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Causes of Cancer
A number of factors produce cancer in a proportion of exposed individuals. Among these factors are heredity, viruses, ionising radiation, chemicals, and alterations in the immune system. For a long time these various factors seemed to work in different ways, but now researchers are studying how they might interact in a multifactorial, sequential process resulting in malignancy. Basically, cancer is a genetic process. Gene abnormalities can be inherited or they can be induced in a body cell by a virus, or by damage from an outside source. Probably a series of sequential mutations eventually leads to a single cell that is malignant and proliferates as a clone. Originally it was thought that a malignant clone was completely abnormal, and that the only way to cure cancer was to rid the body of all the abnormal cells. Considerable evidence now indicates that the problem may be a loss of the ability of the cell to differentiate into its final, functioning state, perhaps because of the inability to produce a necessary factor.
It is estimated that no more than 20 per cent of cancers are based on inheritance. Several types of cancer, however, do run in families. Breast cancer is an example. Cancer of the colon is more common in families that tend towards polyps in the colon. A type of retinoblastoma has been demonstrated to occur only when a specific gene is deleted. These genes, called tumour-suppressor genes or antioncogenes, normally act to prevent cellular replication. Their deletion prevents the normal check on abnormal multiplication of cells, that is, "removing the brakes". In some hereditary disorders, the chromosomes exhibit a high frequency of breakage; such diseases carry a high risk of cancer.
Viruses are the cause of many cancers in animals. In humans the Epstein-Barr virus is associated with Burkitt's lymphoma and lymphoepitheliomas, the hepatitis virus with hepatocarcinoma, and a papilloma virus with carcinoma of the cervix. These viruses associated with human tumours are DNA viruses. The HTLV virus that produces a T-cell leukaemia is an RNA virus, or retrovirus, as are most of the viruses associated with animal tumours. In the presence of an enzyme called reverse transcriptase, they induce the infected cell to make DNA copies of the virus's genes, which can be incorporated into the cell genome (the full complement of DNA). Such viruses may contain a gene, called a viral oncogene, capable of transforming normal cells into malignant ones. Research indicates that each viral oncogene has a counterpart in the normal human cell called a proto-oncogene, or cellular oncogene. Oncogene gene products (i.e., proteins for which they code) have been identified as growth factors (or proteins necessary for the action of growth factors), which stimulate the growth of tumour cells.
Ionising radiation is a potent cause of cancer. Radiation induces changes in DNA, including chromosome breaks and transpositions, in which the broken-off ends of two chromosomes are exchanged. It acts as an initiator of carcinogenesis, inducing a change that progresses to cancer after a latent period of years. This delay provides opportunity for exposure to other factors.
The process by which chemical agents cause cancer has been extensively studied. Some chemicals act as initiators. Only a single exposure is required, but cancer does not follow until a long latent period has occurred and after exposure to another agent that acts as a promoter. Initiators produce irreversible changes in DNA. Promoters do not change DNA, but they do increase synthesis of DNA and stimulate expression of genes. They have no effect if given before the initiator, only if given after the initiator and given repeatedly over a period of time. For example, tobacco smoke contains many chemical initiators and promoters. The promoter action of cigarettes is very important, and if smoking is stopped, the risk of lung cancer falls rapidly. Alcohol is another important promoter; chronic abuse greatly increases the risk of cancers known to be induced by other agents, such as lung cancer in smokers. Carcinogenetic chemicals also produce chromosome breaks and translocations.
The immune system appears to be able to recognize some forms of malignant cell and stimulate the production of cells able to destroy them. An important factor in the development of cancer may be a disease or other damaging event leading to a state of immune deficiency. Such states are a consequence of AIDS (Acquired Immune Deficiency Syndrome), inherited immune deficiency diseases, and the administration of immunosuppressive drugs.
It is estimated that about 80 per cent of cancers may be caused by environmental factors. The best-established cause is tobacco smoke, actively or passively inhaled, which is responsible for about 30 per cent of all deaths from cancer. Dietary factors may account for about 40 per cent, but the causative relationship is not as clear, and the responsible constituents of the diet are not clearly defined. Obesity is a risk factor for a number of cancers, especially cancers of the breast, colon, uterus, and prostate. Dietary fat and low dietary fibre are associated with high incidence of colon cancer. Dietary fat and obesity, like alcohol, appear to act as promoters.
The Oncogene Factor
The common component that unites these seemingly disparate mechanisms may be the oncogene. Oncogenic viruses may insert their genes at many places in the animal genome. A viral oncogene that is inserted in connection with a cellular oncogene influences the expression of the oncogene and induces cancer. Radiation and carcinogenetic chemicals produce DNA damage, mutations, and chromosome changes, and oncogenes are often located on the chromosome near the fragile site or breakpoint.
A malignancy appears to be the result of a series of mishaps beginning with an abnormal gene or a somatic mutation (a mutation of a normal body tissue cell), probably more than one, followed by a promoting activity that stimulates the expression of one or more oncogenes, or inhibits the effects of one or more antioncogenes, thus leading to the release of growth factors. Perhaps the earlier event leads to the loss of production of metabolites necessary for the normal differentiation of the cell. The stimulation of growth factors then causes the clone of undifferentiated cells to proliferate, and a defect in the immune system permits the abnormal cells to escape destruction by the normal surveillance mechanism.
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