Carcinogenesis: basic principles.

Many steps are required to convert a normal cell into a cancerous one. The cancer cell must be able to multiply under conditions that a normal cell would not and to invade surrounding tissue and spread throughout the body. Both genetic changes, such as activation of oncogenes or inactivation of tumor suppressor genes, and epigenetic changes, such as stimulation of cell proliferation, contribute to the development of cancers. Chemical agents can increase the probability of malignant transformation by inducing mutations that can ultimately lead to tumor formation, by promoting the development of tumors in cells with preexisting genetic damage, or by increasing the rate of acquisition of malignant traits by benign tumors. Chemical carcinogens are structurally diverse, but all initiating agents are either already electrophiles or can be converted to electrophilic reactants through metabolic activation. Genetic and environmental factors can alter an individual's ability to metabolize carcinogens, to repair DNA damage, and to respond to mitogenic stimuli, all of which can alter susceptibility to chemical carcinogenesis. The incidence and time required for appearance of tumors appear to be dose-related, but the existence of no-effect doses of carcinogens remains controversial.