Facts and theories concerning the mechanisms of carcinogenesis.

Carcinogenesis can be induced experimentally by exposure to exogenous agents or it can occur spontaneously without intentional or active intervention. Carcinogenesis can be actively induced by chemicals, radiation, infectious biological agents, transgenesis, or selective breeding. In the human and occasionally when testing potential carcinogens in animals, cancer may result from passive exposure to carcinogens encountered in the ambient environment or from changes in the internal milieu of the animal. Many carcinogens alter the structure of DNA resulting in carcinogenesis, but a significant number of carcinogens do not appear to act through this mechanism. When the action of specific carcinogenic agents is considered in relation to the stages of cancer development, initiation, promotion, and progression, the mechanism of the induction of carcinogenesis by DNA-reactive agents that alter genomic structure can be reconciled with those agents that do not act in this manner. As some cells are fortuitously initiated by uncontrolled variables such as irradiation and through changes in normal processes, the stimulation of growth and altered genetic expression by nongenotoxic agents may result indirectly in cancer development. The final stage of carcinogenesis, progression, can occur spontaneously, enhanced by formation and propagation of genetic errors due to increased cellular proliferation associated with the promotion stage. In addition, chemical and viral agents that lack the capacity for initiation and promotion may actively convert cells in the stage of promotion to the stage of progression. Therefore, the diverse mechanisms of action of carcinogenic agents in relation to their effects on specific stages in the natural history of cancer development allow for greater congruence of many of the theories of carcinogenesis. The influence of the roles of nongenotoxic carcinogenic agents and the potential role of progressor agents on the carcinogenesis process allow a more accurate identification of the potential risk that specific carcinogenic agents pose for increasing human cancer.