LESSON 3.5 WORKBOOK. How do cancer cells evolve? Workbook Lesson 3.5

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1 LESSON 3.5 WORKBOOK How do cancer cells evolve? In this unit we have learned how normal cells can be transformed so that they stop behaving as part of a tissue community and become unresponsive to regulation. Once this transformation occurs and each individual cell in a tumor starts to compete with other cells for limited resources. This lesson wraps up the unit by exploring how each individual tumor cell evolves differently so that the end product may be a tumor that is composed of many different kinds of cells with different mutations and functions that are adapted to the environment. Monoclonal and polyclonal tumors In this unit we have learned how the random accumulation of critical DNA mutations can cause a normal cell to transform itself into a tumor cell. We have learned about mutations to proto-oncogenes and tumor suppressor genes that can allow cells to hyperproliferate and how mutations that permit telomerase expression can prevent cell aging and death and allow cells to become immortal. We have also learned about environmental carcinogens that damage DNA directly or that promote transformation by stimulating cells to proliferate and acquire mutations. We have learned how the immune system can act as a carcinogen by promoting chronic inflammation. In each case we have learned about these behaviors by focusing on individual cells. For this lesson we need to take a step back and consider transformed cells in a population rather than singly. A single normal cell may give rise to a single transformed cell, but as soon as that transformed cell hyperproliferates a number of times, each time acquiring mutations randomly, it will not be long until the cells in the tumor look very different from each other. The fact that tumors are composed of multiple different populations of transformed cells has a huge influence on how the tumor as a whole will behave. Some transformed cells may eventually acquire mutations that lead to apoptosis. Others may divide faster than normal. The process of cell transformation and the road from benign tumor to malignant tumor and then to metastatic cancer is similar to evolution. And as in evolution where the fittest survive, cells must compete with surrounding cells, both normal and transformed for nutrients and resources so that they can grow within the confined space of the tissue. 1. Which of the following is an immediate outcome of exposure to carcinogens? (Circle all correct.) Cell death. Cell differentiation. Cell sprea Cell transformation. 107

2 DEFINITIONS OF TERMS Monoclonal a group of cells produced from a single cell by repeated cycles of cellular replication. Polyclonal a group of cells produced from multiple different cells through repeated cycles of cellular replication. For a complete list of defined terms, see the Glossary. Tumors that appear to be composed of a single population of cells are said to be monoclonal (the left hand side tumor in Figure 1), whereas tumors that appear to be composed of multiple different populations of cells are said to be polyclonal (the right hand side tumor in Figure 1). In reality a tumor is highly unlikely to be monoclonal, for the reasons outlined above, but it is not always very easy to detect the different populations of cells in a tumor from their DNA sequence characteristics. First of all DNA sequencing techniques are not yet sensitive enough to detect very small numbers of cells of a specific population in a large tumor, especially if one type of cell is dominant. For instance, Figure 1: Two models of tumor formation. if one population divides more rapidly, it may swamp out other smaller populations, so the tumor appears monoclonal. Additionally, as we learned in Unit 2, not all changes to cells that promote transformation occur because the DNA sequence has change Epigenetic modifications to DNA will not be detected by conventional sequencing techniques and will require more specialized methods to detect acetylation and methylation for example. Hence while most tumors may appear to be monoclonal, they are in fact, polyclonal. Tumors can be polyclonal for many different reasons. First, they could have arisen from one cell of origin that has acquired different genetic and non-genetic changes as it proliferates, as we discussed above. Alternatively a tumor can arise from multiple different cells of origin. It is fair to say that the future of understanding the biology of cancer will depend on us being able to understand the true nature of different cells in a tumor, both genetically and epigenetically. We have learned that as tumors develop they become malignant by moving through the basement membrane into the strom At that stage they go beyond simply being polyclonal, because they also begin to incorporate non-cancerous cells into the tumor mass. For example, it is not uncommon to see cells of the stroma (stromal cells) and immune cells within the tumor mass. In fact, as many as 90% of the cells in a malignant tumor in the breast, colon, stomach and pancreatic tissues may be either stromal or immune cells. This number goes as high as 99% in Hodgkin s lymphoma, a cancer of the immune system. We have learned that these normal cells can provide critical signals that help the cancer cells grow, survive, evade the immune system, and spread through the bloodstream to surrounding tissues, and we will learn more about this in the next unit. 2. True or False: Tumors are composed of multiple different types of cells True. False. 3. Which of the following can be incorporated into a pancreatic tumor? (Circle all correct.) Immune cells. Neurons. Stromal cells. Stromal proteins. 108

3 DEFINITIONS OF TERMS Selective advantage any property of a cell that gives it a survival advantage over other cells. Selective disadvantage any property of a cell that gives it a survival disadvantage over other cells. Selective pressure any external cause that reduces the ability of cells to replicate. Selective pressure on tumor cells We have learned that a single mutation is not enough to transform a normal cell into a tumor cell, even if that mutation is critical such as to a proto-oncogene. In fact a tumor cells needs a minimum of 3-6 critical mutations in order to become stably transforme Why so many? In order to answer this question we need to examine how cancer cells need to be able to compete against other cells in the environment. If we think about the process of evolution in general, random mutations confer benefits that promote survival of some organisms at the expense of others. Cancer cells behave in exactly the same way. As they acquire random mutations, those that make the cell more efficient at growth and survival will provide a selective advantage to some cells over others. Conversely random mutations that prevent growth with provide a selective disadvantage. But why do some mutations provide a selective advantage whereas others do not? The reason is because the external environment provides selective pressures that co-operate to prevent the limitless growth of cancer cells, preventing the selective advantage of whatever mutations they may have at any one time. Figure 2: Mutations can either increase the chance of cancer by promoting survival or growth, or promoting death. Cancer occurs by accumulation of more pro-growth/pro-survival mutations than any other type of mutation. Acquiring other mutations will increase the chance the cell dies. One common example of selective pressures is the availability of oxygen. Cancer cells that are dividing rapidly will require a plentiful supply of oxygen to grow, and must compete with other cells that may have the same mutations for a limited supply. One way in which a cell could gain a selective advantage in response to this selective pressure would be to acquire a mutation so that it can divide rapidly even in low concentrations of oxygen. In fact many cancer cells do change their metabolism in this way. The immune system can provide another example of selective pressure. We have learned previously that the immune system can behave as a carcinogen, but the immune system can also detect and kill cancer cells very effectively. This role of the immune system is called immunosurveillance, and will be described more in the next unit. 4. How many mutations are necessary to transform a normal cell to become hyperproliferative? , Which of the following can be considered to be a selective pressure? (Circle all correct.) p53 activation of apoptosis. Immunosurveillance. Cyclin activation. Telomere shortening. 109

4 DEFINITIONS OF TERMS Immunosurveilance the principle that the immune system is responsible for identifying and killing cancer cells. Clonal expansion the process by which a single cell replicates to give rise to many other cells within a population. Clone a single cell that gives rise to many cells. Understanding the different selective pressures a cancer cell experiences makes it more evident why 3-6 mutations are necessary for a normal cell to transform stably into a cancer cell. For example, a mutation in a proto-oncogene might lead to hyperproliferation, but then the activity of a normal tumor suppressor gene would prevent that hyperproliferation and simply activate apoptosis. The cancer cell would gain a selective advantage to this selective pressure if it then acquired a mutation in a tumor suppressor. But even this would not be enough for stable transformation since the immune system is continually surveying tissues for abnormalities (we will see how later). So the immune system will exert selective pressure on the transformed cell, which could gain a selective advantage if it acquired a mutation that allowed it to evade immune surveillance. The ability of a highly proliferative, heavily mutated cell to escape immune surveillance is a key step in tumor development. This step, which allows one cell with significant selective advantages to dominate a tumor, at least in the short term is called clonal expansion. This dominant clone explains why many tumors appear to be monoclonal in nature, even though they are composed of other cell types that did not win the struggle for survival within the tumor. It is important to realize also that not all cells acquire the same mutations in the same order. Hence a cell that has already acquired mutations that will allow it to metastasize is primed and ready to go once it has reached the clonal expansion stage. Cancer evolution Clonal expansion allows one choice cell that has acquired just the right set of mutations to dominate a tumor in the short term. But development of cancer as a disease requires more selective advantages than hyperproliferation and clonal expansion. Hyperproliferative cells are not the same as cancer cells. The dominant clone now able to evade immune surveillance can grow happily in place, but oxygen supplies are limited, so maybe the cell gains a selective advantage by acquiring a mutation to alter its metabolism. But a different cell in the dominant clone that has now acquired a mutation enabling it to break through the basement membrane will have more of an advantage, while yet another cell that can migrate into the bloodstream and travel to distant locations will have even more. Finally the cell that can settle in a secondary location and grow there will be most successful in this evolutionary race. But as this secondary tumor grows, selective pressures appear again. The traits of cancer cells are therefore in constant competition with each other. 6. Why do tumors appear to be monoclonal in nature? They are monoclonal. One cell outcompetes its rivals. Immune system kills all but one type of cell in a tumor. Only one cell in a tumor can inactivate p Why do cancer cells require multiple mutations for transformation? (Circle all correct.) Cells are in competition with each other. At least 3 genes need to be mutated to inactivate a signaling pathway. Cells must avoid detection of immune system. Multiple mutations inactivate DNA repair mechanisms. 110

5 The environment that a cancer finds itself in is critical for how it will evolve as a disease. We learned in Lesson 3 of this unit that cells that are chronically infected will experience chronic inflammation that can lead to cancer traits such as hyperproliferation. Similarly, tissues that are regularly exposed to carcinogens or toxic agents, provide a selective advantage to cancer cells as they grow and spread to surrounding tissues, because the surrounding normal cells are so weakened by the carcinogen/toxin exposure. Figure 3: A normal cell progresses to a tumor by becoming transformed and hyperproliferative. The progression to cancer requires further mutations and development of the ability to migrate through surrounding tissue. These past two units have described how a normal cell progresses through its life cycle and how specific points of the cell cycle are particularly vulnerable to the kind of DNA mutations that can radically alter cell behavior and affect cell function. These mutations turn a normal member of the tissue community into a hyperproliferative tumor cell that can no longer respond to regulation. The next unit will shift from the cell-centered perspective of cancer to the an investigation of the interactions between cells, tissues, and organs that allow transformed cells to become disease-causing malignant tumors and metastatic cancers. Cancer is a disease of evolution, and as we shall see in the next unit, the environment of the cancer plays an important role in the development of full-blown disease. 8. Which of the following is a trait of cancer cells? (Circle all correct.) Activate inflammation. Evade immune system. Growth. Adhere to blood vessels. 111

6 STUDENT RESPONSES Describe the steps necessary for a normal cell to become a cancer cell, keeping in mind what types of genes must be mutated, how they must be mutated, and how the mutations are a product of evolution. Remember to identify your sources 112

7 TERMS For a complete list of defined terms, see the Glossary. TERM Clonal expansion Clone Immunosurveilance Monoclonal Polyclonal Selective advantage Selective disadvantage Selective pressure DEFINITION The process by which a single cell replicates to give rise to many other cells within a population. A single cell that gives rise to many cells. The principle that the immune system is responsible for identifying and killing cancer cells. A group of cells produced from a single cell by repeated cycles of cellular replication. A group of cells produced from multiple different cells through repeated cycles of cellular replication. Any property of a cell that gives it a survival advantage over other cells. Any property of a cell that gives it a survival disadvantage over other cells. Any external cause that reduces the ability of cells to replicate. 113