Nakahara Memorial Lecture. Pathways of carcinogenesis--genetic and epigenetic

Considerable experimental evidence has developed to argue that carcinogenesis occurs in a series of stages whose characteristics allow division into the distinct stages of initiation, promotion, and progression. The stage of initiation results from subtle genetic alterations in individual target cells caused both by experimental perturbations as well as by ambient environmental factors. Initiation of a cell may result from the mutation of one or a few key genes whose expression is modified by many other genes. Promoting agents induce the clonal development of initiated cells susceptible to the proliferative effects of the specific promoting agent. The stage of progression is characterized by evolving karyotypic instability and may be induced by specific clastogenic effects and/or agents, the latter termed progressor agents. Carcinogens may induce cancer by an action at all three stages or selectively by an action at any one or two of the individual stages of carcinogenesis. Cancer then develops as a result of fortuitous, endogenous, or ambient environmental factors, thus accounting for the action of both genotoxic and nongenotoxic agents as carcinogens.