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

Abstract

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.

G Protein βγ Subunits Augment UVB-induced Apoptosis by Stimulating the Release of Soluble Heparin-binding Epidermal Growth Factor from Human Keratinocytes

“…Cells-To identify the molecule that mediates the UVB-induced activations of EGFR and MAPKs, conditioned medium from UVB-irradiated HaCaT cells was examined to determine whether it could activate EGFR and MAPKs of nonirradiated cells, because UV irradiation is known to release various growth factors and cytokines that can activate EGFR (16,27). Treatment of nonirradiated HaCaT cells with the conditioned medium obtained from UVB-irradiated HaCaT cells induced the phosphorylations of EGFR, p38, and ERK but not that of JNK, in contrast to UVB, which induced the phosphorylations of all three MAPKs, including JNK (Fig.…”

Production of transforming growth factor-α in human tumour cell lines

“…There are several reports of the production of TGF-oa by melanoma cell lines (Marquardt et al, 1983;Derynck et al, 1987;Ellem et al, 1988). Since TGF-a has been considered to be one of the possible autocrine growth factors in cancer cells, several studies were performed previously to clarify the role of TGF-a as the autocrine growth factor for melanoma cells.…”

“…Singletary et al (1987) reported that EGF enhanced the growth of almost all melanoma cells prepared from surgical specimens. Ellem et al (1988) reported that in melanoma cells and melanocytes the secretion of TGF-a was stimulated by ultraviolet radiation and that TGF-a promoted their own growth. In contrast, Kudlow et al (1984) reported that a monoclonal antibody against EGF receptor did not inhibit the cellular growth of a melanoma cell line, suggesting that TGF-oc could not function as an autocrine growth factor for melanoma cells.…”

“…Received 2 November 1988, andin revised form, 16 January 1989. carcinoma (Hela). SEKI (Fujita et al, 1980), Lu-130, Lu-134-A, Lu-135 (Terasaki et al, 1986) and Li-7 (Beattie et al, 1982) were established at the National Cancer Center Research Institute (Tokyo, Japan). (Motoyama et al, 1986) and KITAJIMA (Hitomi et al, 1986) were kindly provided by Dr Hidenobu Watanabe (Niigata University, Niigata, Japan).…”

Erbb2 Regulates Inflammation and Proliferation in the Skin after Ultraviolet Irradiation

“…3 UV exposure also alters receptor degradation [3][4][5][6] and increases EGFR ligand expression. 7,8 Activation of EGFR by UV stimulates both MAPK and phosphatidyl inositol 3-kinase/Akt signaling. 9 EGFR activation also suppresses apoptosis, increases proliferation, delays hyperplasia, and increases skin carcinogenesis following UV exposure.…”