The natural history of neoplastic development: the relation of experimental models to human cancer

The natural history of the development of neoplasia in experimental systems may be separated into at least three different stages, those of initiation, promotion and progression. Evidence for such distinct stages has been demonstrated in at least half a dozen different experimental systems. The stage of promotion is that stage most easily modulated. The actions of promoting agents are reversible and only effective above certain threshold levels of the promoting agent. This is in contrast to the stage of initiation, which can be induced at any dose of the carcinogenic agent in an irreversible manner. Agents exhibiting both initiating and promoting activities are termed complete carcinogens while incomplete carcinogens are those capable only of initiation. Promoting agents do not initiate but may promote cells initiated by ambient environmental means, giving the appearance of complete carcinogens in standard bioassay procedures. The stages of initiation and promotion have been extensively studied in skin and liver carcinogenesis and show almost identical characteristics. A variety of promoting agents in the human environment have been demonstrated both by experimental and epidemiologic methodologies. The importance of an understanding of tumor promotion in relation to the prevention of human cancer is emphasized.