Principles of Biology

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1 Principles of Biology contents 55 Cancer The Genetic Basis of Cancers Chances are that you know someone who battled cancer, because one in every two men and one in every three women will develop cancer. After heart disease, cancer is the second most common cause of death in the United States, responsible for one of every four deaths. Although the current cancer survival rate is higher than the survival rate from a few decades ago, it is still far lower than that of many other diseases. Why is cancer so common? Why is it so deadly? And, of all the diseases we have cured, why does cancer continue to puzzle the medical community? Cancers are caused by abnormalities that cause normal cell lines to turn into cancerous ones. These abnormalities are caused by a complex set of interactions that usually involves combinations of genetic risk factors and environmental exposures, such as smoking and certain pathogens. This creates unique challenges for treatment because many common cancer therapies simply target all proliferating, or dividing, cells throughout the body. This means that cancer treatments frequently harm healthy cells in addition to the cancerous cells. Cancer is multifactorial, meaning it is not solely caused by genetics, the environment, or lifestyle choices. Certain genotypes and lifestyle choices may predispose a person to the disease, but many different factors must come together for cancer to develop. This often makes it challenging to determine the root cause. For example, mutations in the BRCA1 or BRCA2 genes increase a person's risk for breast cancer. However, having these mutations does not guarantee that a person will develop breast cancer. Conversely, not having mutations in these genes does not guarantee that a person will not develop breast cancer. Many other factors are involved in the process. Many different kinds of cancers can arise in different tissues. These cancers are often very different from one another in their causes and consequences. Some cancer types form masses, or tumors, that stay in place, and some metastasize, or spread to distant tissues via the bloodstream (Figure 1). The causes, symptoms, and treatments for one type of cancer may be very different from those for another type of cancer. Large variability may exist even within the same type of cancer. For instance, prostate cancer, the most common cancer in men, varies widely in terms of how aggressive the cancer cells may be. Some men have prostate cancer cells that quickly metastasize and spread to other parts of the body, and other men have prostate cancer cells that never metastasize. Unfortunately, scientists and physicians are not yet able to reliably identify what makes one person's cancer more likely to spread than another. There are, however, some commonalities between the different types of cancers that give researchers clues about how cancer cells function. In general, cancer is a disease that results from alterations in the ways that cells divide. Figure 1: Development of solid tumors vs. liquid tumors (e.g., leukemia). All cancer is the result of uncontrolled cell division. Some cancers develop solid masses and then have to undergo further changes to metastasize into the bloodstream and throughout the body. Blood cancers, on the other hand, already arise within the body's transport system. of biology / /1 1/12

2 2014 Nature Education All rights reserved. Transcript How far away is a cure for cancer? Due to the complex differences between the various types of cancer, a uniform cure is unlikely. However, cancer research is a highly active field, and significant advances have already been made in understanding the processes of different types of cancers and in using that knowledge to devise new and more effective therapies (Table 1). With each new discovery, researchers move a step closer to thoroughly understanding the biology driving the different forms of cancer, and perhaps to finding a cure. Year Scientists Development in cancer research 1775 Percival Pott 1890 David von Hansemann 1909 Paul Ehrlich 1910 Peyton Rous Proposed that cancer is related to environmental factors such as chimney soot. Discovered that cancer cells show abnormal mitosis. Discovered that the immune system usually suppresses the formation of cancers. Demonstrated that viruses may cause some tumors Gordon Idle Discovered tumor angiogenesis R. Doll and A. Hill Peter Nowell and David Hungerford Elwood Jensen Alfred Knudson Multiple researchers Andrew Linked smoking to lung cancer. Discovered the Philadelphia chromosome, which is linked to chronic myelogenous leukemia (CML). Demonstrated that hormone therapy may be used to treat certain cancers. Discovered tumor suppressor genes. First described the p53 tumor suppressor gene. of biology / /1 2/12

3 Wyllie and Alastair Currie Robert Weinberg, Michael Wigler, and Mariano Barbacid 1989 S.J. Baker s onward Napoleone Ferrara Multiple researchers Todd Bolub and Donna Slonim Multiple researchers Proposed the role of apoptosis (programmed cell death) in cancer development. Cloned the first cancer gene. Demonstrated the role of p53 as a tumorsuppressor gene. Identified and purified vascular endothelial growth factor (VEGF), a major angiogenic factor involved in tumorigenesis (tumor production). Genetic testing for predispositions to specific cancers becomes available. Used gene expression profiling to identify different cancer types. New and more precise molecular therapies target individual cancer types. Table 1: Timeline of cancer research. Research continues to advance our knowledge about the progression of and potential treatments for cancer. Although we often think of cancer as a relatively new class of diseases afflicting humans, there is evidence of different types of cancers far back in human history. There are examples of cancers being present in in mummies dating back several thousand years, and bone cancers have been found in extinct Neanderthals (Homo neanderthalensis) from more than 120,000 years ago. The Ancient Greek word carcinos was first used by Hippocrates to describe a tumor in 400 B.C. This word is the root of the modern terms carcinogenesis and carcinogen; carcinogenesis refers to the process by which cancer develops, while carcinogen refers to a factor that can cause cancer. The understanding of human health continued to progress over the centuries, and, by the 1700s, scientists began to link cancer with exposure to environmental toxins. By 1900, cancer was linked to improper mitosis in cells. Throughout the 1900s, researchers began to understand the mechanisms of cancer more thoroughly, and, even today, details of the molecular changes leading to cancer are still being uncovered. The ultimate goal of this work is to design therapies that will take advantage of the unique cellular changes in cancer. What genetic changes cause cancer? How do genetic mutations lead to cancer? Cancer is often due to mutations that alter the regulation of the cell cycle. Healthy cells use protein signaling pathways to respond to two types of extracellular cell cycle signals: signals that trigger a cell to begin dividing, and signals that trigger a cell to stop dividing. Cancer cells aren't able to respond properly to these signals because they have accumulated mutations in genes that encode the responding proteins. These key genes may be categorized as either oncogenes or tumor suppressor genes. Proto oncogenes encode proteins that promote cell division, regulate cell differentiation, and inhibit cell death. The root onco is Greek for "tumor," and the prefix proto means first. One common misconception is that proto of biology / /1 3/12

4 oncogenes are "cancer genes," but this isn't the case. These genes are necessary for normal growth and development, but cancer may be an undesired byproduct when they are inappropriately expressed. Protooncogenes are most active during embryonic development, when an organism is rapidly increasing its cell numbers. As an organism develops into an adult, proto oncogenes are turned off in many cell types. There are only a few cell types, such as skin cells and the cells that line the intestines, in which proto oncogenes remain active throughout adulthood to enable the continuous replacement of damaged cells. A proto oncogene becomes an oncogene a gene associated with cancer when it acquires a mutation or is otherwise altered in a way that abnormally increases its activity and encourages cells to continue to divide, even in the presence of growth inhibitory signals. In this way, mutations in proto oncogenes contribute to tumor formation and cancer progression. BIOSKILL How Mutations Alter Signaling Pathways What types of proto oncogene mutations result in cancer? A mutation in a proto oncogene that leads to uncontrolled cell division is classified as an oncogenic mutation. The process by which cells grow and divide is highly regulated by a network of protein signaling pathways. Alterations to key proteins in these signaling pathways may promote cancer development. Figure 2 shows a simplified version of one signaling pathway that regulates cell division. Each of the steps in the pathway is susceptible to mutations that can result in uncontrolled cell division. The first step in the pathway is growth factor receptor binding. During this step, oncogenic mutations may cause the excess production of growth factors, the excess production of receptors, or the production of receptors that may be activated even in the absence of growth factor binding. The ErbB2 growth factor receptor is an example of such an oncogene and is overexpressed in many different cancers, including 30% of human breast cancers. The second step in the pathway is signal transduction. During this step, certain mutations in the ras gene may occur that lead to the production of a Ras protein that is perpetually active. These mutations are found in a wide variety of cancers, including 90% of pancreatic cancers. The gene was named for rat sarcoma, a cancer of the connective tissue in which the gene was first discovered. The Ras signaling pathway is a kinase cascade, meaning it is a series of proteins that activate each other by adding phosphates. The first kinase activated is Raf, which in turns phosphorylates MEK, the next kinase in the pathway, activating it, and so on. B Raf, a specific variant of Raf kinase, is the most frequently mutated kinase in human cancers. In most of these cancers, B Raf is inappropriately activated, leading to hyperactive transduction of cell division signals. The last step in the pathway is activation of gene expression. Myc (which stands for myelocytomatosis, a tumor of immune cells called myelocytes) is a gene encoding a transcription factor that regulates 15% of all genes in the genome. Normal control of Myc activity is essential for normal regulation of the cell cycle. Mutations in myc are associated with a number of cancers, including 80% of breast cancers, 70% of colon cancers, and 90% of gynecological cancers. Some of the genes regulated by the Myc transcription factor include the cyclins and cyclin dependent kinases (CDKs), which regulate cell division and progression of the cell cycle. One key regulator is cyclin D1, which is required to drive the transition from the G1 to S phase in cell division. Mutations in cyclin and CDK genes are frequently observed in a number of cancers. of biology / /1 4/12

5 Figure 2: Oncogenes. This diagram shows activation of the Ras signaling pathway, a commonly altered pathway in cancer, by binding of epidermal growth factor (EGF) to its receptor. The Ras signaling pathway involves sequential activation of several kinases and growth factors, culminating in the binding of an active transcription factor (Myc) to target genes in the nucleus Nature Education All rights reserved. Figure Detail Test Yourself IGF 2 (Insulin like Growth Factor 2) is active during fetal development, during which it promotes cell division in many different tissues. Normal variations in this gene may help determine adult height and/or weight. Increased activity of this gene has been linked to many types of cancer, including blood, breast, prostate, lung, colon, and liver cancers. Explain how an increase in the IGF 2 protein could lead to cancer. Submit BIOSKILL p53 and other tumor suppressor genes. In addition to cell cycle drivers, normal development also depends on signals that turn off cell division or trigger apoptosis, which is programmed cell death. The genes that regulate these processes are called tumor suppressor genes, so named because they halt uncontrolled cell division, thereby preventing tumor formation. The expression of tumor suppressor genes acts as a balance to proto oncogene expression. For instance, if a of biology / /1 5/12

6 particular proto oncogene inappropriately signals for excessive cell division, a tumor suppressor gene could be up regulated to counteract the signal and prevent the cell from becoming cancerous. In addition, if a cell has accumulated a significant amount of irreparable damage, some tumor suppressor gene products may even initiate apoptosis to prevent that cell from undergoing further cancerous transformation. One famous tumor suppressor gene encodes for the major regulator protein p53. The p53 protein, which is named because of its size (53 kda), is a multifunctional transcription factor protein that contains DNA binding, oligomerization, and transcriptional activation domains. It is frequently inactivated in all types of cancer because of the central role it plays in maintaining healthy cells by properly regulating the cell cycle. Cellular stressors, such as metabolic stress, starvation, errors in mitosis, DNA damage, or oncogenic mutations, all trigger the p53 pathway (Figure 3). If the damage is not severe, p53 activates the transcription of DNA repair enzymes in an attempt to fix the damage; however, in the case of excessive damage or severe stress, p53 may initiate apoptosis instead. Figure 3: A tumor suppressing gene. The p53 protein is central to the response of the cell to stress or damage. Cell stress, errors in mitosis, DNA damage, and oncogene activation trigger the p53 pathway. Mild stress can lead to DNA repair or growth arrest, and severe stress leads to apoptosis, or programmed cell death, all via p Nature Education All rights reserved. Figure Detail Test Yourself Compare and contrast proto oncogenes and tumor suppressor genes. Submit Cells have a variety of enzymes involved in repairing DNA because DNA is continually damaged by environmental factors (such as UV light), by metabolic byproducts (such as reactive oxygen species produced from respiration), and by errors during DNA replication. Since cancers are the of biology / /1 6/12

7 result of mutations, the lack of a fully functional repair system may lead to a predisposition for cancer. For example, the BRCA genes, which are mutated in many breast cancers, encode DNA repair proteins. How does the type of mutation determine the type of cancer? The particular type of mutation that leads to cancer depends on whether the gene is a proto oncogene or a tumor suppressor gene. Proto oncogenes become oncogenes if transcription of the gene is abnormally up regulated. This can occur if the promoter is mutated to become more active or if the gene is moved to a new area of the genome that is more actively transcribed. Another potential problem is duplication of a proto oncogene; the extra copies of the gene that result from duplication may lead to more protein synthesis and increase overall activity. Finally, the proto oncogene may suffer a mutation that causes it to produce a hyperactive protein. Tumor suppressor genes may become harmful if they acquire mutations that reduce their level of function. These mutations may result in the down regulation of transcription, the loss of functional protein expression, or an insufficiently active gene product. Figure 4 diagrams how each type of mutation affects protein production in a cell. Figure 4: Mutations and cancer. Mutations in both proto oncogenes and tumor suppressor genes can result in increased cell division. (a) Mutations that increase the activity of of biology / /1 7/12

8 proto oncogenes, such as promoter activation (top), gene duplication (middle), or expression of a hyperactive gene product (bottom), may lead to increased cell division or decreased apoptosis. (b) Mutations that decrease the activity of tumor suppressor genes, such as promoter inactivation (top), gene deletion or other loss of functional protein expression (middle), or a mutation to create an inactive gene product (bottom), may also result in increased cell division or decreased apoptosis Nature Education All rights reserved. Figure Detail Since the cell receives two copies of every gene, one from the mother and one from the father, a mutation in only one of the two copies of a tumor suppressor gene is not generally sufficient to cause a complete loss of function and lead to cancer. The cell needs "two hits" mutations in both copies of the tumor suppressor gene to lose the full benefit of the tumor suppressor. However, although tumor suppressor gene mutations are recessive, oncogenic mutations are generally dominant. This means that a mutation in only one copy of a proto oncogene may be enough to promote cancer formation. Where do these genetic errors arise from in the first place? In some cases, the mutated version of a gene may be inherited from one's parents. This is one reason a health care professional may ask for a family history of cancer. However, even though the presence of an oncogene or mutated tumor suppressor gene in a family may increase the risk of developing cancer, other mutations are also needed in order for cancer to develop. For example, a woman who inherits a certain harmful BRCA mutation has only a 13% to 18% increased chance of developing breast cancer. Although having a cancer associated gene mutation may lead to an increased risk, having the mutation does not guarantee the development of cancer. Other DNA mutations that may or may not develop over one's lifetime will affect the outcome. These mutations may even occur during cell division because, in a normal cell, DNA polymerase makes one mistake for every 100,000 bases replicated. This means that a human cell, with its 3 billion bases, may acquire up to 30,000 mistakes each and every cell cycle. Fortunately, cells have enzymes that recognize and repair these mistakes, but mutations are still missed and build up over time. This is one reason that scientists believe the risk for cancer increases with age. Environmental factors called mutagens may also lead to mutations in the DNA. Some mutagens are chemicals, such as food preservatives, the reactive oxygen byproducts of aerobic respiration, and chemicals found in cigarette smoke. Mutagens may also be physical, such as X rays and UV light. Mutagens that have been experimentally shown to cause cancer in animal studies are called carcinogens. Cancer can also result from certain viral infections. Viruses often increase or alter the expression of host genes. Virus related genetic changes may trigger a proto oncogene to become an oncogene or may inhibit a tumor suppressor gene. For example, human papillomavirus (HPV) has been shown to inactivate p53 and is linked to the incidence of 99% of cervical cancers. Treating cancer is challenging, but fortunately, in this particular case, we may be able to prevent the incidence of cancer by preventing viral infection. The current HPV vaccines are safely administered and very effective against blocking the types of HPV that cause cervical cancer. The CDC recommends these vaccines for all females between the ages of 11 and 26; males of a certain age also have the option of receiving this vaccination to prevent genital warts and anal cancer. How does the accumulation of genetic changes cause cancer? In general, no single mutation will result in cancer. From what we can tell, of biology / /1 8/12

9 most cancers contain more than 60 different mutations. On its own, the conversion of a single proto oncogene to an oncogene is not carcinogenic because of the intricate safety net of tumor suppressor genes. Similarly, the loss of a single tumor suppressor gene is not enough to cause cancer because transformed, over active cells still need an increased blood supply to survive. If these cells don't receive sufficient levels of nutrients, they will essentially starve to death. Even if tumor cells are able to receive a plentiful supply of nutrients, they still need to avoid the normal aging process and the body's immune system, which recognizes and attacks mutated cells. Despite the large number of mutations that could potentially contribute to cancer, Douglas Hanahan and Robert A. Weinberg identified six overriding "Hallmarks of Cancer" in These mutations may occur in any order, and often more than one mutation must occur in each category, but Hanahan and Weinberg postulated that all six of them must arise in order for cancer to form. Six Hallmarks of Cancer: 1. Through the improper activation of oncogenes, the cell is able to divide in the absence of growth factors. 2. The cell is able to divide even in the presence of growth inhibiting signals. For instance, the retinoblastoma protein (prb) blocks transcription factors used to activate the cell cycle. When prb is functioning properly, the downstream transcription factors are not able to trigger the cell cycle. However, when prb is non functional, the downstream transcription factors become active and may trigger the cell cycle. Mutations in prb have been found in a variety of cancer types. 3. The cell has the capacity to evade apoptotic signals due to mutations in tumor suppressor genes. 4. The cell is able to divide indefinitely. Most cells have a biological clock that is set by the length of the telomeres, regions at the ends of the chromosomes. Normally, a piece of the telomere is lost each time the cell divides, and, when enough of the telomere is lost, the cell dies. Embryonic cells, with limitless growth potential, maintain the ends of their telomeres with an enzyme called telomerase. This enzyme is deactivated in many adult cells but is reactivated in some cancer cells. 5. ATP production by the cell increases, which requires increased oxygen. As a result, tumors induce the formation of new blood vessels to increase their exposure to oxygen. The building of blood vessels is called angiogenesis. One protein involved in this process is vascular endothelial growth factor (VEGF), secreted by many tumor cells. 6. The cell may metastasize, or invade, surrounding tissue and spread throughout the body. Without metastasis, a tumor may form but would remain localized, and, typically, be non lethal. In normal tissues, cells are held together by cell to cell adhesion proteins. Mutations in adhesion proteins may allow cells in a tumor mass to break off from their neighbors and to travel to and populate new locations. Since Hanahan and Weinberg's seminal review was published in 2000, four more hallmarks have been added to the list: 7. The cell uses unusual metabolic pathways to satisfy its excess energy demand. Current research is looking into how these pathways may be used in treatment approaches. 8. The cell is able to evade the immune system. The immune system is responsible for finding and destroying damaged cells. In order for cancer to develop, cells must acquire mutations that allow them to avoid the immune system. One important area of research involves ways to increase the efficiency of the immune systems to fight cancer. of biology / /1 9/12

10 9. The cell has a higher than normal mutation rate. Mutations in DNA repair enzymes (such as BRCA1 and BRCA2) promote cancer development because they allow other mutations to accumulate more rapidly. 10. The cell causes local inflammation within the tissue it resides in. This hallmark was included to highlight the importance of cell to cell interactions. Cancer cells are not simply a disconnected group of cells; they are more like a rogue organ interacting with the rest of the organism. Test Yourself Why do you think four new hallmarks for cancer were added? Submit Future perspectives. Although Hanahan and Weinberg's Hallmarks of Cancer demonstrate that there are some similarities between cancer cells, many different pathways may lead a cell to become cancerous. New research is even showing that the pathways are often different for each individual. For example, after Matthew Ellis and his colleagues sequenced the entire genomes of healthy and cancer cells in 50 patients with breast cancer, they found over 17,000 different mutations. They also found that even though most of the specific mutations were particular to one individual, 10% of the women had mutations in a set of three shared genes. Surprisingly, over half of the women had a mutation in at least one of the three shared genes. This study demonstrates the complexity of cancer. The researchers plan to repeat the study with 1,000 more tumors. Perhaps with more data, they will begin to see patterns emerge, but it is clear that much more research is needed to fully understand the complexities of this disease. Molecular cancer therapies. How is the advanced knowledge of cancer biology used today to treat patients? New molecular treatment options may be administered based on the type of gene alterations detected for each patient. For instance, the inactivation or removal of an oncogene product is one line of molecular treatment. Herceptin (trastuzumab) is a therapeutic antibody that binds to and blocks the activity of the ErbB2 receptor (encoded by the HER2 gene, the namesake of the drug) and is used in breast cancer therapy. It is currently approved for the treatment of metastatic breast cancers that have a particular HER2 mutation. Clinical trials are currently under way to test whether the drug is safe and effective for other types of cancer as well. Therapies targeting other genes that produce overactive or overabundant products have similar strategies. One such treatment option is Avastin (bevacizumab), which blocks the angiogenic factor VEGF. These strategies are more straightforward than those needed to restore the loss of tumor suppressors such as p53. Current research. One challenge to finding new and better treatments is the increased mutation rate that is a hallmark of cancer cells. This, along with an increased rate of division, means that cancer cells are able to quickly adapt to new environments and evade new therapies. The failure of B Raf kinase inhibitors is one such example. These drugs were developed to treat melanomas (skin cancers) because 60% of melanomas have mutations that produce a constitutively active B Raf protein that drives the cell cycle. Researchers soon found that inhibitors could be used to block B Raf and that the treatment worked well in early stages. However, cancer cells soon of biology / /1 10/12

11 developed new mutations that allowed them to use alternate pathways to again activate the cell cycle. The simultaneous targeting of other proteins in this pathway would be the next logical step, assuming that the inhibition of multiple oncogene products at the same time should make it more difficult for the cells to develop resistance. Trials are currently underway for combination therapies that target two different proteins in the same pathway. The road to understanding and treating cancer using targeted molecular approaches is slowly starting to show success. One such success story is the current treatment for chronic myelogenous leukemia (CML). Nearly all CML patients have a common genetic abnormality, the "Philadelphia chromosome," so named after the location of its discovery. The Philadelphia chromosome is created by a translocation, or a breakage and reattachment, between chromosomes 9 and 22. This translocation creates a fusion gene that produces an abnormal tyrosine kinase, which in turn inappropriately increases cell division. Gleevec (imatinib) is a drug that targets this particular tyrosine kinase and decreases its concentration by 92% to 98%. Because Gleevec is specific to this fusion protein, it does not affect normal cell signaling. As a result of this discovery, CML patients went from having a 30% survival rate to having an 89% survival rate. CML is an unusual case, because its incidence is attributed to a single, consistent genetic defect. Other cancers, which are much more multifactorial, will not likely have such a straightforward response to treatment. However, with further scientific research and medical breakthroughs, new effective treatments will surely be discovered. IN THIS MODULE The Genetic Basis of Cancers Summary Test Your Knowledge WHY DOES THIS TOPIC MATTER? Cancer: What's Old Is New Again Is cancer ancient, or is it largely a product of modern times? Can cutting edge research lead to prevention and treatment strategies that could make cancer obsolete? Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential? PRIMARY LITERATURE Innovation in Cannabis medicine Cannabinoid potentiation of glycine receptors contributes to cannabis induced analgesia. View Download Adaptor proteins regulate cell signaling Structural basis for regulation of the Crk signaling protein by a proline switch. View Download Can we expand the genetic code? Converting nonsense codons into sense codons by targeted pseudouridylation. View Download The role of cyclin D1 in DNA repair linked to cancer growth A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. View Download Mutation in p53 protein spreads cancer by causing protein aggregation Gain of function of mutant p53 by coaggregation with multiple tumor of biology / /1 11/12

12 suppressors. View Download Classic paper: How reverse transcriptase turns RNA into DNA (1970) RNA dependent DNA polymerase in virions of Rous sarcoma virus. View Download page 277 of pages left in this module of biology / /1 12/12