Cisplatin 19. Cancer

Cancer, a group of diseases in which cell growth spirals out of control, is a killer that moves across race and class lines and has a devastating effect on its victims and their families. While much work remains to be done to understand all the causes of cancer, recent research has shed some light on how cancer develops.

< face="Arial">Types of Cancer One of the reasons that the cure for cancer has been so elusive is that cancer is not a single disease but rather a complex set of diseases. One way to classify different types of cancer is to describe the type of affected tissue:

• Carcinomas are the most common cancers (80-90% of cases) and originate in epithelial tissue, which includes the skin and the covering and lining of the organs and internal passageways. Some examples of carcinomas are breast cancer, lung cancer, and colon cancer.

• Sarcomas begin in connective tissue such as bones, tendons, cartilage, muscle, and fat.

• Leukemias encompass all the other types of cancers that do not fit into either of the above two broad categories. Leukemias develop in the bone marrow and lymph systems, which make blood.1,2

< face="Arial">Causes of Cancer Cancer can be either genetic or inherited or both. A genetic disease results from faulty DNA (see the module on DNA). Mutations can occur in genes, causing normal cells to become cancerous. More specifically, a defective gene leading to increased cellular proliferation in one cell can be passed down to a daughter cell; the accumulation of mutations in subsequent generations of daughter cells can cause cells to proliferate even more rapidly and eventually undergo structural changes to become malignant. An inherited disease is caused by a defective gene that is passed from parent to child.3 Cancer cells are believed to result from at least two genetic mutations, or "hits," to a normal cell. This explains why people with a family history of cancer do not necessarily get cancer themselves. These people may inherit a defective gene through the sperm or egg of their parents, but a second mutation must occur if cancer is to develop. This theory also explains why people with no family history of cancer can get the disease: As long as least two genetic defects occur (from a variety of possible causes), cancer can result. Figure 1 shows how a series of genetic mutations, known as clonal evolution, results in the formation of cancer cells.3

Figure 1. Emergence of a cancer cell from mutations of a normal cell through the process known as clonal evolution. First, one daughter cell (pink) either inherits or acquires a cancer-promoting mutation; this defect is passed on to subsequent generations. Later on, a descendant acquires a second mutation (red), and a later descendant acquires a third (green). Once a cell accumulates enough mutations (purple), the cell can become malignant and cancer can occur. Reprinted with permission.3

When researchers realized that cancer cells were merely normal cells with altered genes, they sought to understand which type of mutations led to cancer. They realized that certain genes are quiescent most of the time but capable of causing cancer if activated; such genes are called proto-oncogenes. Activation of proto-oncogenes can occur when certain viruses (called DNA tumor viruses) invade a normal cell. Once the correct mutation has occurred to convert a proto-oncogene into a carcinogenic form (called an oncogene), cancer results.3 Along with activation of normally quiescent proto-oncogenes, cancer can develop as a result of a different type of genetic damage. Sometimes genes coding for proteins that inhibit cell replication are damaged; the result is that the cell no longer knows when to stop reproducing itself, and cell replication proceeds unchecked. Since these genes halt cell growth, they are known as tumor suppressors (see Figure 2).3

Figure 2. The reproduction of a normal cell occurs in response to stimulation by external growth factors (green). Reproduction is halted by the action of growth-inhibiting factors (red). Abnormal activation of growth factors or inactivation or loss of growth-inhibiting factors can lead to cancer. Reprinted with permission.3

Activation of proto-oncogenes to form oncogenes and damage to tumor suppressors are two ways that cancer disrupts the normal cycle of the cell. To understand more fully how cancer operates through the cell cycle, we will examine the cell cycle by looking at their different phases, as well as the regulation of these phases. We will then discuss some of the ways that normal cell growth can go awry and lead to cancer. We will see some specific instances of both oncogenes and tumor suppressors within the cell cycle. The cell cycle (shown in Figure 3) consists of two overall phases: division and interphase. Division comprises both nuclear division (mitosis, or M) and cell fission (cytokinesis). Before cell division can occur, the cell must double its mass and duplicate all its contents. This period of growth in the cell cycle is referred to as interphase. Interphase typically makes up 90 percent or more of the total cell cycle time and comprises three phases of the cell cycle: a gap phase (G1), in which the cells resume the biosynthetic activity which has been dormant during mitosis; a synthesis phase (S), in which the DNA content of the cell is doubled and the chromosomes are replicated; and a second gap phase (G2).2,4,5

Figure 3. The cell cycle, whose two overall phases are division (including mitosis, or M phase) and interphase (including DNA synthesis, or S phase, as well as two gap phases, G1 and G2). Reprinted with permission.2

The levels of certain enzyme proteins regulating the cell cycle rise and fall over the course of the cell cycle; these proteins are called cyclins. Cyclins activate proteins called kinases (also known as cyclin-dependent protein kinases, or Cdk proteins). Cdk proteins must be complexed with their corresponding cyclins in order to act. Cyclins and Cdk proteins work together to help control the progression from one stage of the cell cycle to the next (Figure 4).

Figure 4. Two key components of the cell cycle. Together they form a complex that causes the cell to progress through its normal cell cycle. Reprinted with permission. 2

There are two main classes of cyclins: Mitotic cyclins are required for mitosis and bind to Cdk proteins during G2 phase. G1 cyclins bind to Cdk proteins during G1 phase and are required for entry into S phase (see Figure 5).2 There is mounting evidence that certain cyclins and kinases are directly involved in cancer. Some of the most compelling evidence suggests that cyclin D1, which is a G1 cyclin, is an oncogene. The cyclin D1 gene has been found to cause both benign tumors of the parathyroid gland and B cell lymphoma. In addition, overexpression of the gene for cyclin D1 may contribute to more common cancers, such as cancers of the breast and esophagus. Indeed, studies conducted on cancer patients have shown amplification of the cyclin D1 gene and elevated levels of the cyclin D1 protein in up to a third of cases of esophageal and breast cancer. Experiments done on cell culture have shown that overexpression of the cyclin D1 gene can contribute to tumor production. Furthermore, the cyclin D1 gene has been shown to cooperate with another oncogene, the ras oncogene, to transform normal cells into cancer cells; this result is consistent with the growing body of evidence that several genetic changes are necessary for cancer to occur. In short, the D cyclins are active during a crucial part of the cell cycle, and they signal the cell to enter its synthesis phase. Once a cell has committed to DNA synthesis, it must carry on with the rest of the cell cycle. Cell division can then occur without any external stimulus—one of the hallmarks of cancer.5 In addition to the D cyclins, cyclins E and A may also play a role in the development of cancer. Cyclin E, another G1 cyclin, is overexpressed in breast cancer cell lines grown in culture, as well as in primary human breast tumors. Moreover, cancer cells have been shown to contain three different varieties of cyclin E protein, whereas normal cells contain only one. Finally, the overexpression of the gene for cyclin A, also a G1 cyclin, allows cells to grow without being anchored to a surface—another classic feature of cancer cells.5

Figure 5. The role of specific cyclins and Cdk proteins in the cell cycle. Reprinted with permission. 5

The cell-cycle control system triggers a cascade of events that take time and must be completed before the cell can proceed to the next phase of the cell cycle. If this series of events is not allowed to occur as intended, the cell may mutate or die. To counteract these negative consequences, several feedback controls exist in the cell. An example of a feedback control is a protein called p53, which accumulates in the cell in response to DNA damage and halts the cell cycle in the G1 phase until the damage has been repaired.2 p53 is believed to act within the cell cycle by blocking the activity of certain kinases—specifically, Cdk2, as well as other Cdks; in this way p53 acts as a tumor suppressor. When the DNA damage has been repaired, p53 no longer exerts its effect, and Cdk2 can again work in conjunction with its cyclin to cause the cell cycle to progress.5 Mutations in the gene that codes for the p53 protein represent the most common genetic malfunction in human cancers and are present in more than half of all cases of the disease. Apparently, these genetic mutations disable the feedback control and allow the cell cycle to progress with damaged DNA.2 Cancer appears in many different types of tissue in the body and results from a variety of factors. In general, cancer is a genetic disease; either defective genes are passed from parent to child (in these cases, cancer is inherited as well as genetic), or a mutation occurs as the result of the action of an oncogene. However, more than one mutation is necessary for cancer to develop. Genetic mutations can lead to malfunctioning proteins that wreak havoc on the cell cycle machinery. For example, if proteins necessary for cell division are activated at the wrong time, the cell may start to grow uncontrollably and become cancerous. Furthermore, if proteins that normally tell the cell to stop dividing are inactivated or lost, cell growth may continue beyond what is normal. As more research is done on cancer and its causes are better understood, more methods of treatment can be developed. (see module on other treatments)

1. (1) Murphy, G. P., Morris, L. B., Lange, D. Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery. Viking Penguin: New York, 1997.
2. (2) Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K., Watson, J. D. Molecular Biology of the Cell, 3rd ed.; Garland Publishing, Inc.: New York, 1994.
3. (3) Cavenee, W. K., White, R. L. Scientific American ,1995, March, pp. 72-79.
4. (4) Stryer, L. Biochemistry, 4th ed. W. H. Freeman and Company: New York, 1995.
5. (5) Marx, J. Science, 1994, 263, pp. 319-321.