Stimulatory role of transforming growth factors in multistage skin carcinogenesis: Possible explanation for the tumor‐inducing effect of wounding in initiated nmri mouse skin

Abstract

Mechanical wounding provides a convertogenic (“stage 1 tumor-promoting”) stimulus in initiated NMRI mouse skin, indicating that this stage of carcinogenesis can be entirely controlled by endogenous factors. A search for such factors led to the finding that both platelet-derived Epstein-Barrvirus-inducing factor (EIF), alias human TGFβ₁ and porcine TGFβ, exhibited—upon intracutaneous injection—convertogenic efficacy in initiated NMRI-mouse skin in vivo provided that their injection was combined with a single topical application of the non-convertogenic tumor promoter 12-O-retinolyphorbol-13-acetate (RPA). Since TGFβ inhibits epidermal cell proliferation, the RPA treatment is thought to provide a mitogenic stimulus required for conversion. The RPA treatment can be replaced by intracutaneous injection of transforming growth factor α (TGFα). These results indicate that the stage of conversion consists of two components, one of which is related to mitogenesis (RPA or TGFα), the other to a still unknown activity exhibited by TGFβ-like factors. Thus, endogeneous factors with the quality of “wound hormones” may be involved in multistage skin carcinogenesis. This finding could explain the convertogenic effect of skin wounding.