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Although there are many different forms of cancer, the basic multistage process by which various tumors develop is similar for all cancers. This process is called carcinogenesis. Carcinogenesis begins when carcinogens (cancer-causing substances) damage the DNA in a cell (e.g., a genetic mutation) and/or cause changes in other cell components or cell activities that can predispose them to cancer. These altered cells look normal, but they grow faster than the surrounding normal cells—a stage called hyperplasia. In time (often years), another mutation occurs: the mutated cells grow excessively and appear abnormal in shape and orientation. This stage is called dysplasia, and the cells are called premalignant lesions. After more time, a third mutation occurs. The cells now become more abnormal in rate of growth and appearance, and a tumor develops. If the tumor does not break through the boundaries between tissues, it is "in situ" cancer. In situ tumors can develop further mutations, break through tissue boundaries, and invade surrounding tissues; at this stage, they become malignant tumors that can send cells throughout the body to establish new tumors (metastasis). During the development of a malignant tumor, DNA damage occurs as an accumulation of mutations in as many as six or more genes.

Two types of genes, proto-oncogenes and tumor suppressor genes, play important roles in tumor development. A proto-oncogene codes for proteins that stimulate cell division. When a mutation occurs in a proto-oncogene, it can become a carcinogenic oncogene that causes these proteins to be overactive, resulting in the formation of large numbers of cells. In contrast, tumor suppressor genes code for proteins that inhibit cell division. When a mutation occurs in a tumor suppressor gene, the inhibitory proteins may not function properly, and inappropriate growth of cells remains unchecked. Mutated forms of other genes, such as those that help regulate the invasion of surrounding tissues and metastasis, also may contribute to tumor development. Some people inherit certain cancer-related gene mutations, and these people may be at risk for early development of cancer.

Carcinogenesis can be initiated by chemical agents (e.g., tobacco smoke, pesticides, certain metals); physical agents (e.g., ionizing radiation, ultraviolet [UV] radiation, mineral fibers such as asbestos); and viruses (e.g., Epstein-Barr virus, hepatitis B and C viruses, human papillomavirus). In addition to cancer-causing agents from the environment, highly reactive oxygen-containing molecules that can damage DNA are formed continuously in the body (e.g., endogenously) as a result of biochemical reactions. Other endogenous mutagenic mechanisms also exist. The relative importance of environmental agents versus endogenous molecules in causing the genetic mutations that contribute to carcinogenesis is a matter of debate.

Once inside the body, most chemical carcinogens are metabolized; that is, they are transformed in some way by the body's physical and chemical processes. Chemical carcinogens can be converted into highly reactive compounds that can damage DNA and other cell components, or they can be detoxified and thus prevented from doing cellular damage. The metabolic fate of chemical carcinogens is linked to the activities of particular enzymes—protein molecules in the body that help chemical reactions occur but are not themselves changed in the reactions. The activities of these enzymes can differ among individuals because of the occurrence of genetic polymorphisms (different forms of the genes that code for the enzymes) and the differing activities can either increase or decrease a person's susceptibility to environmental carcinogens. For instance, a higher risk of lung cancer is associated with certain polymorphic forms of the gene CYP1A1, which codes for an enzyme that acts on chemical carcinogens in tobacco smoke. Thus, even though genetic factors (e.g., polymorphisms, inherited mutations) and environmental factors (e.g., carcinogens, radiation, viruses) can make independent contributions to carcinogenesis, these factors also can interact to influence cancer development. A clear example of a gene-environment interaction is observed in people who have inherited a defective copy of the gene that directs the repair of DNA damaged by UV radiation; these people are more susceptible to sunlight-initiated skin cancers than people without the defective gene.

Hundreds of diverse chemicals have been tested to determine whether they are carcinogens, including air pollutants (e.g., gasoline vapors, carbon tetrachloride), water pollutants (e.g., chlorination byproducts), industrial materials (e.g., asbestos, polychlorinated biphenyls), pesticides (e.g., malathion, lindane), herbicides (e.g., chlorophenoxy compounds), pharmaceuticals (e.g., adriamycin, chloramphenicol), food additives (e.g., butylated hydroxytoluene [BHT], food coloring agents), and naturally occurring compounds in foods (e.g., aflatoxins, saffrole). Data for approximately 1,300 compounds tested in animal experiments can be found in the Carcinogenic Potency Database (http://potency.berkeley.edu/app14.html). It is difficult, however, to predict human cancer risk resulting from low-dose exposures based on information from animal experiments that use extremely high doses of chemicals; thus, the value of animal experiments for assessing human risk is still being debated.

PETER GREENWALD

SHARON MCDONALD

(SEE ALSO: Behavioral Determinants; Cancer; Carcinogen; Environmental Determinants of Health; Genes; Genetics and Health; Medical Genetics)