Russian rivers of radiation.

Epidermal tumourigenesis can be achieved in rodents by the application of a single subthreshold dose of a carcinogen (initiation) followed by repeated applications of a tumour promoter such as 12-0-tetradecanoyl phorbol, 13-acetate (TPA). TPA induces terminal differentiation in the majority of epidermal keratinocytes in vitro. However, transformed keratinocytes respond weakly to this terminal differentiation signal, and it is suggested that this property allows initiated cells and their progeny to obtain a selective advantage over their normal counterparts during promotion of papilloma formation by TPA. New data are reviewed which suggest that a putative wound hormone TGF-P has similar differential effects on normal and transformed epithelial cells to those of TPA. It is proposed that the release of TGF-,B from platelets following deep skin wounding may be an explanation as to why wounding is a promoting stimulus but milder forms of epidermal injury are not. Weakly promoting hyperplasiogenic agents are also discussed within the context of a selection theory of tumour promotion. The two stage (initiation-promotion) system of epidermal tumourigenesis is achieved by a single application of a subthreshold (initiating) dose of a carcinogen (usually DMBA) followed by repeated applications of a tumour promoter such as 12-0-tetradecanoyl phorbol, 13-acetate (TPA). This method of inducing epidermal tumours has been reviewed many times or deep epidermal abrasion (Argyris 1980a) promote the growth of an initiated cell into a tumour has until recently remained obscure. The purpose of this review is to evaluate evidence supporting the suggestion (Yuspa et al., 1981) that TPA stimulates the development of tumours by selecting for keratinocytes which have acquired a reduced response to terminal differentiation signals as a result of initiation (Yuspa & Morgan, 1981). The application of this selection hypothesis to other promoting stimuli, particularly physical injury will also be discussed. 1. Two-stage epidermal tumourigenesis The initiation-promotion protocol produces primarily clonal benign papillomas (Iannacone et al., 1978; Reddy & Fialkow, 1983), the majority of which are promoter-dependent lesions, (i.e. their growth is reversible) although the probability that the papillomas will become autonomously growing and develop into carcinomas increases with the duration of promoter treatment (Burns et al., 1978; Verma & Boutwell, 1980). TPA itself does not detectably increase the conversion rate of papillomas into carcinomas and at certain doses actually decreases it (Verma & Boutwell, 1980). The inability of TPA to enhance malignant conversion may be related to its inactivity as a mutagen in mammalian cells (Trosko …