Chapter 11: The Continuity of Life: Cellular ReproductionIssues in Biology |
It is nearly a certainty that you or someone you know will develop a cancer at some point in your life. In fact, about 1 in 5 of us can expect to die as a result of a cancer. Why is cancer so difficult to treat? The sad fact is that cancers result from defects in our own genes, particularly the genes that regulate mitotic cell division. When these genes are defective, cells progress through the cell division cycle without regard to the molecular messages that normally control whether and how often a cell will divide. Inappropriate cell division is a serious problem. Even one extra division every few months (as in many breast cancers) is enough to produce a tumor within several years. Eventually, if not controlled, cells accumulate additional mutations that allow them to invade the surrounding tissue. At this point, a full-blown cancer exists: cells are undergoing unregulated cell divisions, refusing to do their proper jobs within the body, and moving into new locations.
To understand the series of genetic changes that convert a normal cell into a cancer cell, scientists have examined the DNA sequences of key cell-cycle regulation genes. In about 60% of the cancers they examine, a gene called p53 is defective. The p53 gene is a member of the class of genes called “tumor-suppressor genes” whose normal function is to inhibit cell division. The role of the p53 protein is particularly important, because p53 is produced in response to DNA damage. If such damage exists, p53 is produced and activates genes that inhibit cell cycle progression. This pause allows time for the cell to repair the damage, thus helping to prevent mutations from being passed on to the daughter cells. This role has given p53 the nickname, “The Guardian of the Genome.” In cells that have mutations in the p53 gene, cell division progresses even though DNA damage has occurred. The resulting increase in mutation rate is undoubtedly very important in allowing cancers to develop.
In some cases, the DNA damage that occurs is too great to repair. Consequently, rather than simply pausing the cell cycle, p53 can alternatively activate a cell suicide program called apoptosis. In this process, the cell gently releases its connections to neighboring cells, produces digestive enzymes that break its DNA into small fragments, and disintegrates into bite-sized pieces that are eaten and digested by other body cells. Following apoptosis, the cell disappears without a trace. In addition to its importance in inhibiting potential cancerous cells from being produced, apoptosis is also important for removing unnecessary cells during development. For example, you have fingers and toes instead of paddles because the cells between your fingers and toes underwent apoptosis.
Apoptosis is a major reason why cancer chemotherapy and radiation therapy work. Radiation therapy and many chemotherapy agents cause profound DNA damage—enough to induce apoptosis. Unfortunately, these treatments do not discriminate between cancer cells and normal cells. Any cell that is dividing is a potential target. In fact, the apoptosis of normal cells produces most of the side effects of chemotherapy and radiation therapy, including nausea and hair loss.
Given the connection between p53 and apoptosis, can you see a potential problem for physicians treating a patient who has cancer? In many cancers, the p53 gene is defective, but p53 is needed for efficient induction of apoptosis in response to DNA damage. Thus, for those cancers caused by cells with defective p53, chemotherapy and radiation therapy may be less effective that for other cancers. Indeed, examining the p53 gene in a particular cancer can help physicians decide on appropriate courses of therapy. A recent approach to this problem involves gene-therapy. Experiments are being done in which normal p53 genes are injected into tumors. The idea is that the tumor cells will take up the p53 DNA and begin to express the p53 protein. It is hoped that restoring the “Guardian of the Genome” will activate the apoptosis pathway by itself or make the cancer cells once again sensitive to DNA damage.