Understanding the roles of growth factors in carcinogenesis: Modulation of autocrine growth control by differentiation

It is widely believed that abnormal proliferation of tumor cells is due, at least in part, to the production of autocrine growth factors that are not produced by their normal counterparts. However, direct support for this belief is seriously lacking. The normal counterparts of the vast majority of tumor cells have not been identified adequately and, thus, the growth factors produced by the normal counterparts of tumor cells have not been described. This review summarizes the remarkable similarity in the types of growth factors and growth factor receptors produced by early mouse embryos and by mouse embryonal carcinoma cells, the stem cells of teratocarcinomas. Based on these similarities and the likelihood that embryonal carcinoma cells are derived from the totipotent cells of the mammalian embryo, it is argued that there is reason to suspect that ectopic production of growth factors is not a major cause of tumor induction and tumor growth. It is further proposed that differentiation under normal conditions can limit autonomous cell proliferation by shifting cells from a population that produces growth stimulatory factors to cell types that produce growth inhibitory factors instead. Consequently, blocks in differentiation may lead to tumor growth by maintaining the production of growth stimulatory autocrine factors.