The Role of Cell Proliferation in Multistage Carcinogenesis

Abstract

Carcinogenesis is a complex process in which it is believed that normal cellular growth control genes are altered by sequential mutational events, with subsequent clonal growth of the resulting precancerous or cancerous cells (1, 2). The induction of mutations and the preferential clonal growth of the resulting premalignant or malignant cells, thus, become critical events in the stages of initiation, promotion, and progression in chemical carcinogenesis (Fig. 1). One class of chemical carcinogens are the genotoxicants. These compounds or their metabolites are DNA reactive and directly induce mutations or clastogenic changes. The observation that most mutagens are also carcinogenic is the basis for many current predictive assays and risk assessment models. However, there are also different classes of nongenotoxic carcinogens that do not interact with the DNA. The class designated as mitogens directly induces cell proliferation in the target tissue. Another class, the cytotoxicants, produces cell death followed by regenerative cell proliferation. For the mitogens and cytotoxicants, differential toxicity and growth stimulation may provide a preferential growth advantage to spontaneous or chemically induced precancerous or cancerous cells. Furthermore, mutagens are much more effective as carcinogens at doses that also induce cell proliferation. Mutational activity may occur as an event secondary to cell proliferation caused by the mitogens or cytotoxicants. Thus, chemically induced cell proliferation is an important mechanistic consideration for the genotoxic and nongenotoxic carcinogens. Both genotoxic activity and induced cell proliferation have been associated with the known human chemical carcinogens (3, 4). Knowledge of the relationship of induced cell proliferation to carcinogenic activity would be valuable in setting doses for cancer bioassays, classifying chemical carcinogens, and providing more realistic carcinogenic risk assessments.

Initiation

Initiation represents initial or early events in the carcinogenic process that predispose a cell to malignant transformation.