Non-genotoxic mechanisms of carcinogenesis: studies of cell transformation and gap junctional intercellular communication.

It is widely accepted that a series of genetic changes accumulate during carcinogenesis. In addition, it is likely that various non-genotoxic mechanisms also operate at different stages of carcinogenesis. It is even possible that non-genotoxic mechanisms indirectly generate genetic changes, e.g., through induction of cell proliferation, active oxygen species or cytosine methylation. This may partially explain why many carcinogens are devoid of activity when tested in the usual genetic toxicology assays. In vitro cell transformation mimics certain stages of in vivo carcinogenesis. It has therefore been proposed that both genotoxic and non-genotoxic aspects of carcinogenesis can be studied in cell transformation systems, with tumor formation by transformed cells in syngenic animals or nude mice as the endpoint. Many genotoxic as well as non-genotoxic carcinogens induce transformation of Syrian hamster embryo, murine Balb/c 3T3 and murine C3H10T1/2 cells; interaction of genotoxic and non-genotoxic mechanisms can be clearly seen in 2-stage cell transformation studies in which a genotoxic initiating agent and a non-genotoxic promoting agent act synergistically to induce transformation of rodent cells. Aberrant control of gap junctional intercellular communication (GJIC) in cell transformation and carcinogenesis is well documented. Possible genotoxic as well as non-genotoxic mechanisms involved in abnormal gap junction communication control in multistage carcinogenesis are discussed.