Chemically induced cell proliferation in carcinogenesis

Carcinogenesis can proceed by a variety of pathways involving the sequential mutation of normal cellular growth control genes and the clonal expansion of the resulting precancerous or cancerous cells. Chemical carcinogens may act by inducing mutations and/or altering cellular growth control. 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 different classes of nongenotoxic carcinogens that do not interact with DNA. Mitogens directly induce cell proliferation in the target tissue; cytotoxicants produce cell death followed by regenerative cell proliferation. Differential toxicity and/or growth stimulation induced by mitogens and cytotoxicants may provide a preferential growth advantage to spontaneous or chemically induced precancerous or cancerous cells. Mutagens are much more effective carcinogens at doses that also induce cell proliferation, and mutational activity may occur as an event secondary to cell proliferation. Thus, chemically induced cell proliferation is an important mechanistic consideration for both genotoxic and nongenotoxic carcinogens. The complex quantitative relationships between chemically induced cell proliferation and carcinogenic activity are under study in many laboratories. Such information should be considered in setting doses for cancer bioassays, for classifying chemical carcinogens and in providing more realistic approaches to risk assessment. Of particular concern in extrapolating cancer risk from rodent models to humans are those nongenotoxic agents that exhibit carcinogenic activity only at doses that also produce cytolethality and regenerative cell proliferation in the target organ.