UVR induction of TGF alpha: a possible autocrine mechanism for the epidermal melanocytic response and for promotion of epidermal carcinogenesis.

The occurrence of the epidermal growth factor homologue, transforming growth factor alpha (TGF alpha), in embryonic and neoplastic tissues suggests that it may be an oncofetal version of epidermal growth factor. A strong case is developing for TGF alpha to have an autocrine mode of action in sustaining the autonomous growth of several types of tumour. We propose that TGF alpha normally has an autocrine role not only in stimulating the growth of some fetal tissues but also with postnatal epidermal cells in response to local stimuli--in particular ultraviolet radiation (UVR). As a first step to test this hypothesis we have checked whether UVR will induce the production of TGF alpha, measured by radioimmunoassay, using a highly specific monoclonal antibody which recognizes native, biologically active human TGF alpha. We found that cultures of normal foreskin melanocytes do not produce detectable amounts of TGF alpha when grown under routine conditions, but, within 12 h of exposure to low doses of short-wavelength UVR, significant quantities of TGF alpha are produced. The UVR-induced TGF alpha is both cell associated and released into the medium of these cultures. Also, UVR has a promoting action on epidermal cells which have been initiated by carcinogenic activity. A significant part of the promoting activity may be due to autocrine stimulation of multiplication of partially transformed epidermal cells. In this regard we found that UVR induced TGF alpha in HeLa cells and all human melanoma lines so far tested. Induction was complete within 24 h of a single exposure. Dose-response curves of TGF alpha induction in a malignant melanoma cell line showed a distinctive peak of factor induced by low (2 J/m2) doses of UVR. Higher doses which inhibit [3H]thymidine incorporation resulted in lower levels of induced TGF alpha. These findings are consistent with the participation of TGF alpha as an autocrine mediator of UVR-induced tumour promotion, as well as cell multiplication, in sun-exposed skin.