Like the inherited genetic diseases described previously, cancer results from gene mutations. However, with a few exceptions, cancer is not an inherited genetic disease that depends on mutations in the reproductive cells. Rather, most cancers arise from mutations that can occur in any cell at anytime. As noted earlier, most mutations in a single nonreproductive cell have no effect upon the overall functioning of an organism, even if they lead to the death of that particular cell. If, however, mutations result in the failure of the control systems that regulate cell division, a cell with a capacity for uncontrolled growth, a cancer cell, may form and lead to the full-blown disease.
Cancer is the second leading cause of death in America after heart disease, with approximately 25 percent of all deaths due to cancer. Fifty percent of cancers occur in three organs—lung (28 percent), colon (13 percent), and breast (9 percent). About 90 percent of cancers develop in epithelial cells and are known as carcinomas. Those derived from connective tissue and muscle cells are called sarcomas, and those from white blood cells are leukemias and lymphomas.
The abnormal replication of cells forms a growing mass of tissue known as a tumor. If the cells remain localized and do not invade surrounding tissues, the tumor is said to be a benign tumor. If, however, the tumor cells grow into the surrounding tissues, disrupting their functions, or spread to other regions of the body via the circulation, a process known as metastasis, the tumor is said to be a malignant tumor (used synonymously with cancer) and may lead to the death of the individual.
The transformation of a normal cell into a cancer cell is a multistep process that involves altering not only the mechanisms that regulate cell replication but also those that control the invasiveness of the cell and its ability to subvert the body's defense mechanisms. (As will be discussed in Chapter 20, the body's defense system is normally able to detect and destroy most cancerous cells when they first appear.) A cancer cell does not arise in its fully malignant form from a single
Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition
PART ONE Basic Cell Functions mutation but progresses through various stages as a result of successive mutations. The incidence of cancer increases with age as a result of the accumulation of these mutations. Some of the early stages of transformation result in changes in the cell's morphology, known as dysplasia, a precancerous state that can be detected by microscopic examination. At this stage, the cell has not yet acquired a capacity for unlimited replication or an ability to invade surrounding tissues.
As mentioned earlier, a number of agents—termed mutagens—in the environment can damage DNA, increasing the mutation rate. Mutagens that increase the probability of a cancerous transformation in a cell are known as carcinogens; examples of carcinogens are the chemicals in tobacco smoke, radiation, certain microbes, and some synthetic chemicals in our food, water, and air. Some of these carcinogens act directly on DNA, while others are converted in the body into compounds that damage DNA. It is estimated that approximately 90 percent of all cancers require the participation of environmental factors, some of which have been added to the environment by our modern lifestyle.
A growing number of genes have been identified that contribute to the cancerous state when they mutate. These cancer-related genes fall into two classes: dominant and recessive. The dominant cancer-producing genes are called oncogenes (Greek, onkos, mass, tumor; the branch of medicine that deals with cancer is known as oncology). Oncogenes arise as mutations of normal genes known as proto-oncogenes. For example, some oncogenes code for abnormal forms of cell surface receptors that bind growth factors, producing a state in which the altered receptor produces a continuous growth signal in the absence of bound growth factor. The oncogenes are considered dominant since only one of the two homologous proto-oncogenes needs to be mutated for the mutation to contribute to the cancerous state.
The second class of genes involved in cancer are genes known as tumor suppressor genes. In their un-mutated state, these genes code for proteins that inhibit various steps in cell replication. In the absence or malfunction of these proteins, cell replication cannot be inhibited by the normal signals that regulate growth. Mutation of one of the pair of alleles of tumor suppressor genes inactivates its function, but leaves a normal gene on the homologous chromosome that can still suppress tumor development. It is only when both alleles have been mutated that a cell may become cancerous. Thus, this type of cancer phenotype is recessive.
One of the most frequently encountered mutations in cancer cells is a tumor suppressor gene that codes for a phosphoprotein known as p53 (because it has a molecular mass of 53,000 daltons). Normally, p53
functions as a transcription factor that stimulates transcription of a gene that codes for a protein that inhibits the cdc kinase required for progression of a cell from the Gj to the S phase of the mitotic cycle. The concentration of p53 increases in cells that have suffered damage to their DNA and acts to prevent the replication of these damaged cells, including cells that have undergone cancerous mutations at other gene sites. Mutation of both homologous copies of p53 results in the loss of a cell's ability to inhibit the proliferation of damaged cells and thus provides one step in the progression to a fully malignant cancer cell. Cells carrying one copy of a mutated p53 are at increased risk of progressing to a cancerous state if the remaining normal gene becomes mutated.
Although most cancers are not directly inherited, the risk of developing cancer can be increased if, for example, one mutant p53 gene is inherited and is therefore present in all cells of the body. Because cells contain multiple control systems to regulate various stages of cell proliferation, disruption of one system, although it may produce a precancerous state, is not usually sufficient to form a fully malignant cell.
If a cancer is detected in the early stages of its growth, before it has metastasized, the tumor may be removed by surgery. Once it has metastasized to other organs, curative surgery is no longer possible. Drugs and radiation can be used to inhibit cell multiplication and destroy malignant cells, both before and after metastasis, although these treatments unfortunately also damage the growth of normal cells. Some cancer cells retain the ability to respond to normal growth signals, such as the growth of breast tissue in response to the hormone estrogen. Blocking the action of the hormones on hormone-dependent tumor cells can inhibit their growth. Chapter 20 describes therapies that utilize the weapons of the immune system. The development of more selective drugs and the mechanisms for targeting them to cancer cells is one of the benefits that may arise from the field of genetic engineering.
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