor cells can be so large in numbers that they will overwhelm the immune system, and they may not have the new protein or the new molecule they are making in an exposed way so that the immune system can see it. The new protein or molecule is often inside the cell, and the immune system cannot see past the cell membrane.

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Immune presentation is a very important phenomenon in the process of immune systems killing cells by these natural killer cells. There is a whole lot of science going on to try to coax the tumor into exposing its new proteins to the immune system. Once those proteins are exposed, then essentially the immune system will take over and kill the tumor cell.

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With people who are immunodeficient—such as people who have AIDS, for example—their immune system is not working well, so they are much more susceptible to cancer. There are a number of cancers that are characteristic of AIDS patients.

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Unfortunately, tumors may evade the killing system. If the proteins are not exposed, the tumor is going to continue to grow. This is where the tumor burden becomes an issue: How big and how harmful is the tumor to the person who is carrying it?

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Tumors can cause illness by damaging tissues (like blood vessels) or obstructing organs (like the bowel or brain). About a third of all cancer deaths are caused by cachexia, which is the wasting and loss of appetite due to proteins released by the tumor.

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Cancer treatments such as chemotherapy and radiation are notoriously hard on patients and may further weaken the body’s resistance.

Important Terms antibody: A highly specific protein made by the immune system in response to a substance foreign to the body that is involved in immune protection against that substance. Antibodies can be engineered to act as therapeutic agents. cachexia: Bodily state late in cancer where an individual “wastes away,” losing appetite and weight. This can occur late in the cancer progression. promoter: A DNA sequence adjacent to the coding region of a gene, to which RNA polymerase binds to initiate gene expression. The events at the promoter are highly regulated in location and time. Prompters regulate the expression of genes involved with cancer.

Suggested Reading Almeida and Barry, Cancer. Collins, The Language of Life. Cooke and Koop, Dr. Folkman’s War. DeVita, Lawrence, and Rosenberg, Cancer. 73

Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. LaFond, Cancer. Sadava, Hillis, Heller, and Berenbaum, Life. Sompayrac, How Cancer Works.

Questions to Consider 1. What are the similarities and differences between metastasis and angiogenesis? Why are both processes important to cancer?

2. Think of a person you know or a public figure who died from cancer. If

Lecture 11: How Tumors Spread and Thrive

you wrote a “biography” of the tumor, how would you describe the steps in its development? How did it kill the patient?

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What Are Tumor Viruses? Lecture 12

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his lecture describes viruses. First, you will learn about what viruses are. Then, you will learn about tumor viruses and how they are identified. How do you prove that something is a virus that causes cancer? There are two ways to do this: by epidemiology and by analysis of DNA. In the last part of the lecture, you will be exposed to several examples of major cancers that are implicated with viral causes. What Are Viruses?  In 1909, Peyton Rous proved (by filtering) that a chicken sarcoma was caused by an agent smaller than a bacterium. For years, the scientific world did not quite know what to do with this information, but finally, viruses were linked with other cancers, and Rous received his Nobel Prize in 1966. 

There are many types of viruses, and they infect all types of cells. All viruses contain genetic material (either DNA or, in some cases, RNA—the copy of DNA that is sent out during the synthesis of proteins) that is wrapped up in protein. Almost all viruses also have something on the outside of the virus that allows the virus to attach to the host cell, and it’s called an overcoat.

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This is a highly specific interaction. You may be exposed to a lot of viruses that are in the air, and those viruses are going into your body, but those viruses may not land and bind to cells in your body unless the cells express the receptor. In the evolution of life, viruses have evolved such that they’ll have receptors to get into the cells that they want to get into or are able to get into.

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Viral infection follows several steps. In the first stage, the virus lands on a cell that has the receptor. Then, the virus puts its DNA inside the cell. The DNA looks like it’s just regular DNA, and the cell does not know that it is any different. It is a small piece of 75

Lecture 12: What Are Tumor Viruses?

DNA compared to the rest of the cell; it usually only has a couple of genes.

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Once the DNA is inside the cell, genes are expressed. The viral DNA has signals—or sequences of DNA (A, G, T, C)—that the host mechanisms for expressing genes recognizes. The host mechanism notices this piece of DNA and copies it into RNA, sealing the fate of the cell because the RNA then is translated into a viral protein that lops onto the DNA of the host and shuts it down. The host is no longer making its own proteins, and the virus is free to make its proteins, which are the little genes of the virus.

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The virus replicates itself and expresses its own genes and coat protein, and later on, it expresses genes that lyse, or disrupt, the cell. In the case of a bacterial virus, it will take only 20 minutes. In the case of a human virus, it will take about a day, and then hundreds of virus particles come out. At that point, viral DNA has taken over the cell; it has changed the genetic program of the cell.

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Viruses can have, however, alternate lifestyles. Some viruses don’t kill the host cell and produce new ones. Instead of the viral DNA hanging out in the cell, it splices into the host DNA and just kind of carries along. The reason for doing this is because the host cell is not healthy, so it may not be able to have the mechanism to make many new virus particles.

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In the case of a tumor, the virus stimulates the host cell to divide, so there will be lots of cells containing this latent tumor virus DNA. When the conditions are ripe for making a lot more virus, then there will be a lot of cells to make a lot more virus, so it’s a terrific advantage for the virus.

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Viral DNA sitting in a host cell stimulates cell division by stimulating oncogenes or having active oncogenes that push the cell and make it divide. It will block tumor suppressors; it will block the genes that block cell division.

Identifying Tumor Viruses  Because tumor viruses integrate with the host cell DNA, they are not floating around free in the body and may be difficult to detect. There are two ways to identify tumor viruses: epidemiology and DNA analysis. 

In terms of epidemiology, there are three types of studies that can be done to identify that a tumor virus is somehow causing or involved in the causation of a cancer. The first is a population study, which would determine whether the cancer phenotype appears to be transmissible between people. The second is a case-control study, in which you take cancer patients with a cancer and a control group and ask which ones are infected with the virus. The flip side is a cohort study, in which you look at the people with the virus or not with the virus and see which ones get cancer.

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Some antibodies to the original infecting virus may be found in blood serum. When a person is infected with a virus, the first thing that happens is the host immune system reacts by making antibodies. The advantage of antibody storage is that you can take a blood sample from someone and store it for as many years as you want, and you can detect antibodies that are evidence that the person was infected with various viruses and other pathogens. The clues can be beneficial to both case-control and cohort studies.

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The second way to prove that something is a tumor virus is finding viral DNA spliced into the genome. One method is to extract DNA from the tumor and compare it to DNA from adjacent nontumor tissue. A DNA “probe” can be used to search for its complementary strand; if the strand is long enough, the probe can be diagnostic of the disease. Polymerase chain reaction (PCR) uses virus DNA as a starter for DNA replication in the test tube; if amplified, the virus DNA is present in the tissue.

Cancer-Causing Viruses  Only about 10 percent of cancer is caused by viruses, but some of them are significant. There is no logic in regard to the types of 77

Lecture 12: What Are Tumor Viruses?

viruses that cause cancer—some of them have DNA, some have RNA, some are big, some are small. All of them integrate their genetic material into the host DNA. There are only a few instances where the virus is the primary cause of cancer.

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The viruses very often stimulate cell division, or they might knock out tumor suppressors, but other genetic changes have to be there. Multiple events happen to get cancer; the virus is an important one, but it is not the only one.

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Three important viruses for humans are EBV (EpsteinBarr virus for lymphoma), HPV (human papilloma virus for cervical cancer), and HBV (hepatitis B virus for liver cancer). Each of these viruses actually requires other factors to induce cancer.

© Hemera/Thinkstock.

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HPV, or human papilloma virus, enters the uterine lining through an abrasion during sexual intercourse.

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Epstein-Barr virus causes a lymphoma, which is a cancer of the lymph nodes, primarily in the mouth and oral area. There are about 100,000 new cases every year in the world. A papilloma virus, which is a wart virus, causes cervical cancer, and there are about a half a million new cases every year in the world. (The HPV vaccine has now been developed.) Hepatitis B virus is involved with liver cancer, and there are about a half a million new cases every year in the world.

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The total number of virus-caused cases of cancer is about 1.3 million, and the total number of new cases every year of cancer is about 13 million, so viruses account for about 10 percent of all cancer cases.

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HBV is especially widespread, affecting perhaps 360 million people worldwide. In many areas of Asia and Africa, over 10 percent of the population are HBV carriers. China has a million new cases of liver cancer per year. An HBV vaccine universally administered to infants represents a major public health advance.

Important Terms lymph node: Accumulated tissue in the tubes of the lymphatic system that drains fluids in between tissues and returns it to the blood system. Because tumor metastasis often occurs via lymphatic vessels, tumor cells can accumulate in lymph nodes, and detection of them there indicates metastasis or its potential. polymerase chain reaction (PCR): A method of amplifying a DNA sequence in a test tube by adding DNA polymerase and other necessary components for replication. A sequence can be amplified a million times in a few hours.

Suggested Reading Almeida and Barry, Cancer. Bishop, How to Win the Nobel Prize. Collins, The Language of Life. DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. LaFond, Cancer. Sadava, Hillis, Heller, and Berenbaum, Life. Sompayrac, How Cancer Works. Weinberg, The Biology of Cancer. Zimmer, A Planet of Viruses. 79

Questions to Consider 1. Using the human papilloma virus as your example, what is meant by the expression, “a virus is a piece of bad news wrapped in a protein”?

2. Most cervical cancer is in part caused by infection with human

Lecture 12: What Are Tumor Viruses?

papilloma virus (HPV). A vaccine against HPV has been developed, and it protects women from infection and, hence, cancer. Physicians recommend vaccination of young girls, before they are active sexually. Has this been controversial in your community?

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How Do Tumor Viruses Cause Cancer? Lecture 13

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his lecture discusses viruses that are involved with cancer and how these viruses operate on a molecular level. In this lecture, you will learn that the level of gene expression can be controlled. In addition, you are going to see how tumor viruses and oncogenes use these genecontrol mechanisms to cause cancer. Then, you will learn about normal cells: How do normal cells that aren’t infected by a virus get cancer if they don’t have extra genes from the tumor virus that invade them? Controlling Gene Expression  Some of the polio vaccine used in the late 1950s and 1960s was infected with a monkey virus called SV40 that can transform normal monkey cells into monkey cancer cells. This discovery confirmed the idea that viruses can bring cancer-causing genes into cells, which then hijack normal cell mechanisms to create tumors. These same genes are active in non-virus-infected cancer cells. 

Genes express themselves as phenotypes through the proteins that are produced by DNA. There are three major ways that the expression of phenotype is controlled: by making more copies of a gene, by controlling transcription of a gene through activators and repressors, and by control after transcription involving microRNA strands.

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In the first way that the expression of phenotype is controlled—by making more copies of a gene—DNA duplication happens with the original DNA getting copied into two strands. This happens during the cell cycle, just before chromosomes get very short and go into cell division. A typical human chromosome has maybe 1,000 growing points—called replicons—all working at the same time to get all of the DNA duplicated during the few hours of the cell duplication cycle.

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Lecture 13: How Do Tumor Viruses Cause Cancer? 82

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There are multiple growing points, and each one just duplicates once. However, sometimes slippage occurs, resulting in more than one copy. The gene is amplified, and amplified genes can cause cell division if they are genes that produce proteins that are important to stimulate dividing cells.

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The second way of controlling the expression of a gene is to control the DNA getting copied to RNA. Cell differentiation results in specializes cells, with each specialized cell making a different specialized product. The control spot is just a switch—it’s the ignition switch where transcription, or copying the DNA, begins. That region is called the promoter, which is a region on DNA where the DNA-copying machinery copies to RNA, lands, and begins the expression to RNA.

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By manipulating conditions at the promoter, you can make things go faster or slower. Whole biotech companies are devoted to single types, for example, of activator and inhibitor molecules because to manipulate them, you can manipulate what a cell is doing.

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The third mechanism for controlling expression of genes is controlling after transcription. After the RNA has been copied and translated into protein, it can be manipulated. A recent discovery in nature is small RNAs. A lot of the genome is involved in making small RNAs, and their job is to target messenger RNAs, RNA copies of genes, to either block them or promote them. The small RNA will typically bind to a target RNA, called a microRNA, and stop it from making a protein.

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MicroRNA is a very hot topic in cancer diagnostics. Different cancers are being found to make different RNAs. This is a very, very current area of research in which people are trying to see which small RNAs, made in large numbers in the cell, are targeting certain RNAs for destruction. For example, you might target in a tumor cell a tumor suppressor RNA and destroy it so that the tumor can grow.

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The phenotype of a cell can also be affected after it is made, and a major way to do that is to alter the shape of a protein, including by adding phosphates or kinases.

How Oncogenes in Viruses Cause Cancer  When the SV40 virus splices itself into the DNA of a host cell, it produces a protein—a viral protein called T, for transformation, because it transforms a cell into a tumor cell. The protein T binds to RB protein, a tumor suppressor that normally blocks division of the cell. In other words, RB normally blocks a cell from making its DNA. With RB blocked, the cell is allowed to divide in an uncontrolled way, leading to cancer. 

The part of the gene that codes for the T protein is called an oncogene. It was one of the first oncogenes, or cancer-causing genes, to be discovered. The virus brings this gene into the cell, and the gene blocks RB so that the cell can proceed. It also blocks another tumor suppressor called p53.

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The Rous sarcoma virus (RSV) has three major genes for reproduction and packaging. Researchers found that there were two types of viruses: the Rous sarcoma virus that causes cancer and the other—in the same cell—that doesn’t cause cancer.

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Researchers compared those two viruses and discovered that the Rous sarcoma virus brought an extra gene called Src (short for sarcoma) into the host cell’s DNA that produces protein kinase, which promotes rapid cell division (by adding phosphate to target proteins). This kind of gene is called an oncogene. If you remove that gene and add it to normal cells, they become tumor cells.

Proto-Oncogenes in Normal Cells  “Normal” cells are cells that are not infected with a virus. Protooncogenes are normal genes that can become oncogenes when viruses pick them up and get mutated. Oncogenes are activator genes that can cause cells that are normally programmed for cell death (apoptosis) to divide and proliferate, causing cancer. 83

We know that 90 percent of cancer is caused with no viral infection at all. When approaching this problem, we already know about oncogenes, the genes that the tumor virus is bringing in, and we can surmise that the oncogene got into the tumor virus by the tumor virus picking it up from the host.

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Viruses don’t necessarily have protein kinases; in fact, most viral genomes were originally in the host cells, and they kind of got packaged into a protein. The gene in the host is called a proto-oncogene.

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The host protooncogene should not be exactly the same sequence as the viral oncogene. If you think of evolution and change through time, there are going to be Tumor viruses manipulate the system that controls how genes are expressed. more spontaneous mutations in the virus, and viruses don’t repair, so the gene sequence will be slightly different in the virus than it is in the host.



This prediction is that in all cells is a set of genes that, when put into a virus, can cause cancer when the virus brings it into the cell in an active form. The assumption is that the set of genes is just kind of dormant and, under the right conditions, can become activated.



Scientists Michael Bishop and Harold Varmus decided to look for the SRC gene (from the Rous sarcoma virus), which is involved in causing cancer in uninfected host cells, in chicken DNA. There are a billion nucleotides in chicken DNA. These scientists took the SRC gene—1,200 nucleotides—and went looking for the SRC sequence

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Lecture 13: How Do Tumor Viruses Cause Cancer? 84



by matching the base pairs in the haystack of the huge amount of DNA in the genome of the normal chicken who was uninfected. 

Lo and behold, they found the SRC gene. It wasn’t exactly the same sequence as the SRC gene in the virus, which was predicted because there have been mutations that have piled up over time. Pretty soon, other viruses were found. Viral proto-oncogenes were found in human cells, and now we have this whole set of protooncogenes that could cause cancer. Both Bishop and Varmus jointly were awarded the Nobel Prize for this discovery.



A second way of looking for proto-oncogenes is to isolate them from a tumor. You take a tumor that you think has a proto-oncogene in it, and you take all of its DNA out and chop it up into gene-sized pieces. Then, you take some normal cells and add these pieces to the cells. You analyze each piece to see whether it caused a cell to grow into cancer. When researchers did this, they actually isolated cancer-causing genes from normal cells.



The result of these two approaches was that there are cellular homologues of oncogenes in uninfected tumor cells. That is, normal cells have many proto-oncogenes.

Important Terms nucleotide: The building block of a nucleic acid. Each nucleotide has an identical sugar and phosphate group, but there is one of five different bases: A, G, C, T, and U. proto-oncogene: A gene in a cell that, when activated, forms a product that stimulates cell division and cancer. Homologous to oncogenes carried by viruses. transcription: The expression of a gene by the production of RNA from a DNA template, catalyzed by RNA polymerase.

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transformation: In cancer, the conversion of a normal cell into a cancer cell. In experimental science, the introduction of DNA from an outside source to a cell, causing it to become genetically different.

Suggested Reading Almeida and Barry, Cancer. Bishop, How to Win the Nobel Prize. Collins, The Language of Life. DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. LaFond, Cancer. Sadava, Hillis, Heller, and Berenbaum, Life.

Lecture 13: How Do Tumor Viruses Cause Cancer?

Sompayrac, How Cancer Works. Weinberg, The Biology of Cancer.

Questions to Consider 1. Using an automobile as the analogy, what are the differences in function between proto-oncogenes and tumor suppressor genes with regard to cell division and cancer? How does this relate to carcinogens that damage DNA?

2. Why aren’t all cancers caused by viruses?

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How Do Cancer-Causing Genes Work? Lecture 14

T

his lecture describes three functions of oncogenes. First, some oncogenes make products that control gene expression, which is the synthesis of protein from a sequence of DNA, and they usually do this by turning on genes involved with cell division. Second, some oncogenes involve the system of a growth factor, or a substance outside the cell binding to the cell and stimulating cell division by knocking on the door and making some action go on in the cell nucleus. Third, some oncogenes control cell death by reducing it. Oncogenes and Gene Expression  Oncogenes are the “gas pedals” that stimulate cell reproduction. Tumor suppressor genes are the “brakes” that keep cells from dividing. Both overstimulation of oncogenes and blocking of tumor suppressor genes can promote cancer. 

Proto-oncogenes are mutated in 90 percent of cancers, and these are the cancers that are not caused by a virus. Some protooncogenes control gene expression. The protein synthesis system begins at a place called the promoter—the ignition switch at the start of a gene that essentially controls whether the rest of the gene is going to be expressed.



There are repressors and activators, and it is the sum total of all of them that determines whether something is going to happen. The promoter sort of evaluates all of the proteins and acts based on the majority.



MYC is an example of an oncogene that acts at the promoter as a paradigm for this whole system. There is a virus called the avian myeloid (a blood tumor) leukemia. The oncogene it carries into the bird cell is an MYC oncogene. The bird (or host) DNA also

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Lecture 14: How Do Cancer-Causing Genes Work?



In normal cells, MYC is expressed typically during cell division, when cells are reproducing. In cancer cells, MYC expression is uncontrolled, so a lot of it is being made. MYC is uncontrolled in 80 percent of breast cancers, 70 percent of colorectal cancers, 90 percent of gynecological cancers, 50 percent of liver cancers, and 80 percent of lymphomas.



Neuroblastoma is a childhood tumor of the central nervous system. It is much more treatable than it was previously, but initially, people found that the MYC gene was amplified; In cells, proto-oncogenes can become there was more MYC activated to become things that can cause cancer and stimulate cell division. protein, and it correlated with a poor prognosis. About 20 years ago, studies were conducted in which researchers would biopsy the neuroblastoma, and the children who had an overexpression of MYC had much worse prognoses.



Fortunately, children who had this overexpression of MYC were treated aggressively with therapy, and children that now have an overexpression of MYC are doing much better than they did in the past. Molecular biology allowed researchers to stratify patients and choose those patients that should receive aggressive therapy.

Oncogenes and Cell Signaling  Cell reproduction is controlled in two ways: internally by kinases (etc.) and externally by growth factors, or proteins. In the external

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© iStockphoto/Thinkstock.

has a proto-oncogene called MYC, and MYC is present in many vertebrate organisms, including humans.

case, something binds to the receptor protein on the outside of the cell, and then the receptor protein stimulates the inside of the cell. 

The signal is a growth factor that comes from somewhere outside of the cell and binds to a receptor. The process of receptor binding somehow causes a change inside the cell, and then there are signaling proteins inside the cell. Like a bunch of dominoes, one protein pushes another. Many of these signaling proteins are protein kinases.



Once one of the protein kinases is activated, the next step is to put a phosphate on its target protein. The next step gets activated, and it puts phosphate on the next step, which puts phosphate on the next step, etc. The end result of this signaling pathway is usually a transcription factor in the cell nucleus that alters the expression of genes.



The interesting thing is that there are oncogenes at almost every step in this process. Many of the intermediary steps can be oncogenes because if you turn one of them on, then all of the subsequent steps get turned on.



RAS, a proto-oncogene, was isolated first in a rat sarcoma (a muscle type of tumor), and it is a protein at the cell membrane. RAS is the first of the dominoes. After a growth factor binds to the receptor, the receptor jiggles a protein, and sitting right there is a molecule called RAS, which then becomes active. RAS changes its three-dimensional structure indirectly by binding with the receptor protein inside the cell.



If the gene that codes for RAS was mutated such that the RAS protein was changed so that it is always active, then it doesn’t need the push from the outside. Then, in the non-virus-infected sarcoma, there is this abnormal signaling. The RAS protein is always on; it doesn’t care about growth factor anymore. The RAS protein stimulates all of the other dominoes in the pathway, resulting in an

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Lecture 14: How Do Cancer-Causing Genes Work?

active transcription factor in cell division. Fifty percent of human cancers have an activated RAS. 

Researchers have tried to design drugs that block RAS, but RAS is a tough target because even though it is mutated in many cancers and is very active, it is also active in many, many other cell types. The side effects of just blocking RAS probably are going to be pretty severe if that’s selected as a therapy.



However, if we look at all the other dominoes—all the other steps in the signal-transduction pathway—there are many targeted therapies being developed for each one of those steps because all we have to do is block one of the dominoes from falling so that the last on the list will not fall. Many of these intermediate steps are protein kinases, so there is a whole family of targeted drugs in therapy now called protein kinase inhibitors.

Oncogenes and Cell Death  Viral oncogene/cellular proto-oncogene types have been described for many types of tumors, especially in animals. An example is B-cell lymphoma: B cell is a white blood cell that happens to produce antibodies, and lymphoma is a tumor of it from the lymph node. There is a gene that was characterized called BCL2, which was brought in by a virus in animals but also as a proto-oncogene that gets activated.

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

Initially, BCL2 was thought to be an oncogene; it stimulates cell division. However, in a certain type of cancer called follicular large cell lymphoma, it is just one of those lymphomas that comes from the line of differentiation of white blood cells. A doctor named Stanley Korsmeyer showed that the BCL2 protein is present where cells do not die. In other words, the BCL2 protein seems to block programmed cell death.



When they are activated, some oncogenes and proto-oncogenes block cell death, and the ultimate proof of this was when mice were

genetically engineered to have an overactive BCL2, which means no programmed cell death (apoptosis). 

Normally, if there is DNA damage, then the DNA gets repaired and the cell is okay. If there is extensive DNA damage, then the cell will sense that and go into programmed cell death. There will be execution signals, and the cell dies. If BCL2 is overexpressed, however, the apoptosis does not happen, then the cell is going to survive, and mutations will accumulate in cells that normally would have died through programmed cell death. This has been shown to occur in human melanoma, breast, prostate, and lung cancers.



The goal is to design a drug that blocks BCL2. Currently, an antiBCL2 drug to block the BCL2 protein—so that the cells go into programmed cell death and die—is used for leukemia.

Gene Activation in Cancer  Proto-oncogenes can be activated to promote cancer in three main ways: amplification, translocation, and mutation. 

Amplification of the proto-oncogene makes more copies of the gene, which in turn produce more protein that stimulates cell division or inhibits cell death. The growth factor receptor HER2 is overexpressed in 30 percent of breast cancers and in aggressive uterine cancers due to amplification. Herceptin is a promising drug for cancers with HER2.



Translocation of the proto-oncogene to an active promoter can create a fusion of two genes, as in Kareem Abdul-Jabbar’s CML cancer. In follicular lymphoma, the BCL2 gene on chromosome 18, which has a very low level of expression, is translocated to chromosome 14, which has a high level of expression. Chromosome abnormalities with translocations are common in both blood cancers and solid tumors, with over 50,000 now reported in the literature.



Mutation of a proto-oncogene changes the protein phenotype being expressed. The RAS gene, when mutated, acts as an “always on” 91

molecular switch for cell growth. RAS is active in melanoma and in colon, lung, and pancreatic cancers; the presence of an RAS mutation indicates a poor prognosis for bile duct cancer.

Important Term growth factor: A protein made in mammals by one tissue that stimulates cell division in a target tissue.

Suggested Reading Almeida and Barry, Cancer. Bishop, How to Win the Nobel Prize. Collins, The Language of Life. DeVita, Lawrence, and Rosenberg, Cancer.

Lecture 14: How Do Cancer-Causing Genes Work?

Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. LaFond, Cancer. Sadava, Hillis, Heller, and Berenbaum, Life. Sompayrac, How Cancer Works. Weinberg, The Biology of Cancer.

Questions to Consider 1. Do all proto-oncogenes stimulate cells to divide? What is the other “half” of the population growth rate of a tumor, besides cell division rate?

2. Normally, proto-oncogenes are “quiet.” What “wakes them up” in cancer cells? Use the example given at the start of the course of leukemia in the basketball player Kareem Abdul-Jabbar. How does this “awakening” happen?

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Can Cancer Be Inherited? Lecture 15

I

n this lecture, you will be introduced to the concept of hereditary cancer. You will learn how cancer in families can be inherited and what the criteria are for defining cancer as inherited. Then, you will learn about several cancers that we know are inherited. In addition, you will learn about susceptibility in genes—genes that make people more prone to getting cancer and how those genes are inherited as well. The Inheritance of Cancer in Families  Cancer in families occurs with close relatives maybe 10 or 12 percent of the time. Many families have cancer in their families, and when you think about it, it shouldn’t be that unusual because one person in four develops malignant cancer in a lifetime and one in three dies of it. It’s not surprising that cancers run in families. 

Some cancers, like retinoblastoma, can be either hereditary or sporadic (not hereditary). A cancer may be hereditary when two or more close relatives have the same rare cancer. Hereditary cancers tend to occur at a young age with multiple tumors at one organ whereas sporadic cancers of the same kind occur later in life and are more likely to have a single tumor. The mechanism for these kinds of cancer seems to involve not one, but two mutations of a tumor suppressor gene. In the hereditary form, one mutation is inherited and, thus, present at birth. Only one further mutation is needed for cancer to occur. In the sporadic form, both mutations have to occur independently—thus, the later onset of the disease.



One way to determine whether cancer in a family is hereditary or sporadic is to look at epidemiology. When you do a case-control study, you have a lung cancer patient and a control that doesn’t have lung cancer, and you ask what the relative risk is of another person, close relatives in the same family, having lung cancer. You can correct for smoking and passive smoke, etc. You get a relative risk 93

94



Overall, the results of epidemiology and genetics indicate that about five to seven percent of cancer is inherited as a single gene or a few genes, and maybe a few more percent of cancer is inherited susceptibility to cancer—making up a total of close to 10 percent. If 10 percent of cancer is caused by viruses and 10 percent is caused by heredity, that leaves 80 percent that is caused by spontaneous and environmental mutation.



Heredity cancers are often childhood tumors. They all have a sporadic form as well, which is more common than the hereditary form.



An example of a hereditary cancer is retinoblastoma. The ideal model of retinoblastoma is that the sporadic form is the same as the hereditary form and that everybody with retinoblastoma has the same mutation of the same gene. However, this is probably not true for most cancers, which are caused by multiple genes, so it is much more complicated than inheritance of a single gene. That’s probably why hereditary cancer per se is pretty rare. You might inherit a bad allele of a gene that might get cancer going, but you might need a whole lot of other genes to be mutated for the cancer to become malignant.



Colon cancer begins as a small growth in the colon called a polyp, which is what doctors look for in a

A small growth in the colon, called a polyp, is how cancer begins in the human body.

© Hemera/Thinkstock.

Lecture 15: Can Cancer Be Inherited?

of about two, which shows that even correcting for environmental factors the best we can, there is a genetic component because one person is smoking and the other is more likely to get it.

colonoscopy. The peak incidence of colon cancer is in people who are in their 60s, and 98 percent of colon cancer arises from polyps. There is a hereditary form of colon cancer, which makes up about five percent of colon cancer, while 95 percent of colon cancer is sporadic. 

The Wilms kidney tumor starts in the embryo of the kidney. If it is hereditary, there will be bilateral multiple tumors and early onset. If it is sporadic, there will be a single tumor, one kidney, and later onset. It’s a fairly rare situation. It’s very treatable now, with chemotherapy, surgery, and radiation, and most people with Wilms tumor are now living to reproduce.



Another hereditary cancer that usually begins young is called neurofibromatosis. A neurofibroma is a tumor that comes from the fibrous tissue in the nerve tracts of the body. Half of the cases of neurofibromatosis are hereditary, and half are sporadic. Neurofibromatosis is pretty common; it occurs in about one birth in 3,500. There is a very high spontaneous mutation rate in the germ line cells of parents to give rise to this. Its onset is typically in the first decade of life. Sometimes, the person can get skin lesions, and other times, the person can get eye lesions. The lesions are highly variable in size. It can be a problem if tumors arise internally in the brain and blood.



If we do the epidemiology of breast cancer and decide that a family by those criteria has hereditary breast cancer (multiple tumors, both breasts, early onset, more than one blood relative with it), then we can look at the family and see what the data show. For example, in a case-control study from 52 studies of 58,000 cases and 101,000 controls, if there are zero relatives with breast cancer—and the probability is defined as 1.0, which is 10 percent lifetime—for one first-degree relative with it, the probability goes up to 1.8; for two first-degree relatives with it, it goes up to three; and for three firstdegree relatives with it and above, it goes up to four. The more relatives who have breast cancer in the family, the more the risk is, and the more probable it’s hereditary. 95

Lecture 15: Can Cancer Be Inherited?

Inherited Susceptibility to Cancer  Inherited susceptibility to cancer can also occur. There are a number of genetically determined diseases that make people more susceptible to cancer, and these diseases involve DNA repair. Every day, there are thousands of mutations that happen spontaneously to DNA. If you can’t repair those, then you are going to be more susceptible to cancer.

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

Examples of such diseases are xeroderma pigmentosum (people with this cannot repair ultraviolet light, so they get skin cancer damage), Bloom syndrome (people with this cannot unwind DNA for repair, so they end up with lymphomas), and Lynch syndrome (people with this cannot repair DNA errors, so they end up with colon cancer).



Some people may have genetic variants that allow either a different rate of activation to carcinogenesis or deactivation from carcinogenesis. Maybe their defect is in a repair gene that is only expressed in that particular type of cell. A consequence of the failure of repair of DNA damage is xeroderma pigmentosum, for example. In xeroderma pigmentosum, children get skin cancer just by going outside because they can’t repair ultraviolet light damage to DNA.



Another inherited susceptibility involves the process whereby a molecule gets taken in by the body and goes through the liver, and the molecule becomes more soluble. The system that does this is a system that is inherited. It’s a series of proteins, a family of genes, that has genetic variants. There might be genetic variants that do not do the activation really well, and indeed, that is the case.



Heavy smokers who never get lung cancer may have a genetic variant that protects them. Maybe they got the right genes—the genes that do not activate a particular carcinogen called benzpyrene.



Genome sequencing looks for genetic variants that affect cancer susceptibility. The DNA sequencing of tumors is a major effort, and

we are looking for variants that might be associated with cancer susceptibility. The idea is that in a sequence of DNA, researchers look at a certain spot for a variation and try to relate that particular genetic difference to cancer. If that relates to cancer, then that might be part of the genes that are causing the cancer or making people susceptible to the cancer. 

We can classify people having this change as common homozygotes, which are people who might be normal; heterozygotes, which are people who have one gene that is bad; and variants of homozygotes. The people who have the variant homozygotes might be the most susceptible to cancer. It is easy to classify people on the basis of these small DNA variations, and then you can begin to determine which people might be more prone to getting certain types of cancer.

Important Terms alleles: Different forms of the same gene. A tumor suppressor gene can have alleles that encode proteins that block cell division and cancer, and others that do not. DNA repair: Chemical correction by cells of errors that occur in DNA during its replication or by outside agents, such as chemicals and radiation. Some cancers are caused in part by defects in DNA repair. heterozygote: An particular gene.

organism

with

two

different

alleles

for

a

homozygote: An organism with two identical alleles for a particular gene. hereditary cancer: Cancer that develops because of gene mutation(s) passed on from parent to offspring. sporadic cancer: Cancer that occurs without a known hereditary cause.

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Suggested Reading Almeida and Barry, Cancer. Collins, The Language of Life. DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. LaFond, Cancer. Sadava, Hillis, Heller, and Berenbaum, Life. Sompayrac, How Cancer Works. Weinberg, The Biology of Cancer.

Questions to Consider 1. Examine the cancers that have occurred in your own family or another

Lecture 15: Can Cancer Be Inherited?

family. Does “running in the family” necessarily mean that cancer is inherited? Just looking at the case histories, how can you conclude that the cancers in the family you examine are/were inherited or sporadic?

2. You probably know someone who has been exposed to a known carcinogen (e.g., a long-time smoker) but has not developed cancer. Can you suggest how cancer susceptibility genes are involved in this?

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How Do Normal Genes Suppress Tumors? Lecture 16

I

n this lecture, you will learn about the strategies for identifying tumor suppressor genes. You will also learn how some of these tumor suppressor genes work at the DNA level. Some of them repair DNA damage while others control the cell division cycle. In addition, some tumor suppressor genes prevent DNA damage from becoming permanent. You will be exposed to examples of each of these types of genes. The hope is that understanding tumor suppressor genes can lead to a treatment and a cure for cancer. Identifying Tumor Suppressor Genes  Oncogenes stimulate cell division, but there is another way to promote cancer in the cell as well, and that is to disable the normal tumor suppressor genes. If oncogenes are like stepping on the gas pedal, then this second strategy is more like taking your foot off the brake. Either way, cell division is going to accelerate. 

Breast cancer is one kind of cancer that seems to require two mutations to express as cancer. In one kind of hereditary breast cancer, a woman inherits a mutated tumor suppressor gene called BRCA1 or BRCA2, and a second mutation in breast cells only may result in breast cancer. The lifetime risk for such women is 80 percent. Genetic testing can reveal the inherited mutation, and surgery can prevent cancer by removing the breasts and ovaries.



Many tumor suppressor genes have been isolated at this point. There are three main strategies for identifying tumor suppressor genes: DNA mutation linkage (which located BRCA1), chromosome analysis (Kareem Abdul-Jabbar’s leukemia translocation), and cell experiments (add active tumor suppressor genes to cancerous cells in a lab dish and see if they return to normal cells).



The first strategy to isolate tumor suppressor genes is DNA mutation linkage to the disease phenotype. Researcher Mark Skolnick 99

Lecture 16: How Do Normal Genes Suppress Tumors?

isolated the gene BRCA1/2 by linkage to a single nucleotide difference between people. 

The second strategy is chromosome analysis. Kareem Abdul-Jabbar had a translocation, a shuffling of the chromosomes, between chromosomes 22 and 9, and this translocation was diagnostic of his disease. Sometimes, DNA damage is not chromosome shuffling, but an actual missing piece of a chromosome, and you can actually see this under a microscope.



In the human genome, there is a chromosome known as chromosome 13, and a piece of this chromosome is sometimes missing in people. Nature allows chromosome deletions in DNA when DNA fails to replicate. In other words, nature is, through some accident, causing a deletion of the chromosome.



By mapping all of the chromosome deletions, we can figure out where a retinoblastoma gene must be—where the tumor suppressor gene must be—because if a person has a deletion of the tumor suppressor gene, then they’re going to have the disease retinoblastoma. That’s how researchers narrowed it down to a very small part of chromosome 13 and then were able to isolate it. This process also has been done with other tumor suppressors.



The third method of looking for tumor suppressors is looking at isolating a gene that might be a tumor suppressor gene and using gene therapy to cure the cancer. It involves taking cancer cells in a laboratory dish and adding what is suspected to be a tumor suppressor gene. We take some breast cancer cells that have a mutation in BRCA1 (and are cancer cells), and if we put them in a mouse, the mouse will get cancer. Then, we take the normal gene and we do a gene therapy by adding the normal gene to the cancer cells, which become normal.

Functions of Tumor Suppressor Genes  BRCA1 is a protein that repairs DNA damage. The tumors affected are breast and ovarian cancer. All cells do not have the same genetic 100

program for repairing DNA damage. Some cells use BRCA1; it’s in the genome. Other cells, even though they have the gene for BRCA1, use other proteins for doing it. Breast and ovarian tissues express BRCA1, so they use it for repairing DNA damage. It’s going to be a tumor suppressor because the DNA will not be damaged, and the cell won’t become a tumor if it’s damaged at the oncogene. 

A gene called p53 is active in most cell types. The cytoskeleton allows cells to move and also gives the cells shape. There’s a gene called APC that’s involved with colon cancer that involves the control of the cytoskeleton, among other things.



Differentiated cells don’t divide, so if you have a gene that controls differentiation in some ways in a tissue and that gene is defective or mutated, then the cell will no longer be differentiated. This is the case of a gene called PTCH in basal cell carcinoma of the skin.



There are tumor suppressor genes for cell adhesion—for example, a CAD gene in stomach. If there are two cells sticking together, then there is a gene that codes for this and a protein that allows the cells to stick together. The protein might be mutated, causing the cells to separate, and they’re going to be more cancerous.



DNA damage due to radiation involves splitting of the DNA, and the damage ultimately leads to cancer. A cancer cell is formed, which grows into a tumor. If DNA is damaged in genes controlling cell division, these mutations can activate oncogenes or inhibit tumor suppressor genes.



In the cell cycle, when cells are dividing, BRCA proteins are repairing DNA and are active during the synthesis phase, when DNA is being made. In other words, BRCA1/2 repairs DNA damage during DNA replication. Mutations in BRCA1/2 cause breast and ovarian cancers. Mutations of other tumor suppressor genes with roles in DNA repair can result in colon and other cancers. In other tissues, other tumor suppressors work to do this same repair. 101

The retinoblastoma (RB) protein blocks the expression of cell division genes. In a normal cell cycle, an activator protein called E2F binds to promoters for cell division, and RB binds E2F to switch it off, stopping cell division. If RB is mutated, it no longer binds E2F, which switches on for uncontrolled cell division, which can result in retinoblastoma, osteosarcoma, and lung cancer.



A related tumor suppressor gene is p16, which codes for the proteins that regulate the cell cycle. Specifically, it makes a protein that binds to the kinase. If p16 knocks out the kinase, then the kinase can’t add phosphate groups to RB. If you can’t add phosphate groups to RB, then RB stays, and the cell cycle is blocked.



When p16 is mutated, the kinase is free to modify RB, which no longer binds, and the cell cycle goes ahead. Because p16 is a tumor suppressor, when it is mutated, you can get cancer. Mutations of p16 occur in pancreatic, stomach, and esophageal cancers.



There are all of these control mechanisms because p16 stops the cell cycle in differentiated cells for pancreatic, esophageal, and stomach tissues. They stay differentiated, or specialized, and they don’t divide. They’re going to have less DNA damage because of p16 because they’re not dividing—and less cancer. In a number of pancreatic, stomach, and esophageal cancers, p16 is mutated, which allows the cell cycle to proceed.



Some tumor suppressor genes prevent DNA damage from being permanent. SV40 infects normal rodent cells and transforms them into a tumor. Researchers

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Lecture 16: How Do Normal Genes Suppress Tumors? 102



In pancreatic cancer and other cancers, p16 is mutated, allowing the cell cycle to proceed.

compared a mutant SV40 that didn’t transform and a good SV40 that did (the “normal” one), and they found that the normal one had an extra gene, or protein, called T (for transformation) that knocks out tumor suppressors. 

If there’s DNA damage, p53 (a molecular Swiss Army knife) gets activated, normally at a low level, and binds to DNA, causing apoptosis (cell death), repairing DNA, and arresting tumor growth—all of which involve preventing cancer. At least 50 percent of cancers have a mutated p53 gene. Other tumor suppressor genes intervene at different points in the cell cycle.



Researchers have figured out how a single mutagen—for example, benzpyrene—binds to a specific region of a specific gene and changes the synthesis of a specific protein, which is p53, so that it doesn’t bind to DNA and so that you don’t get transcription. It’s connected to the cell cycle and blocks the cell cycle.



We now know how cancer gets caused from carcinogen, to DNA, to specific mutation, to inactive protein, and to tumor suppression. Understanding how these tumor suppressor genes work, and what happens when they mutate, should lead to very specific and effective therapies.

Important Term gene therapy: Addition of a natural or artificially made gene to a tumor to therapeutically alter its properties.

Suggested Reading Almeida and Barry, Cancer. Collins, The Language of Life. DeVita, Lawrence, and Rosenberg, Cancer.

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Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. LaFond, Cancer. Sadava, Hillis, Heller, and Berenbaum, Life. Sompayrac, How Cancer Works. Weinberg, The Biology of Cancer.

Questions to Consider 1. A family with many seemingly unrelated cancers at an early age may have a single gene mutation in common. What kind of gene might be involved? Give an example of this kind of gene and how a mutation in it causes cancer.

2. In one type of inherited colon cancer, there is a mutation in a gene that Lecture 16: How Do Normal Genes Suppress Tumors?

encodes a protein involved in DNA repair. How does this mutation result in cancer? Why do you think that this mutation only causes colon cancer and not, for example, breast cancer?

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How Do Genetic Changes Result in Cancer? Lecture 17

T

his lecture will describe the series of events that happens at the molecular level to give rise to cancer. Specifically, you will be exposed to molecular descriptions based on tumor type, including in colon and lung cancer. For many cancers, the specific molecular events are known, and this is the achievement of modern cancer research. In this lecture, you will also learn about the Cancer Genome Project and how it aims to describe all of these molecular changes in tumors of individuals. Then, you will learn about genetic testing and the ethical and legal considerations of this field. The Path to Colon Cancer  Cancer develops in a series of molecular events. The multistep model for cancer progression describes the initiation and growth of cancer as a series of events at the organ, tissue, and cell levels. We can now describe the events inside the cancer cells that underlie these processes, and this is our road to specific, targeted therapies. 

Cancer starts off with mutations happening from bringing in new genes and from mutations due to chemicals and radiation, resulting in an initiated cell. That cell then develops more mutations, leading to a pre-lesion and then a malignant tumor. Then, a clinical cancer gets larger, and a metastatic tumor results. All mutations are accumulated.

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Colon cancer, for example, often develops in a sequence from polyp to carcinoma cells, to cancer, and at each step, there are changes in oncogenes and tumor suppressor genes that accumulate (probably at least six events) on the path to full-blown metastatic cancer.

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The colon is the second to last place besides the rectum where food is after digestion. Most nutrients have been absorbed at this

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The path to colon cancer begins with a small lesion. That lesion begins to grow and eventually grows into a polyp, which is what can be seen in a colonoscopy. In a typical colonoscopy, a physician will thread a camera with a little snipper on the end of it into the colon, and when a polyp is seen, the physician just snips it out and tests it.

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The next step is a full-fledged carcinoma—a cancer. It now has mostly cancer cells. The carcinoma then grows into more advanced stages, and then you can get a stage III or IV metastatic cancer that can spread to elsewhere in the body. Bert Vogelstein and others took samples from each of these steps and described specific genes being mutated at each step.

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In colon cancer, some of the affected genes are APC, which normally binds to a promoter to stop cell division; MLH, which normally repairs mismatch mutations of DNA; RAS, which normally regulates growth factors; DCC, which codes for a cell adhesion molecule; and p53, the “genome guardian” that signals repair of DNA mutations.

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The path to colon cancer involves a polyp in the colon is what can be series of mutations A seen by a doctor when performing a accumulating over colonoscopy on a patient. time. A single mutation event may get it started, like a person born with APC mutation, but a bunch more mutations are needed for cancer to result. The fact that you need

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Lecture 17: How Do Genetic Changes Result in Cancer?

point by the small intestine, and now the stuff that’s in the colon is being concentrated.

a lot of mutations happening over time explains why tumors, even in people who have inherited colorectal cancer, take a long time to develop. The Path to Lung Cancer  Lung cancer develops in stages as well. The lung has tubes, and the tubes end in sacs (little balloons at the end) called alveoli, so there is a lot of surface area. These sacs are lined with cells and blood vessels to receive the oxygen and release the carbon dioxide. Cigarette smoke lands there, and asbestos particles can land there, too. 

You begin with a normal lung tissue with air sacs, and then you can have precancerous cell divisions, lung carcinoma, and invasive lung cancer. People have taken biopsies of all these steps, and they’ve done a molecular biography of lung cancer development. It turns out that there are several genes involved, including a mutation in the p16, RAS, and p53 genes.

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In fact, p16 is a tumor suppressor gene, and when you get a mutation, it allows cell division. RAS is an oncogene, and when you get a mutation, it stimulates cell division. In addition, p53 is a tumor suppressor gene, and when you get a mutation, it allows cell division.

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In all sorts of cancers, we now have the impressive achievement of being able to write their molecular biography at the DNA level— and at the protein level as well, because DNA encodes proteins. This can lead to targeted therapies involving blocking one or more of those steps.

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Sometimes, there aren’t just DNA changes that are permanent; there are epigenetic changes, which are changes in gene expression. An example is the p16 gene. In the p16 gene that’s mutated in colorectal cancer, the promoter in p16 is usually turned on, so it’s a tumor suppressor. The gene is expressed, and it blocks cell division. However, when methylation happens—when methyl groups are put on the cytosines at the promoter—they attract a bunch of proteins 107

that attach to DNA and stop it from being expressed. In lung cancer, the p16 gets turned off, so you don’t get expression and you don’t have any protein being made of p16. Therefore, cell division is not blocked, so it proceeds.

Lecture 17: How Do Genetic Changes Result in Cancer?

The Cancer Genome Project  With cancer, there are both genetic and epigenetic changes that can happen, and these can be detected by modern genome-sequencing techniques. Given everything we seem to know about cancer, how could we go about looking at individual patients for these changes to make diagnoses and to make more detailed descriptions?

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At the cellular level, not all tumors are the same; at the DNA level, they’re not either. There are probably many different mutations in genes, and many different mutations in different people, and these differences lead to differences in clinical course and response to treatment.

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To try to individualize therapy—to try to do target therapy for people’s own genetic problems—there is something called the Cancer Genome Project. The idea of this project is that every tumor is different, and every cancer patient is different. The goals of this project are to identify changes in the genomes of tumors that drive the progression of cancer. By doing that, we can identify new targets for therapy, and we can select drugs for therapy based on the genomics of that particular tumor.

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The goals of the Cancer Genome Project are to obtain a comprehensive description of sequence changes, expression, and epigenetic factors. Researchers are trying to do this in 50 different tumor types and subtypes that are the most important in terms of numbers all around the globe.

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There are many genome projects around the world investigating different kinds of cancer, and many genomes from tumors have already been sequenced. The global goal is to compete and cooperate, but not to overlap.

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A related effort to looking at the DNA sequence is to test for drug sensitivity. Different drugs work on different tumors, and the idea is, as we’re doing the sequencing of DNA, to take cells and biopsies from tumors and screen them for drug sensitivity in the lab. By doing this, we may uncover new mutations that involve resistance or sensitivity to chemotherapy.

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One of the results from the Cancer Genome Project is that tumors have a lot of mutations. Another result is that not all mutations are important to cancer. Some mutations are not in DNA that’s involved with oncogenes or tumor suppressor genes, and even some of them that are involved in oncogenes and tumor suppressor genes are not the drivers that are pushing the tumor to divide. Identifying which are the drivers and passengers is a major challenge. A third result is that tumors are heterogeneous, even among themselves—not just between patients. In other words, different mutations accumulate in different cancers.

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The outcomes of this knowledge are going to be better classification of tumors—for predictors, for prognosis, and for response to therapy. Another outcome is to develop new, targeted therapies. There’s going to be a lot of genetic testing, both of tumors and of people. When genetic testing is done, we need to decide what to do with that information.

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Ethical and legal issues abound in this field, including patent issues on gene sequences and mutations, doctor and patient responsibility in genome testing for susceptibility to disease, and privacy issues. Ethical issues include issues of autonomy, malfeasance, and beneficence and justice. Legal issues include the patenting of gene sequences and DNA.

Important Term progression: Growth of a tumor from a baseline size. Various definitions are used to measure tumor size. Progression is used as an endpoint in some clinical trials. 109

Suggested Reading Almeida and Barry, Cancer. Collins, The Language of Life. DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. LaFond, Cancer. Love and Lindsey, Dr. Susan Love’s Breast Book. Sadava, Hillis, Heller, and Berenbaum, Life. Sompayrac, How Cancer Works.

Lecture 17: How Do Genetic Changes Result in Cancer?

Weinberg, The Biology of Cancer.

Questions to Consider 1. Why was the molecular history of development of colon cancer a major step in understanding and therapy? Which genes involved are oncogenes and tumor suppressor genes, and what are their normal functions? How do you suppose that these genes in colon cells get mutated?

2. According to the World Health Organization, one criterion for a medical test is that the results should provide information for improvement of health of the patient. Is this true (and should it be true) of all medical tests? How do cancer gene tests such as BRCA1 testing for breast cancer fit this criterion?

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Treating Cancer with Surgery Lecture 18

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his lecture discuses the science behind cancer therapy. In this lecture, you will learn how treatments, in general, are curing cancer in some cases and prolonging survival in others. Then, you will learn about cancer treatments and how they are evaluated by clinical trials, which serve as a general introduction to all of cancer therapy. You will also learn about surgical procedures that can prevent and diagnose cancer and how surgical procedures can be the main treatment for cancer. Cancer Treatments  Mastectomy (removal of all breast tissue and lymph nodes) was the standard surgical treatment for almost all breast cancer since W. S. Halsted introduced it over 100 years ago in combination with antisepsis and anesthesia. Clinical trials in the 1970s showed that lumpectomy (removal of tumor and affected lymph node only) was equally successful with fewer side effects for patients, and by the 1990s, surgeons had switched over to the more effective, less invasive procedure, responding to the scientific evidence. Contrary to popular belief, surgical change comes only gradually in response to scientific understanding. 

Treatments can cure cancer or prolong survival. There are 13 million people in America living with cancer, and by 2022, it’s estimated that there will be 18 million people living with cancer. Survival rates for some types of cancer have improved, but the prognosis is still dismal for cancers of the lung, pancreas, esophagus, brain, and stomach.

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The main treatments for cancer include surgery, radiation, and chemotherapy. Surgery is most effective for localized cancers. In other words, if we can get the cancer really early—before it spreads—then surgery can be curative. If the cancer has spread at diagnosis, which unfortunately is the case at least half of the time 111

Lecture 18: Treating Cancer with Surgery

at diagnosis, then regional radiation can be used, and chemotherapy has to be used.

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Clinical trials are conducted to evaluate treatments. Legally, any doctor in America can use any therapy, as long as the doctor has reasonable ideas about the therapy. However, in practice, doctors only use therapies that are scientifically proven.

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The key of therapy is to identify the patient for whom the treatment will work. This is called personalized medicine, and in cancer, we’re working toward that at the molecular level. If we can get DNA mutations that we know happen in a particular patient and then use targeted therapies just for that patient, medicine will be a lot better.

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Clinical trials prove the scientific merit of a new therapy. For example, a clinical trial on lumpectomy versus mastectomy in the breast would involve women who have breast cancer being randomly assigned to one group or another with their consent. Very often, researchers don’t know who is assigned to which group when they analyze the data.

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Clinical trials are used to evaluate cancer treatment protocols and may be interventional (two competing protocols) or observational (people are given treatment and observed). In both cases, the key points are survival, disease progression, and response (tumor shrinkage).

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Groups are carefully matched for many traits, such as tumor type and stage, and informed consent must be obtained. Informed consent means that the patient knows why they’re participating in the trial, what the potential results could be, and what the potential drawbacks or side effects could be of the experimental therapy.

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Typically, clinical trials begin after preclinical research, which often involve testing on animals. Human clinical trials go through three phases to study maximum tolerated dose: safety, side effects,

and effectiveness compared to current standard therapies—referred to as phases I, II, and III, respectively. 

In phase I, which typically includes 20 to 80 patients, we’re looking for safety and side effects of the drug. Typically, these are patients with an advanced stage of the target cancer for whom other treatments have failed. We’re not looking for a cure with these patients; instead, we’re looking to see if the maximum tolerated dose works a little bit.

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If a drug passes phase I, it’s not toxic, and it looks like it’s doing some good, it might go to phase II, which involves about 100 to 300 patients with a specific cancer who may or may not have been treated. We’re looking for effectiveness.

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Phase III, which includes several thousand patients, involves control and experimental groups that we hope are equal in every way except treatment by this medication, or radiation. In this phase, we’re looking for side effects as well as effectiveness.

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The long road to therapy starts with basic research, and then it goes to preclinical and clinical development and FDA filing. It is a long and expensive process, costing in the range of hundreds of millions of dollars.

Surgical Procedures  Surgical procedures are sometimes used to prevent cancer. For example, an operation to descend an infant’s undescended testis may prevent later testicular cancer; or, where a mutated BRCA1 gene is present, surgical removal of breasts and ovaries may be indicated. 

Cancer is diagnosed, over 90 percent of the time, by surgery. There are a bunch of ways to do this. You can take a needle or a tube if it’s in a lung (as in a cancer of the lung). The cells will be floating sometimes in fluid of the lung. Just take a syringe and draw out some of the fluid. The tissue is broken up. It’s hard to get intact groups of cells, but you can do it. 113

More than 90 percent of all cancers are diagnosed by some form of biopsy: needle aspiration, core needle biopsy, incisional biopsy (piece of tumor), or excisional biopsy (entire tumor—e.g., mole).

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More than 60 percent of all cancers are treated by surgery at diagnosis. The key to successful surgery for cancer is localization and absence of metastases because if the tumor is treated at a localized stage, and there is no metastasis present, it can be curative.

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Advantages of surgery are that the tumor has no biological resistance to it; unlike radiation and chemotherapy, there are no carcinogenic side effects; tumor heterogeneity is not an issue; and if the cancer is localized, surgery can affect a total cure. Disadvantages include the unintended removal or damage of normal tissues, loss of normal function, and increased growth of metastases if the tumor is not localized.

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There are many highly specialized surgical procedures for cancer. The trend is smaller, less invasive surgeries that are not as

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Lecture 18: Treating Cancer with Surgery

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Often, prostate cancer involves a slow-growing tumor, so most patients with prostate cancer do not die of it. 114

disfiguring and involve minimized incisions, such as lumpectomy and laparoscopy. 

Doctors are doing robot surgeries, where he or she sits by a computer console and manipulates the robot to do the surgery. The advantage of the robot is usually to reduce hospital stays. Very often, it involves a smaller incision in some surgeries. In addition, it reduces blood loss if the doctor is very careful.

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Robotic surgery is being heavily marketed, but so far, there is no proven benefit for survival. It is more expensive because the robots cost a lot of money, so a cost-benefit analysis needs to be conducted to determine whether robotic surgery is used.

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The question of whether to do surgery when cancer is found is sometimes a very difficult one. If a small tumor, like a prostate cancer, is found in the prostate, then the prostate cancer may be an indolent, or slow-growing, tumor. Because of its slow rate of growth, the patient will probably die of something else before dying of prostate cancer.

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The problem is that we sometimes don’t know which tumors are the ones that are rapidly growing and slow growing. Perhaps as time goes on, molecular signatures will help, as they did for breast cancer. A gene expression signature can be used to stratify patients who might need surgery. Surgery beliefs will yield to changes in practice as science progresses.

Important Terms clinical trial: Experimental treatment of a group of patients under carefully controlled conditions to determine the effectiveness of a new treatment. phases I, II, and III: In clinical trials for new therapies, the sequence of protocols needed before a drug or other modality is approved for use as standard care. In phase I, patients with the disease are given the therapy to determine toxicity and tolerability of the dose. In phase II, a small number 115

of patients are given treatment while others are given no treatment, and effectiveness and side effects are evaluated and compared. In phase II, a large number of patients are given treatment or no treatment, and the results are compared.

Suggested Reading Davis, The Secret History of the War on Cancer. DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. Inber, Genius on the Edge. Love and Lindsey, Dr. Susan Love’s Breast Book. Mukherjee, The Emperor of All Maladies. Sadava, Hillis, Heller, and Berenbaum, Life.

Questions to Consider

Lecture 18: Treating Cancer with Surgery

1. Breast cancer surgery has evolved recently to become less invasive, in many cases. Are there other cancer surgeries with a similar pattern? Are you aware of advertising for less invasive surgeries? What do the ads claim as advantages?

2. Many people, especially those afflicted with cancer and their caregivers/ relatives, are impatient at the slow path and resulting high cost—from discovery in the laboratory to reality—of cancer treatment. Do you think that the three phases for clinical trials are appropriate?

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Treating Cancer with Radiation Lecture 19

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his lecture reviews how radioactivity damages cells, but this time, the focus is specifically on cancer cells. Radioactivity causes mutations, and the process of radiation therapy causes mutations in cancer cells—with the hope that the cancer cells will die. You will also learn about the issue of overcoming the repair mechanisms that cells have when they are damaged by radioactivity. In addition, you will learn how radioactivity is involved with stem cell transplantation for high doses of radiation and chemotherapy. Damage to Cancer Cells by Radioactivity  Radiation, like surgery, can cure a localized cancer, and it is also used as an adjunct to other treatment methods. Radiation is energy released from atomic decay, which can destroy both normal and tumor tissues. X-rays and gamma rays are two kinds of radiation used to treat cancer, but recent advances include a proton beam that can focus its highest energy specifically on the tumor. 

The photons that come out of ionizing radiation are very strong. The energy that is released from a photon of a radioactive element is energetic enough to knock an electron out of its orbit. The photon can interact with an electron in another atom, scattering that electron and causing it to become energetic. The process of removing electrons from chemicals makes them highly reactive. The cell is going to get damaged terrifically by electrons traveling around with no place to go.

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On the other hand, some of the energy that is released will get scattered as more photons, so it is a cumulative effect. There is an extensive group of changes that are going to happen with radiation. Radiation damages not only DNA, but it also damages the entire cell.

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Lecture 19: Treating Cancer with Radiation

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Radiation, with these free electrons, damages the membrane of the cell, which is very important to the integrity of the cell. The membrane is involved with cell recognition and determining what gets in and out of the cell. Extensive damage to cell membranes by free electrons damages proteins in the cell. The free electrons that are energetic will bind to proteins and completely change their property, which changes its overall three-dimensional structure and its function.

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Radiation will break the bonds, called hydrogen bonds, that hold the two strands of DNA together. The way that the two strands of the double-stranded helix of DNA fit together is by having a weak attraction to each other through a hydrogen bond. Radiation breaks those bonds so that DNA, which used to be all nicely curled, is now flopping around.

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DNA irradiation will cause permeating dimers, which result when two adjacent bases bind to each other on the same strand. Then, when DNA replication tries to happen, it can’t make the proper bases because they are askew.

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Radiation causes proteins to become cross-linked to the DNA so that the DNA can’t unwind. Most notably, it causes double-strand breaks in DNA, where both strands of the DNA are broken, and bases are removed.

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The high energy of radioactivity disrupts all kinds of cell activity at the molecular level, not just DNA. Radiation can be beamed at a tumor from outside of the patient (teletherapy), where dose shaping and shielding of normal tissue are important. Radioactive “seeds” can be implanted directly at the tumor site (brachytherapy); these are often used in brain and abdominal tumors.

Radiation Therapy  The key in radiation treatment is how much are the target cells getting of energy, in terms of gray (Gy), which is equivalent to one joule/kg. One gray in a cell will produce 100,000 ionizations, or 118

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Lifetime exposure of radioactivity for a typical person in our society, who is exposed to some cosmic rays and medical radiation, is 1/6 of a gray.

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In radiation treatment, typically the whole treatment scheme is 60 Gy, which is 100 times the lifetime exposure, and you’re getting it in a very short period of time. It’s a whopping amount of radioactivity.

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Radiation therapy has to overcome the tendency of a cell to repair damage. The challenge for radiation therapy is to kill all the tumor cells without killing all the normal ones. Fortunately, normal cells divide slowly and repair damage to DNA; cancer cells divide rapidly, so repair is less effective.

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At 21 Gy, 99.9 percent brain surgery is very of tumor cells are killed, Because complex, radiation therapy is often but so are 93 percent of used to treat cancer in the brain. normal cells—which is too much collateral damage. One method to improve this result is dose fractionation, giving smaller doses spread out over time, so that normal cells have a better chance to repair. The smaller dose will be repaired in normal cells fully, but the tumor cell doesn’t have a chance to repair it, so it’ll be damaged. Then, you give another smaller dose, and the normal

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releases of electrons. It will also produce approximately 100 singlestrand breaks of DNA and 40 double-strand breaks of DNA, and 90 percent of the cells will die.

Lecture 19: Treating Cancer with Radiation

cells repair it, but the tumor cell is damaged, so it’ll become more damaged.

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The overall dose of 60 Gy will typically be divided over a period of about five weeks, and the patient will go in every day for five weeks and get a smaller dose of radioactivity. However, a tumor that is about a centimeter in diameter is made up of about a billion cells, so even if you kill 99.9 percent of the cells, there are still 10,000 tumor cells left.

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A key to radiation therapy, or any medical therapy, is the therapeutic index, which relates damage to the normal cell as compared to damage to the tumor cell, in this case. The therapeutic index shows the dose/response curve.

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The dream of oncology, or any area of medicine, is to have no normal tissue damage in targeted therapy, for example, and a tumor being completely damaged. If you do surgery correctly and take out the whole tumor—and nothing else—that’s great targeted therapy because there’s no collateral damage.

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Different tumors have different sensitivities to radiation damage. Leukemia and lymphoma have high sensitivity, but breast, kidney, and pancreatic cancers have a low response. Brain cancer is a major challenge, and treatment has a very narrow therapeutic index because brain tissues are extremely sensitive.

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If we want to improve the therapeutic index, we can fractionate the dose or protect normal tissues around the tumor by doing brachytherapy, for example. In addition, there are chemicals that make tumor cells more sensitive to radiation. There are radiation sensitizers that only tumor cells will take up that will make them more sensitive—to widen the gap in the therapeutic index curve.

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Overall, radiation is used sometimes as a primary treatment where it can cure cancer in some cases. Usually, radiation is used after surgery or along with chemotherapy as an adjuvant.

Stem Cell Transplantation  Stem cell transplantation, which uses radiation treatment, was developed to treat people exposed to radiation in war, but it was soon discovered that the transplants could help with bone marrow rescue in certain cancers. The idea for bone marrow transplant is to give a massive dose of radiation and/or chemotherapy to kill the tumor (and every other dividing cell in the body), and then replace the marrow by stem cell transplant (stored from self or others). 

The tumors that could be treated with transplantations no longer include just bone marrow; instead, they range from blood cancers to neuroblastoma. However, transplantation doesn’t work that well on solid tumors for a number of reasons.

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Leukemias and lymphomas have been very successfully treated by this method. We can now get stem cells for blood. There are some stem cells from the bone marrow that produce a bunch of white and red blood cells that leak out into the general circulation, so we can get them there and purify them out of a patient as well.

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You can take stem cells from either blood or bone marrow and store them in the refrigerator. Then, you can treat the patient with a high dose of radiation or chemotherapy, and finally bring back and rescue the bone marrow.

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Stem cell transplants can be syngeneic (identical twins), autologous (self donor), or allogeneic (donor genetically different). To get a good match for an allogeneic donor, huge databases are needed. If the match isn’t good enough, the immune system will reject the cells.

Important Terms oncology: The study of cancer as a disease. A medical oncologist is a physician who treats cancer, usually with medications. A radiation oncologist uses radioactivity, and a surgical oncologist uses surgery.

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stem cell transplantation: Replacement of bone marrow stem cells destroyed by cancer chemotherapy or radiation. The new cells may be either from the treated individual (stored previously) or from a donor whose cells are genetically similar to the recipient. therapeutic index: A mathematical comparison between damage done to cancer cells and to normal body cells at a given dose of therapeutic agent. The wider the therapeutic ratio, the more effective the treatment. A major goal of cancer treatment is to widen the therapeutic ratio.

Suggested Reading Cantor, Cancer in the Twentieth Century. Davis, The Secret History of the War on Cancer. DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. Love and Lindsey, Dr. Susan Love’s Breast Book.

Lecture 19: Treating Cancer with Radiation

Mukherjee, The Emperor of All Maladies. Schimmel, Cancer on Five Dollars a Day.

Questions to Consider 1. Like other scientific knowledge, the field of radiation and cancer has both good and bad aspects. What are the beneficial and harmful effects of radiation in cells? How do the management and schedule of radiation therapy minimize the harmful effects of radiation?

2. When a cancer patient needs blood stem cell transplantation, there is often a desperate search for a genetically appropriate donor. Should testing and registration of our blood surface protein markers be required at birth (although donation for stem cells would be optional)?

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Treating Cancer with Drugs Lecture 20

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his lecture describes chemotherapy in several ways. First, it discusses the pathway taken by a drug to the tumor, which is a multistep process. Then, it describes cancer combinations of chemotherapy, and you will learn why, when you see a person getting cancer chemotherapy, there is typically more than one drug used to treat it. In addition, you will learn how drugs are developed from nature, along with an example of a cancer drug that came from nature. The Pathway Taken by a Drug to a Tumor  The modern era of cancer chemotherapy can be traced in part to the discovery of nitrogen mustard, a chemical warfare agent, as an effective treatment for cancer in the 1940s. 

Primary chemotherapy is the initial treatment for localized cancer. Typically, if a cancer is localized, a doctor might try to shrink it with chemotherapy prior to surgery. Induction chemotherapy is treatment for advanced cancer, which is typically metastatic (spread). This is the most common use of chemotherapy. Adjuvant chemotherapy is treatment after another method is used as primary treatment. For example, a surgeon might remove a breast cancer, and then chemotherapy is given to affect other locations for the tumor in the body.

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Pharmacology is the study of drugs and their interactions with human or animal bodies. This is opposed to pharmacy, which is the preparation and dispensation of drugs. Pharmacology is the scientific study of how drugs work.

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The effectiveness of chemotherapy against cancer depends on several factors: the biology of the tumor (sensitivity to chemotherapy), the pharmacology of the drug, and the patient’s condition and tolerance for side effects. 123

Lecture 20: Treating Cancer with Drugs 124

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One of the important aspects of the effectiveness of chemotherapy— the key to tumor biology and the pharmacology interaction—is the selectivity of the drug. You want the drug to kill the tumor and not the normal cells. Unfortunately, in the real world, the therapeutic window is very narrow, and we damage a lot of normal cells when we damage tumor cells.

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As with radiation, the therapeutic index is critical. Tumor cells are typically more sensitive to chemotherapy than normal cells for several reasons. Tumor sensitivity to a drug may be increased if the tumor DNA is already damaged (and more damage will kill it). If it is rapidly dividing, it may be more sensitive than normal tissue to damage by cell division molecules. If the tumor produces new proteins, they may be targeted by a drug. Finally, tumors are more likely to have poor DNA repair.

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If you take a drug, including cancer chemotherapy, the drug has a lifecycle in the body. We can plot how much of the drug is in the blood plasma—because that’s where it all ends up because it’s transported all over the body—over time. If you take a drug and it gets into the stomach, and ultimately goes into your intestines, it gets into the blood system. Depending on the drug, the time could be minutes or hours.

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There is a great increase after you take the drug because it takes time for it to get into the blood and reach a maximum level, and then it disappears over time. It’s very important to know how much that is for how long because when you give a cancer patient a drug, you want to know how long it’s going to be around.

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There are two processes in pharmacology that cause the drug to disappear over time: pharmacokinetics, what happens to the drug as it goes through the blood system; and pharmacodynamics, what happens to the drug when it reaches the tumor.

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If a drug is given orally, then there is an extra set of parameters to consider because it gets into the stomach, dissolves there, gets

into the intestines, and then gets into the blood—and all of those parameters have rates of reaction. On the other hand, many cancerfighting drugs are given intravenously in the clinic, which involves an IV going into a vein and then directly into the blood. 

Once the drug is in the blood, given all the roadblocks that can happen to get it there, there are several questions. For example, is there a good enough blood system in the tumor to get the drug there? How does the drug enter the cells? What happens to the drug inside the tumor cells? How does a drug get to its target? All of these questions can be described mathematically. We must know the answers to these questions as we are giving therapy to a patient.

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For drugs to be effective, the blood supply to the tumor (angiogenesis) must be sufficient; the drug must be able to cross the cell membrane and, in some cases, get into the nucleus of the cell itself.

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There are genetic differences in drug sensitivity from person to person. Some people have genes for high activation for liver conversion of drugs, while others have low activation. A genetic test to determine a person’s individual genotype can lead to more personalized medicine affecting how the drug is administered, how often to give it, and what dose to give.

Combinations of Drugs  Many cancer drugs are given in combinations. In early clinical trials in chemotherapy, some were very variable. There were very few cures; very few people went into remission. The reason was that tumor cells are not all alike. There are new mutations that happen in a tumor as the tumor grows. Some tumor cells are stem cells that could cause tumors while others are not. 

This leads to the idea of heterogeneity of the tumor—the idea that different cells respond to different agents. Selecting which drugs to use is often empirical, but there’s also logical reasoning. Different drugs treat different phases of the cell cycle, for example. 125

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Lecture 20: Treating Cancer with Drugs

Herbal medicine can be used to treat cancer, but this type of treatment is usually not tested in rigorous clinical trials.

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As a result, cancer drugs are often given in combinations rather than singly. In Hodgkin’s lymphoma, researchers found that a single drug was nowhere near as good as combinations. Hodgkin’s lymphoma is one example where great progress has been made with drug combinations.

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Remission, typically measured after five years, means that you can’t find any tumor visibly by normal techniques. It doesn’t necessarily mean there are no tumor cells; they might be hiding out. Cure means that there’s no tumor after 10 years. Tumor control means that the tumor is still there, but it’s not growing. In chemotherapy, there are very few cures. Overwhelmingly, doctors are shooting for short-term remissions.

Nature’s Drugs  Many cancer drugs come from nature. Plants produce many, many molecules for self-defense against cancer-causing chemicals that are found in nature. Plants can’t run away, so they produce toxins. 126

Some of these toxins damage DNA, and they cause cancer. The thinking is that if they damage DNA, then maybe they’re useful to treat cancer. 

The starting point of our investigation for a lot of chemotherapy is medicinal plants that have been used for millennia by traditional cultures. Over 21,000 species of plants have been used as herbal medicines that we know of.

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Very often, herbal medicine focuses on the whole body, and Western medicine focuses on the biology of a specific disease. For example, the Chi in Chinese medicine is a body function—the life force—and we’re redistributing the life force when we treat cancer by manipulating the Chi using herbs.

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Scientists are wary of herbal treatments for cancer because they are often not tested in random, double-blind studies, and their mixtures may not be controlled for content. Herbal medicine is usually not tested in rigorous, controlled clinical trials, so it’s very hard to tell what the herbs are doing. In addition, herbal medicines are mixtures that contain thousands of substances, including the ones that you want, and they might be interacting with each other.

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Some plant medicines have proved effective against cancer, including Taxol from the Pacific yew tree. Taxol works by “freezing” the microtubules in cancer cells into bundles so that they cannot organize cell structure. The microtubules are needed for cell division, so the tumor cannot grow. In clinical trials for ovarian cancer, Taxol extended life by 50 percent and is now used for many cancers as part of combination chemotherapy.

Important Terms combination chemotherapy: Simultaneous use of several drugs, each directed at a different target to treat a disease. Most cancer chemotherapy uses combinations.

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pharmacology: The scientific study of drugs and their interactions with the body (as opposed to pharmacy, which is the formulation and dispensing of drugs). Pharmacology includes pharmacokinetics, describing events occurring before a drug enters a targeted cell, and pharmacodynamics, describing events occurring after a drug reaches a targeted cell. Both must be fully understood for the development of effective cancer-fighting drugs.

Suggested Reading Airley, Cancer Chemotherapy. Cantor, Cancer in the Twentieth Century. Davis, The Secret History of the War on Cancer. DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. Love and Lindsey, Dr. Susan Love’s Breast Book. Mukherjee, The Emperor of All Maladies. Sadava, Hillis, Heller, and Berenbaum, Life. Lecture 20: Treating Cancer with Drugs

Schimmel, Cancer on Five Dollars a Day. Scotting, Cancer.

Questions to Consider 1. One of the original goals of the Human Genome Project was to identify people with different sensitivities to drugs that can treat diseases such as cancer. Should we all get such genes identified, and should testing be done before any person gets drug therapy?

2. After examining the pathway from drug to cancer cells, do you still need to wonder why cancer drugs are so expensive? Can you trace some of the steps in the pathway for a substance that occurs in nature? Should cancer drugs receive a long period of patent protection?

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How Do Drugs Attack Cancer? Lecture 21

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n this lecture, you will be exposed to some specific examples of cancer chemotherapy drugs—which is by no means an exhaustive discussion, but a discussion to show you some of the science behind some typical drugs. You will be introduced to drugs that attack DNA and drugs that attack other cell processes. Then, you will learn about the horrible part of chemotherapy: the side effects and resistance to chemotherapy. Finally, this lecture will cover the most optimistic aspect of chemotherapy: targeted therapies. Drugs That Attack DNA  Tumors grow for two reasons: rapid cell division and reduced cell death. Therefore, any drug that stops or reduces tumor cell division or increases tumor cell apoptosis can be effective in treating cancer. Drugs that promote cells to go into programmed cell death, or apoptosis, are called cytotoxic drugs. 

It’s largely empirical which drugs work on which tumors. Physicians have a lot of drugs that can stop cells from dividing, and they try different ones on different tumors. However, sometimes it’s quite rational as to which drugs are assigned, and this is where targeted therapy comes into play.

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Drugs that target DNA either target the building blocks of DNA—A, T, G, and C—or they target the DNA structure itself. Foods are digested in the body to make the chemical building blocks of foods, and then these phenomenal chemical changes happen, and we make A, T, G, and C. This type of conversion happens inside both normal and tumor cells. For example, thymine, or T, is one of the building blocks of DNA. Food breaks down into a number of molecules, and then a molecule in the cell can be converted into T as the final product.

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Lecture 21: How Do Drugs Attack Cancer? 130

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The conversion of molecules in the cell involves two things: an enzyme, a protein that hastens the reactions; and very often a vitamin, a helper that assists with the chemistry. The vitamin is a derivative of folic acid, which is converted to a molecule called tetrahydrofolate in the body. In the conversion of this molecule of the cell to T in DNA, only one chemical change happens—the addition of a methyl (CH3) group, which the vitamin carries and hands off to the precursor molecule to get T.

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Without T, the cell dies. We need to manipulate this system to stop T from being made because if we block one of the building blocks of DNA from being made, DNA will not be made, and the cell can’t divide—and it will probably go into programmed cell death. A drug called methotrexate stops that conversion. There is no methyl group because there is no tetrahydrofolate. When the reaction tries to happen, it can’t, because it can’t make T, and the cell dies.

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Methotrexate is being used for breast, skin, neck, and lung cancers, and also for arthritis. The problem with this drug is that folic acid (tetrahydrofolate) is used in a number of other important chemical conversions besides making the building block of DNA, so there are going to be a lot of side effects.

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We need to find a drug that will be able to treat cancer cells and stop them from dividing, making T by blocking this in another way. In fact, there is a molecule that looks like tetrahydrofolate but that fools the enzyme: 5-fluorouracil blocks the conversion to T directly and is used widely in cancer chemotherapy. It can be given intravenously or in an oral pill called capecitabine.

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Some drugs essentially bind directly to DNA and alter its function. In order for DNA to function, those two strands of DNA have to separate, and they have to be available. To make a region of DNA available for duplication of DNA or expression, we have to dig into the cell and get a small piece of DNA up to the surface, with the help of an enzyme called topoisomerase.

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Drugs that bind directly to DNA include etoposide from the mayapple plant, which freezes onto a protein that unknots DNA during replication. The strand breaks, leading to apoptosis (cell death). Cisplatin acts by blocking the DNA strand separation needed for DNA expression and replication. Other DNA targeting drugs include cyclophosphamide, doxorubicin, and iniparib, all of which cause errors in DNA replication or repair.

Drugs That Attack Cell Processes  Some drugs attack cell processes. One of the cell processes that is important is cell division, which involves railroad tracks called microtubules. These railroad tracks are laid out, and the railroad car is a chromosome that moves along the railroad tracks. Taxol bundles the tracks so that they’re not available. In other words, it freezes the microtubules needed for cell division. There’s a whole series of other drugs that essentially stop these from being built. 

The microtubule, a long tube, is made up of protein building blocks, and the chromosomes move along the protein tube. Vincristine, for example, which comes from the periwinkle plant, is a natural product, and it was used for over a century in therapy—not chemotherapy for cancer, but for other purposes. Vincristine stops the microtubules from being made, which results in no railroad track, no chromosome movement, and no cell division.

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Other drugs target hormones. Many cancers are stimulated by hormones. For estrogen-replacement therapy in endometrial and breast cancer, for example, estrogen acts by a hormone binding to a receptor protein, which is highly specific for the hormone. Then, the hormone acts, and the receptor protein goes into the nucleus and alters gene expression, resulting in cell division.

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If we could block this interaction between the hormone and the receptor—that is, a molecule that will fit into the receptor, but that does not cause the receptor to be activated—then the estrogen can’t bind.

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Drugs that target hormones include tamoxifen, which blocks estrogen binding to its receptor, like a key that doesn’t turn a lock. A similar drug is used to treat prostate cancer in men. Aromatase inhibitors like anastrazole block estrogen manufacture in the body. Drugs like these are used both in terms of cancer treatment and prevention.

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Sometimes, tumors develop resistance to the drugs that target them, possibly through additional mutations or through selective growth of previously resistant cells, once the weaker ones are weeded out.

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Some tumors have many One of the side effects of chemotherapy, which blocks mechanisms of resistance, and cell division, is hair loss. it is difficult to circumvent all of them: decreased drug uptake by cells (major problem), decreased drug activation and/or increased drug deactivation, increased repair of tumor cell damage, and alteration of the target by mutation (leukemia drug Gleevec).

Targeted Therapy  Most targeted chemotherapy is quite specific; Gleevec, for example, targets the product of a “fusion gene” from the chromosome shuffling in a certain kind of leukemia. It can’t help in other kinds of cancer.

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Lecture 21: How Do Drugs Attack Cancer?

Side Effects and Resistance  Side effects to chemotherapy can be very debilitating and limit patient tolerance to treatment. Drugs that interfere with tumor cell division will also affect gut, bone marrow, skin, and hair. In addition to hair loss and fatigue, nausea is another common side effect to chemotherapy. Some side effects can be treated; others cannot.

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Kidney cancer, a notoriously difficult tumor to treat, has two major characteristics: an extensive blood supply (angiogenesis) and the ability to activate a cell-signaling pathway. One new drug, sunitinib, actually inhibits both of these factors. The tablet form has relatively few side effects and leads to significantly improved survival rates.

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In recent years, the evolution of drug treatment has advanced from just stopping cells from dividing and killing them (nonspecific) to more targeted therapies. There are many targets that are available to treat cancer, including steroids, Herceptin, and proteins expressed on breast cancer, etc. However, the difficult thing to determine is which tumors have which target.

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There are smart cancers and stupid cancers. Chronic myelogenous leukemia, for example, is a stupid cancer. It has a single important mutation and very few other mutations. You can take a single agent, knock it out, and it doesn’t have resistance. Unfortunately, most tumors are smart cancers. They have multiple mutations, and the more we do genome sequencing, the more mutations we find. You will need multiple targeted therapies, and resistance is very common.

Suggested Reading Airley, Cancer Chemotherapy. Bazell, The Making of Herceptin. Cantor, Cancer in the Twentieth Century. Davis, The Secret History of the War on Cancer. DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. Love and Lindsey, Dr. Susan Love’s Breast Book. Mukherjee, The Emperor of All Maladies. Sadava, Hillis, Heller, and Berenbaum, Life. 133

Schimmel, Cancer on Five Dollars a Day. Scotting, Cancer. Vasella and Slater, Gleevec.

Questions to Consider 1. Why are there so many side effects and resistance to conventional chemotherapeutic drugs? How do patients and physicians deal with the side effects?

2. What is targeted therapy for cancer, and how does it compare to

Lecture 21: How Do Drugs Attack Cancer?

conventional chemotherapy? Do you think that ultimately all cancer drug therapy will be targeted? Is it a reasonable objective to make cancer a chronic disease, like arthritis?

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Frontiers of Cancer Treatment Lecture 22

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n this lecture, you will learn about two aspects of cancer treatment that are at the forefront of cancer research: the immune system being harnessed for cancer therapy and antibodies being used as treatments for cancer. In addition, you will learn about cancer gene therapy. Knowledge and science are resulting in new therapies and optimism, but while these new therapies are developed, we can act to detect cancer early enough for current treatments to be effective—and even prevented by avoiding certain activities. The Immune System  Two issues are at the frontiers of cancer treatment: effectiveness and cost. New treatments that can cure a tumor or significantly extend survival may be prohibitively expensive. 

The human immune system has two roles: to recognize foreign substances, which are substances that are normally not part of your body, and then to mobilize cells and molecules in the immune system to reject that foreign substance. The three steps in these two functions are recognition, mobilization, and rejection.

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The foreign substance is called an antigen, which is a group of atoms linked together in a specific way. For example, atoms on a toxin from a bacterium, like the botulinum toxin, has a unique shape, and we don’t have some of those atoms in our body—only the bacterium has it—so the immune system will recognize that and respond. In other words, the antigen provokes a response by the immune system.

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There are two branches to the immune system: the cellular immune system and the humoral immune system. The immune system is present in lymph nodes, in cells in the blood, and sometimes in the skin. However, the body has to know that the antigen is there, 135

Lecture 22: Frontiers of Cancer Treatment

so there are cells in the body whose job it is to put a flag of an antigen on their surface so that the immune system can respond to the foreign substance.

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A T cell is a helper cell that recognizes a foreign substance and sets off a specific response to that foreign substance. First, there are cells in the humoral system called B cells, the cells in the blood serum itself, that make antibodies against the substance if it is hanging out in the blood. Second, there are cells in the cellular response, T cells, that essentially kill any cell that has this substance on it.

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We can get rid of the substance itself using B cells, or the antibodies, and we can kill the cells using T cells. There are tens of hundreds of millions of different combinations of atoms that are going to be foreign to your body, and each person’s system might be different than another person’s. The atoms that you regard as foreign might be different than the ones that someone else regards as foreign, but we all still have specific cellular and humoral responses that make antibodies that will bind highly specifically, like a lock and key, to any specific grouping of atoms.

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After mobilizing, the recognizing cells send their signals to their siblings to rapidly divide to form a clone of identical cells, and the clones kill cells that contain the foreign substance, or the antigen in the blood.

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In cancer, very often the body makes new proteins—there are mutations. The body makes a brand new fusion protein, and the immune system might recognize that protein. However, that protein is hiding out inside a cell. Unless that cell breaks open somehow, it’s going to be hard to display it.

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Because tumors make new proteins, they can be recognized by the immune system as foreign. However, many tumors have evolved to evade immune system surveillance by hiding their antigens. One strategy is to harness the patient’s own cells to reject the tumor, by cultivating them in the lab and adding both an immune stimulant

and the targeted antigen and then reinjecting them into the patient. Another strategy is just to inject copies of the hidden antigen directly into the bloodstream and let the immune system take over. 

Cancer vaccines are also being developed. MUC1 is a gene that is overexpressed in many tumors: lung, breast, colorectal, and ovarian. One strategy is to encapsulate the exposed part of MUC1 and inject it into the body as an antigen. The immune system now recognizes it as foreign and responds. Lung cancer trials with this method produced an amazing 17-month increase in survival in a cancer that usually kills in 24 months. Vaccines are also being developed for liver and cervical cancer.

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Another way to stimulate the immune system is, essentially, to stop it from getting tired. When you react to something that enters your body and you mobilize the immune system to kill whatever is there, the immune system then shuts down, demobilizing the army. The protein that does this on T cells, which are the keys to the immune response, is a protein called CTLA-4, which acts as brakes on the immune system. When the system is no longer needed, it essentially allows those cells to go into programmed cell death.

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If you block the CTLA-4, this molecule that tells the immune system to stop, you’ll get a stronger response. A drug called Yervoy has been developed that stops the CTLA-4 from acting, and as a result, the immune system keeps fighting the cancer. Results of this drug have shown that patients are indeed living longer.

Antibodies  In addition to looking at the cells of the immune system, we can harness these antibodies, which have specific three-dimensional structures, and they will bind to any of the antigens that are in the blood system. 

In the context of immune therapy, one targeted therapy involves a drug called Herceptin that attacks breast cancer cells that have too much of a certain protein, HER2, with an antibody protein that binds 137

Lecture 22: Frontiers of Cancer Treatment

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In addition to Herceptin, there are now antibodies that you can use against many cell surface molecules in many different types of cancer. For example, attack cancer cells by binding Avastin binds the Antibodies highly specifically, like a lock and key, to a signaling molecule particular grouping of atoms. VEGF that is needed for essentially growing up angiogenesis. There is a molecule called Erbitux that binds in another receptor that is in skin and colorectal cancer. Rituxan blocks a receptor in lymphoma cells that stimulates them to divide, so it’s used in treatment of lymphoma. All of these drugs are widely used in a lot of different tumors.

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In addition to antibodies just binding to the cell and stopping the normal stimulant from binding, or acting in some other way, you could couple the antibody to something poisonous—just to ensure the death of the cell. Radioimmunotherapy involves taking the antibody and adding to it a radioactive substance—a targeted “smart bomb.” When the antibody binds to the receptor on the cell surface, it will not only stop the normal stimulant from binding, but it will also fry the cell itself.

Gene Therapy  Cancer gene therapy is still in its very early and primitive stages and is used chiefly on very sick patients who have not benefited from 138

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to the HER2 antigen on the cell surface and destroys the cancer cell. Over a five-year period, 85 percent of the patients will survive whereas 67 percent wouldn’t before, resulting in a 30-percent improvement in survival. This is a lot of people because it is associated with breast cancer, an aggressive form of cancer.

standard therapies. There are three types of gene therapy: mutation compensation, RNA interference, and tumor-specific viruses. 

Mutation compensation attempts to add a good gene to overcome the bad one. This can be useful with tumor suppressor genes that have been switched off. Researchers attached a healthy p53 gene to a virus and sprayed it into a diseased lung with some limited success.

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RNA interference selectively turns off oncogene expression to prevent translation of mRNA. This works in mice, and human clinical trials are beginning.

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Tumor-specific viruses are being genetically engineered to delete the part of DNA that encodes the viral protein that binds the tumor suppressor p53. This therapy has already shown promise in colorectal cancer, and numerous similar viruses are going into clinical trials. This idea of targeted tumor-cell killing is the leading edge of cancer therapy.

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Cancer still kills 500,000 people per year in the United States and seven million people worldwide, but scientific research is leading to new therapies and greater optimism about the future. Meanwhile, we can do things to detect cancer early enough for current treatments to be effective and even prevent some kinds of cancer.

Important Term translation: The synthesis of a chain of amino acids as a protein in response to the information of a nucleotide sequence in a gene as appearing in mRNA.

Suggested Reading Collins, The Language of Life. DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8. 139

Love and Lindsey, Dr. Susan Love’s Breast Book. Mukherjee, The Emperor of All Maladies. Sadava, Hillis, Heller, and Berenbaum, Life.

Questions to Consider 1. Look up the story of Erbitux, an antibody that is used to treat several cancers. What lessons are there in this story, both from the biomedical and business aspects?

2. Gene therapy for cancer has been proposed for several decades, yet

Lecture 22: Frontiers of Cancer Treatment

progress has been slow. Why do you think this is true, and is further work in this area warranted?

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Can Screening for Cancer Be Useful? Lecture 23

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o far, this course has described how cancer develops in the body; it has guided you to take a look inside cancer cells for their secrets. This lecture will circle back to the beginning of the course, to populations, and look at cancer screening. In this lecture, you will learn about screening tests, and you will be introduced to some examples of screening. Specifically, you will learn about investigations of screening for breast cancer, colon cancer, and prostate cancer. Screening to Prevent Cancer  The World Health Organization defines screening as the identification of unrecognized disease by the application of a rapid test. There are four cancers are the most commonly screened for in the United States and most countries: cervical cancer by a Pap smear, breast cancer by mammogram, colon cancer by colonoscopy, and prostate cancer by a PSA test. 

The Pap smear, a test for detecting cells that may become cervical cancer, was developed by George Papanicolau and has resulted in a great decrease in cervical cancer since 1960. Early treatment when abnormalities are found can eliminate the cancer.

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Screening tests sort out apparently well people who probably do not have a disease from those who probably do have the disease. The tests are not diagnostic, and a positive screening is followed up by biopsy.

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Molecular screening, which is an area of research that is just beginning, may improve early diagnoses. The more we do DNA analyses, there may be more ability to diagnose cancer with screening.

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Lecture 23: Can Screening for Cancer Be Useful? 142

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There are two requirements for usefulness of screening: The test must detect cancer early, and there should be evidence that early treatment results in improved outcome. In addition to these two criteria, you want to screen the right population. It doesn’t make sense to do mammograms on men, for example. Men can get breast cancer, but it’s a much more rare cancer than in women, so it’s not cost effective to screen every man for breast cancer.

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The best types of cancer for screening are those with a reasonably high incidence of a population at risk. If a type of cancer only has one in a million in a population, that means we’re screening a million people at great expense to detect one cancer. Second, there should be a long preclinical phase where treatment can begin. If we have a screening result and it takes two weeks to get the result, and in those two weeks, the tumor goes crazy and the patient succumbs, that’s not useful. Third, you want the test to be easily done, and you want it to be a modest cost that’s not prohibitive.

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The detection methods for screening include palpation (breast, prostate), internal methods (endoscopy, mammogram), and biochemical markers (PSA for prostate). Palpation involves looking for lumps or thickening of the breast or prostate. Internal methods include X-rays, like a mammogram; endoscopy for stomach cancer; and colonoscopy for colon cancer. Biochemical markers involves looking for a marker, or chemical, that is hopefully unique to the cancer cell, and if we can detect it even in blood, then a blood test where cancer cells are leaking would be very useful.

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The costs and benefits of any screening tests are going to vary with the kind of test. Costs of screening include financial costs. If a screening test costs $10,000 per person and we’re screening 10 million people, then that’s a lot of money. In addition, we want to know what the cost is in terms of morbidity to the person and discomfort, but also the possibility of a perforation of the colon, for example. If it’s an internal test, then radiation is a risk. Finally, we want to know the acceptability of a test: Will the patient show up for the test?

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The benefit is increased survival, or decreased mortality. Economists have to analyze the numbers in terms of money saved by early detection, as well as lives, versus cost of early detection per case found.

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Screening tests are not perfect. There are two general criteria for evaluating screening reliability and validity. Reliability in screening means the consistency with which the test gives the same results. Validity is a measure of whether the test actually distinguishes people with cancer from those without it.

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Validity includes both sensitivity (the proportion of people with the disease who test positive) and specificity (the proportion of people without the disease who test negative). In terms of sensitivity, you want to give the cancer-screening test to people who you know, by other means, are positive—people who have the cancer. Anyone testing negative is a false negative; they have cancer, but it’s not showing up in the test.

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For example, Pap smear sensitivity is 95 percent, which means that 19 out of 20 cancer cases are detected. The Pap smear test is a very good test, but it has a one-in-20 error rate. In other words, one out of 20 women are told that their Pap smear is normal by their doctor, but unfortunately the cancer goes on to develop.

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The second aspect of validity is specificity, which is the proportion of unaffected people, who don’t have the cancer, who test negative. That’s a much larger group of people, because the number of people with cancer is much smaller than the number of people without.

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You can take a person who doesn’t have the cancer, give them the test, and hopefully the person will test negative. If the person tests positive, then it’s a false positive. They have to be biopsied, and pathologists get involved. The person gets very anxious that they might have cancer, and then they actually don’t. The specificity of a Pap smear is over 95 percent, which means that there are very few

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occasions in which doctors see a positive test on a Pap smear that shows that the person has precancerous cells they don’t really have. 

False positives are a burden on the medical care system because the more false positives there are, the more follow-ups there have to be for no particularly good medical reason. For some cancers, screening in general is not useful—for example, when there is no reliable detection method (pancreatic) or no localized stage for early treatment (leukemia).

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For breast self-exam, the sensitivity is only 21 percent, which means that there are many false negatives. The specificity is only 30 percent. Many countries no longer recommend self-examination.

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Clinical breast examination (CBE) by a medical professional has a sensitivity of about 60 percent and a specificity of 95 percent. CBE results in about 10 percent of all breast cancer diagnoses.

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Mammography has a sensitivity of about 80 to 90 percent, depending on age, and a specificity of about 95 percent. New technology has improved results, and a recent study in Sweden showed a 26 percent reduction in mortality with screening every two years.

Screening for Colon Cancer  Colon cancer has a 90 percent fiveyear survival rate for localized tumors but it’s less than 45 percent 144

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Lecture 23: Can Screening for Cancer Be Useful?

Screening for Breast Cancer  Breast cancer has a 90 percent five-year survival rate from the time of diagnosis for localized tumors and 70 percent when disseminated.

Mammograms use a small amount of radioactivity to detect tumors in breasts.

when disseminated. Screening tests are recommended at age 50 and once per decade if negative thereafter. 

A fecal occult blood test has a sensitivity of 60 percent and a specificity of 80 percent, but there are many false positives and negatives.

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A sigmoidoscopy (office procedure for the lower colon only) has a sensitivity of 95 percent and a specificity of 60 percent.

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Colonoscopy requires sedation and examines the entire colon. Malignant polyps can be removed at the time of the test. The test sensitivity is 95 percent, and the specificity is 100 percent. Done once per decade starting at age 50, it reduces mortality by more than 85 percent.

Screening for Prostate Cancer  Prostate cancer has a 92 percent five-year survival rate for localized tumors, 68 percent for regional tumors, and 22 percent for metastatic cancer. It is usually a very slow-growing cancer, and many men who have it die in their 80s of other causes. Is it worth treating if detected early? 

A digital rectal exam (DRE) has a sensitivity of 55 percent and a specificity of 80 percent.

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The prostate-specific antigen (PSA) test has a sensitivity of 80 percent but a specificity of only 33 percent, which means that there are many false positives. Biopsies are usually negative. If the biopsy is positive, the tumor can be treated with surgery or radiation, but side effects include incontinence and impotence. One long-term study of PSA screening and treatment showed no improved survival.

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Important Term screening: The use of a relatively simple test to identify people who probably have a disease. For example, a mammogram is an X-ray of breast tissue that identifies growths that could be cancer. Diagnosis is made after biopsy.

Suggested Reading DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8.

Questions to Consider 1. Why is the issue of breast cancer screening so confusing? Should recommendations be up to the patient?

2. The inventor of the PSA screening test for prostate cancer has disowned Lecture 23: Can Screening for Cancer Be Useful?

it, calling it a “public health disaster.” Why? What can be done?

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Can Cancer Be Prevented? Lecture 24

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his final lecture addresses two ways to prevent cancer: by avoiding carcinogens, or things that cause cancer, such as smoking; and by identifying preventive agents, or things that might prevent cancer, such as drugs like tamoxifen and raloxifene. Both methods are being tried, but some things are easier to determine than others. Of course, identifying carcinogens is very difficult, and identifying agents that prevent cancer is challenging, but science is making progress in this realm. Avoiding Carcinogens  There are a number of targets for cancer prevention. If we look along the multistep model for cancer, there are a number of things like chemicals, radiation, and viruses that can get into cells and cause initiation and mutations. Then, these genetic changes lead to an initiative cell that is now a potential cancer cell, and then more mutations happen, and you end up with oncogenes and tumor suppressor genes mutated. Finally, you end up with a bunch of cells—a preneoplastic lesion—and then a malignant tumor, which then spreads. 

We can’t avoid spontaneous cancer because it just happens—it’s chemistry. Certainly, we can try to avoid things that we know cause cancer, which is avoidance of the risk. Chemoprevention generally acts on the initiated cell. It stops the cell that has been changed, by just the first few mutations, from developing into cancer.

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Many cancers are caused by carcinogens in our environment, so avoiding those carcinogens should be our first step to preventing cancer. But what do we need to avoid, and how much?

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By far, the two most significant causes of cancer are tobacco and diet. In any situation where you’re asking people to avoid a risk factor, to change their behavior or diet, the person is going to do 147

Lecture 24: Can Cancer Be Prevented?

risk analysis, which involves identifying the hazard, dose response and by what dose, exposure assessment, and risk characterization. In risk analysis, some of these are scientific judgments, and some of them are social judgments of cost and benefits.

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The link between tobacco use and lung cancer is firmly established, and antismoking campaigns and social legislation have resulted in a decline in lung cancer in recent years. Contrary to popular opinion, however, occasional exposure to secondhand smoke carries very little risk.

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Diet is a little more difficult. Epidemiology links diet and cancer. But what are we supposed to avoid? There are many carcinogens that are natural; there are plant pesticides in food. People have done cohort studies where the ideal would be to put people on a modified diet and see if the group eating fruits and veggies gets less cancer. It’s hard to do intervention studies on people and diet; it’s very difficult to control what people are eating.

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Instead, we do retrospective studies, where we look at the diet of tens of thousands of women, classify them according to diet, and then follow them to see if they get cancer. For example, 40 centers in the Women’s Health Initiative looked for breast and colorectal cancer development over a period of decades in many women, and they found that a diet rich in fruits and vegetables does not affect colorectal cancer and breast cancer. However, there are many other benefits to that type of diet.

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Governments are still recommending fruits and veggies to prevent cancer in popular books, but the data are not showing that there’s an effect. Knowing what not to eat is difficult, too; many clinical trials are under way. Hopefully, we’ll make some progress over time, but it’s going to be slow.

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We do know that ultraviolet light from the Sun causes melanoma (skin cancer). If we block ultraviolet light, we can block skin cancer. For Caucasian people with fair skin, using a sunscreen of SPF 16

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Vaccines against microbes like HBV (hepatitis B virus, causing liver By blocking ultraviolet light, sunscreen cancer) and HPV (human can prevent the development of skin cancer. papilloma virus, causing cervical cancer) can lower liver and cervical cancers, respectively. These vaccines are now widely used, and they will definitely lower the rate of those cancers.

Chemoprevention  Chemoprevention is the identification and use of nonpoisonous nutrients or drugs to prevent the development of cancer. The idea is to enhance the body’s own mechanisms against the development of cancer, or to take the cancer cell that is already initiated and stop it from working. 

The hints that chemoprevention might work very often come from epidemiology. People on some diets get less cancer, so you look at the ingredients. Hints also come from studies of drugs. Sometimes, people who are taking certain medications have less cancer, and these drugs might be stopping an activity that is involved in cell division for another reason.

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For example, anti-inflammatory drugs that are used to treat pain and rheumatoid arthritis seem to also block the same molecule involved in pain inflammation that signals cancer cells to divide. Therefore,

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prevents 95 percent of ultraviolet light from reaching skin cells. There have been clinical data in cohort studies showing that sunscreen will prevent the development of both lethal and nonlethal skin cancer.

Lecture 24: Can Cancer Be Prevented?

this is especially true of colorectal cancer, and aspirin is being shown now to be a preventive for the development of colorectal cancer.

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Identification of chemopreventive agents is typically done by experiments on model organisms, followed by human clinical trials. There are three levels of experimentation: cells (see if it prevents cancer in cells), animals (see if it prevents cancer in animals), and then humans.

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There are whole laboratory buildings devoted to cell screens at various cancer institutes around the world. Cells from tissues like lungs and ovaries are put in a laboratory dish, and then a known carcinogen is added, so they get transformed into cancer cells. If you add the carcinogen in the presence of a suspected chemopreventive agent, maybe you’ll get no transformation at the cell level. We can also do chemical tests on cells to find out how this chemical works.

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The second type of study that can be done is animal screens. You can take rodents that can develop cancer—some of them develop it spontaneously while others need to be given a carcinogen to develop cancer—and you do the same experiment that was done on the cells. Chemoprevention studies are going to take about a year in rodents, and they’re going to be very, very expensive.

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The results of these first two lines of experiments show that a number of natural substances and synthetic substances seem to be preventing a wide variety of cancers. For example, a molecule called curcumin, from turmeric, is very good at chemoprevention in animal and cell studies. In addition, there are silibinin from milk thistle, catechins from green tea, and lycopene from tomatoes.

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Medications that seem to be cancer preventive include aspirin, theophylline, and indomethacin for pain relief and verapamil for antiangina. All of these substances are used in various types of clinical trials in cancer prevention. These clinical trials are long term, so the results are going to take many years to develop.

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Tamoxifen and raloxifene for breast cancer are good examples of chemoprevention, with some efficacy but dangerous side effects. Attempts to use beta carotene and vitamin A as preventive agents against lung cancer in smokers actually resulted in more lung cancer and more deaths. Finasteride showed a 25 percent reduction for prostate cancer by inhibiting testosterone activation, but few doctors prescribe it.

Science and Cancer  Epidemiological studies, long-term studies with a lot of people, are going to reveal the part of the role of nutrition in causing cancer, and hopefully, the issues of what nutrients are involved in cancer will get resolved. We are going to need better methods for screening things that cause cancer because we’re missing a third of them in the screens. We will develop that through DNA technology and rapid genotyping technologies. 

At the molecular level, sequencing whole genomes of people and their tumors is happening at a great pace. Looking at the differences between normal and tumor cells, at the mutations that are the drivers of cancer and those that are the passengers, is going to get very important results. As we characterize gene changes as a tumor develops, we’ll get better biographical information of how a tumor develops at the molecular level. This is going to give us terrific tools to allow us to predict what’s going to happen when a person is diagnosed and then deal with it accordingly.

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In terms of treatment, the more science we know, the wider the therapeutic index will be, and the less damage to normal tissues there will be. Laparoscopic, or minimally invasive, surgery will continue. Hopefully, there will be minimal damage due to surgery and radiation with some new techniques. Delivery of drugs to tumors may change through nanotechnology—tiny structures aimed specifically to hone in on the tumor with drugs in them. Finally, targeted therapy, a very exciting field, is going to continue.

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In terms of prevention, tumor markers, circulating cells in tumors, may detect cancer very early, as can radiography. Drugs can prevent cancers, so there may be more acceptance. The most dramatic difference is going to be the reduction in smoking and, hopefully, the reduction in less cancer—not just lung cancer.

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While cancer is daunting, the efforts of science to understand it have borne fruit, and we are on the verge of tremendous progress in reducing the personal toll that this disease exerts on us all.

Important Term chemoprevention: Use of drugs or nutrients to prevent the development of cancer.

Suggested Reading DeVita, Lawrence, and Rosenberg, Cancer. Hong, Bast, Hait, Kufe, Pollock, Wiechselbaum, Holland, and Frei, Cancer Medicine 8.

Lecture 24: Can Cancer Be Prevented?

Questions to Consider 1. Do you take any drug in order to prevent a disease (e.g., aspirin and heart disease)? If a drug were shown to reduce the incidence of a type of cancer, would you take it?

2. Look up an ad for an herbal supplement that is implied to prevent cancer. Note the fine-print disclaimer that the substance has not been certified as effective by the FDA. Despite this, many people still take the supplement. Why?

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Glossary

alleles: Different forms of the same gene. A tumor suppressor gene can have alleles that encode proteins that block cell division and cancer, and others that do not. angiogenesis: Recruitment of a blood supply by a tumor. The tumor sends out a chemical signal to nearby blood vessels, which sprout branches that grow to the tumor. antibody: A highly specific protein made by the immune system in response to a substance foreign to the body that is involved in immune protection against that substance. Antibodies can be engineered to act as therapeutic agents. apoptosis: Genetically programmed series of events that results in the death of damaged cells. Cancer chemotherapy often reduces the size of a tumor by increasing apoptosis in tumor cells. base pairs (nucleotides): Chemical interactions between nucleotides in the same or opposite strands of nucleic acids. A pairs with T or U; G pairs with C. benign tumor: A tumor that is localized and does not spread to other sites in the body. Benign tumors usually grow to a limited size and are encapsulated by fibrous tissue. biopsy: Removal of part or all of a tissue suspected of being diseased and laboratory analysis of that tissue to confirm the presence of the disease. Cancer diagnosis is made after biopsy. cachexia: Bodily state late in cancer where an individual “wastes away,” losing appetite and weight. This can occur late in the cancer progression. cancer stem cells: Cells within a tumor that can form the growing tumor. They may actually be only a small minority of the cells in a particular tumor. 153

carcinogen: A substance or physical entity that causes damage to a cell, leading to cancer. Most carcinogens are mutagens that damage DNA. carcinoma: A tumor arising from epithelial cells that are at or near the surface of the body or linings of organs. Because epithelial cells commonly divide, they are quite susceptible to DNA damage and cancer. Most cancers are carcinomas. case-control study: Epidemiological analysis comparing two populations— one group with a cancer and one group without—and examining the proportion of people exposed to a suspected cancer-causing agent in each group. For example, lung cancer patients versus people without the cancer would be compared for smoking status. cell: The basic unit of biological structure, function, and continuity. It contains the genome as well as the chemical components for biochemistry. cell cycle: The sequence of events by which a cell reproduces (divides). chemoprevention: Use of drugs or nutrients to prevent the development of cancer. chemotherapy: The use of drugs to treat a disease; used most commonly with cancer and some infectious diseases. chromosome: A DNA molecule containing all or part of the genome of an organism and has the ability to replicate.

Glossary

clinical trial: Experimental treatment of a group of patients under carefully controlled conditions to determine the effectiveness of a new treatment. clone: Genetically identical cells or organisms that arise from a single cell. Although cancers are in general clonal, different cells of a tumor may contain different mutations. cohort study: Epidemiological analysis comparing two populations—one exposed to a suspected cancer-causing agent and the other not exposed—and 154

examining the proportion of diseased people in each group. For example, smokers and nonsmokers would be compared with respect to lung cancer. combination chemotherapy: Simultaneous use of several drugs, each directed at a different target to treat a disease. Most cancer chemotherapy uses combinations. differentiated cell: A cell that has a specialized function, such as muscle. Usually, cells are irreversibly differentiated. Cancer cells are relatively less differentiated or undifferentiated. DNA: Deoxyribonucleic acid, a polymer of nucleotide building blocks (A, T, G, and C) that acts as the genetic material in most living things. DNA microarray: A collection of many gene sequences, usually affixed to a glass slide, that acts as a probe for gene expression. Microarrays are being used for cancer diagnosis and prognosis and to monitor treatment. DNA repair: Chemical correction by cells of errors that occur in DNA during its replication or by outside agents, such as chemicals and radiation. Some cancers are caused in part by defects in DNA repair. enzyme: A biological catalyst that speeds up a biochemical transformation without emerging changed by the process; most enzymes are proteins, although some are RNAs. epidemiology: The science of the incidence, course, and determinants of disease in populations. Cancer epidemiology has been useful at pointing to possible causes. epigenetics: Changes in DNA or its expression that can be passed on to daughter cells but do not basically change the genetic capacities of the nucleotides in DNA. These changes include adding methyl groups of C in DNA or altering the proteins that bind to DNA and occur in many cancers.

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eukaryotic cell: A cell with a nucleus and other cell components that are each enclosed within membranes; these cells make up animals (including humans) and plants. gene: The unit of heredity; a sequence of nucleotides on a chromosome that is expressed as a product that is part of the phenotype. genetic code: The sequence of nucleotides along mRNA that is used to translate the genome into amino acids in protein. The code is virtually the same in all organisms. gene therapy: Addition of a natural or artificially made gene to a tumor to therapeutically alter its properties. genome: A complete genetic sequence of an organism or cell. The Cancer Genome Anatomy Project seeks to describe the genomes of tumor types. growth factor: A protein made in mammals by one tissue that stimulates cell division in a target tissue. hereditary cancer: Cancer that develops because of gene mutation(s) passed on from parent to offspring. heterozygote: An organism with two different alleles for a particular gene. homozygote: An organism with two identical alleles for a particular gene.

Glossary

immune system: Body functions that recognize and defend against substances foreign to the body, most notably infectious diseases. The immune system often recognizes cancer cells as foreign due to their genetic changes and kills the tumor. incidence: Frequency of a disease in a population per unit of time. For cancer, incidence is typically expressed as the number of new cases per 100,000 per year.

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induced mutation: Inherited DNA change caused by an external agent, such as a chemical or radiation. If this occurs in an oncogene or a tumor suppressor gene, it can contribute to the development of cancer. Many carcinogens cause induced mutations. leukemia and lymphoma: Cancers of the white blood cell system, usually arising from immature, not fully differentiated cells. loss of heterozygosity: Occurs when both copies of a tumor suppressor gene are mutated, so that there is not a normally functioning allele. As a result, cell division is permitted, and cancer can result. lymph node: Accumulated tissue in the tubes of the lymphatic system that drains fluids in between tissues and returns it to the blood system. Because tumor metastasis often occurs via lymphatic vessels, tumor cells can accumulate in lymph nodes, and detection of them there indicates metastasis or its potential. malignant tumor: A tumor that spreads from its site of origin to other sites in the body. The tumor spreads by cells migrating to the blood or lymphatic systems. metabolism: The sum total of all of the chemical transformations in an organism. metastasis: The ability of a tumor to break off cells, which travel in the blood or lymphatic system to a new location in the body and grow to a satellite tumor. mitosis: Division of the nucleus of a cell, separating two replicated sets of chromosomes. The presence of a large number of cells in mitosis is a hallmark of aggressive cancers. multidrug resistance: Development of resistance in a tumor to previously effective drugs.

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multistep model: Series of sequential events describing the development of a tumor—from initial damage of a cell to tumor metastasis. Each event is mediated by distinctive genetic and cellular changes. mutagen: A substance that damages DNA, leading to permanent genetic changes in the effected cell and its descendants. Most cancer-causing entities in the environment are mutagens. mutation: A change in the genetic material that is passed on to both daughter cells after cell division. If the cell is a germ line cell, then the change can be passed on to offspring and is inherited. If the change is in a somatic cell, then it is passed on only to the cells deriving from the original changed cell. nucleic acid: A large molecule of DNA or RNA made up of nucleotide building blocks. nucleotide: The building block of a nucleic acid. Each nucleotide has an identical sugar and phosphate group, but there is one of five different bases: A, G, C, T, and U. oncogene: A gene carried by a virus that, when activated, forms a product that acts as a “gas pedal” to stimulate cell division, leading to cancer. Some oncogenes form growth factors; others form receptors for growth stimulators. Still others form molecules that block cell death.

Glossary

oncology: The study of cancer as a disease. A medical oncologist is a physician who treats cancer, usually with medications. A radiation oncologist uses radioactivity, and a surgical oncologist uses surgery. pharmacology: The scientific study of drugs and their interactions with the body (as opposed to pharmacy, which is the formulation and dispensing of drugs). Pharmacology includes pharmacokinetics, describing events occurring before a drug enters a targeted cell, and pharmacodynamics, describing events occurring after a drug reaches a targeted cell. Both must be fully understood for the development of effective cancer-fighting drugs.

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phases I, II, and III: In clinical trials for new therapies, the sequence of protocols needed before a drug or other modality is approved for use as standard care. In phase I, patients with the disease are given the therapy to determine toxicity and tolerability of the dose. In phase II, a small number of patients are given treatment while others are given no treatment, and effectiveness and side effects are evaluated and compared. In phase III, a large number of patients are given treatment or no treatment, and the results are compared. phenotype: The outward appearance resulting from the expression of a gene. It can be influenced by the environment. polymerase chain reaction (PCR): A method of amplifying a DNA sequence in a test tube by adding DNA polymerase and other necessary components for replication. A sequence can be amplified a million times in a few hours. progression: Growth of a tumor from a baseline size. Various definitions are used to measure tumor size. Progression is used as an endpoint in some clinical trials. promoter: A DNA sequence adjacent to the coding region of a gene, to which RNA polymerase binds to initiate gene expression. The events at the promoter are highly regulated in location and time. Prompters regulate the expression of genes involved with cancer. prophylactic surgery: Prevention of cancer development in individuals at risk by surgical removal of tissues that might become cancerous. For example, in women carrying mutations that make them susceptible to breast cancer, the breasts are removed before cancer has a chance to develop. protein: A large molecule composed of amino acid building blocks linked together. proto-oncogene: A gene in a cell that, when activated, forms a product that stimulates cell division and cancer. Homologous to oncogenes carried by viruses. 159

radiation therapy: The use of radiation-emitting isotopes of chemical elements to treat cancer. Radiation is typically given in small doses over several weeks to avoid extensive damage to normal tissues. recessive: An allele that is expressed only when homozygous and not expressed when heterozygous (the dominant allele is expressed). restriction point: Stage of the cell division cycle when a “decision” is made to proceed and replicate DNA, setting the stage for division. There is extensive regulation at this point, and cancer cells often lack proper regulation, leading to continuous cell reproduction. risk analysis: Evaluation of both biological and social aspects of an activity in relation to disease. In cancer, risk analysis involves a quantitative estimation of the hazard of exposure to a carcinogen and cost-benefit analysis of its value to the individual. risk factor: Genetic or environmental condition that makes it more likely that an individual will get a disease. In cancer, there are causative risk factors (if removed, a person does not get cancer) and descriptive risk factors (put people at risk but are not causes). RNA: Ribonucleic acid, a polymer of the nucleotides A, G, C, and U. There are several types of RNA in the cell, such as transfer RNA and messenger RNA. They are mostly involved in gene expression. sarcoma: A tumor originating in tissues, such as muscle, below the surface of the body or lining of organs.

Glossary

screening: The use of a relatively simple test to identify people who probably have a disease. For example, a mammogram is an X-ray of breast tissue that identifies growths that could be cancer. Diagnosis is made after biopsy. semiconservative replication: The mechanism of duplication of DNA whereby each of the two strands in the parental DNA acts as a template for a new strand by complementary base pairing so that each of the two DNA molecules produced has one parental and one new strand. 160

somatic mutation: Permanent DNA change in a cell that does not participate in sexual reproduction. Most cancers involve somatic mutations. spontaneous mutation: Permanent, inherited change in DNA caused by the internal chemistry of the cell, commonly due to errors in DNA replication. Cancers without a known cause probably develop by spontaneous mutation. sporadic cancer: Cancer occurs without a known hereditary cause. stem cells: Continuously dividing, undifferentiated cells in the body that replace cells that are lost due to wear and tear or programmed cell death. Cancers can develop from stem cells. stem cell transplantation: Replacement of bone marrow stem cells destroyed by cancer chemotherapy or radiation. The new cells may be either from the treated individual (stored previously) or from a donor whose cells are genetically similar to the recipient. targeted chemotherapy: Use of a drug that has a rather specific target molecule in a diseased cell. This is done to minimize side effects of treatment. It is a frontier of cancer treatment. telomere: The two ends of a chromosome, where specific DNA sequences prevent DNA damage when it replicates. teratoma: Rare cancer in which there are multiple differentiation events within the tumor. For example, a teratoma in the abdomen may contain fragments of bone and kidney. therapeutic index: A mathematical comparison between damage done to cancer cells and to normal body cells at a given dose of therapeutic agent. The wider the therapeutic ratio, the more effective the treatment. A major goal of cancer treatment is to widen the therapeutic ratio. transcription: The expression of a gene by the production of RNA from a DNA template, catalyzed by RNA polymerase.

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transformation: In cancer, the conversion of a normal cell into a cancer cell. In experimental science, the introduction of DNA from an outside source to a cell, causing it to become genetically different. translation: The synthesis of a chain of amino acids as a protein in response to the information of a nucleotide sequence in a gene as appearing in mRNA. translocation: Transfer of part of one chromosome onto another. This shuffling of genes usually results in alteration of gene expression and cell function. Translocations are common in blood cancers and solid tumors. tumor grade: Seen on biopsy, the fraction of cancer cells that are either dividing and do not resemble the cells of origin (high-grade tumor) or are not dividing and resemble the cells of origin (low-grade tumor). High-grade tumors have a worse prognosis than low-grade tumors. tumor marker: A substance either in a tumor cell or released by it to the blood that signals the presence of a tumor to a physician when it is identified. Tumor markers can be used in diagnosis or to monitor treatment. tumor stage: A graded series of evaluations at diagnosis of how far the tumor has invaded its organ of origin. Higher-stage tumors generally have a worse prognosis than lower-stage tumors on the surface of an organ.

Glossary

tumor suppressor gene: A gene in a cell whose product normally inhibits cell division, leading to cancer. Some tumor suppressor genes form molecules that inhibit progress through the cell division cycle, and others form molecules that are involved in the repair of DNA damage. vaccine: A harmless formulation of a disease agent foreign to the body that provokes an immune response that protects the body from infection by the intact disease agent. Vaccines against certain viruses that cause cancer can be used to prevent those cancers. Vaccines can also be made against tumors after they develop. virus: An infectious particle usually composed of DNA and protein that requires a host cell to replicate. 162

Bibliography

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Bibliography

James, Nick. Cancer: A Very Short Introduction. London: Oxford, 2011. Packed into this brief book for the nonscientist is a wealth of useful information, including economic and political aspects of cancer. LaFond, Richard. Cancer: The Outlaw Cell. 3rd ed. New York: American Chemical Society, 2012. Chapters written by experts summarize the science of cancer. Love, Susan, and Karen Lindsey. Dr. Susan Love’s Breast Book. 5th ed. Boston, MA: Merloyd Lawrence, 2010. A handbook for people newly

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