Reversible inhibition of cell differentiation by phorbol esters as a possible mechanism of the promotion step in chemical carcinogenesis.

The potent tumour promoters in mouse skin, phorbol esters and their congeners, inhibit various types of cell differentiation in cell culture systems. There is a good correlation between the tumour-promoting activity of these plant diterpenes and their inhibitory effect on cell differentiation systems. Such findings reinforce the 'aberrant differentiation' theory of carcinogenesis and support Berenblum's (1954b) speculation that tumour promoters may act by interfering with the maturation of initiated cells. FLC are one of the best-defined differentiation systems; and in these, one can see the reversible inhibition of spontaneous and induced differentiation by tumour promoters. Furthermore, clones of FLC have been isolated that are completely resistant to tumour promoter-mediated inhibition of differentiation yet retain the capacity to differentiate normally in response to various inducers. In an attempt to elucidate the mechanism by which tumour promoters inhibit cell differentiation and to obtain a possible clue as to the mechanism of tumour promotion, these variant clones were characterized and compared with tumour promoter-sensitive clonal FLC. The possible relevance of these finding to mouse skin two-stage carcinogenesis is discussed, and is proposed that initiation may be caused by mutagenic actions of carcinogens, whereas unbalanced differentiation triggered by phorbol esters may play a crucial role in the promotion step.