Membrane and other Biochemical Effects of the Phorbol Esters and their Relevance to Tumor Promotion

The pleiotropic effects of TPA and related phorbol esters on a variety of cell cultures provide important clues to the process of tumor promotion and the multistep nature of carcinogenesis. These effects can be divided into three categories: 1) mimicry of transformation in normal cells, and enhancement of transformation by chemical carcinogens or oncogenic viruses; 2) modulation (inhibition or induction) of differentiation; and 3) membrane and receptor effects. Recent evidence suggests that TPA acts by binding to specific high affinity cell surface membrane receptors and that this then leads to rapid alterations in the composition of membrane phospholipids. Presumably, these changes in the lipid matrix of cell membranes produce signals or mediators which lead to the subsequent cytoplasmic and nuclear effects of TPA. Thus, whereas the critical target in the action of initiating carcinogens appears to be cellular DNA, the critical target of the phorbol ester tumor promoters appears to be cell membranes. As a unifying concept of two-stage carcinogenesis, we postulate that during the initiation phase in carcinogenesis the covalent binding of carcinogens to DNA induces a host response somewhat analogous to that of the SOS response in bacteria. However, in mammalian cells this response results in abberations in the commitment of the target cells. This may involve ordered events, for example, gene transpositions, rather than random point mutations. Tumor promoters, via their effects on growth, gene expression and differentiation, enhance the selective outgrowth of Initiated cells and induce them to express their newly acquired but previously dormant committed state. Thus, initiation and promotion parallel events during normal development and differentiation, but during carcinogenesis the new cell populations are aberrant in terms of specialized functions and growth control.