CHEMICAL SKIN CARCINOGENESIS IS PREVENTED IN MICE BY THE INDUCED EXPRESSION OF A TGF-BETA RELATED TRANSGENE

Skin papillomas and squamous cell carcinomas (SCCs) are induced in mic e by tumor initiation with a carcinogen followed by tumor promotion wi th the phorbol eater 12-O-tetradecanoylphorbol-13-acetate (TPA). These usually arise from preneoplastic lesions characterized by epidermal p roliferation and hyperplasia, dermal edema, and inflammation. To evalu ate the role of polypeptide growth factors in chemically induced skin carcinogenesis, we used transgenic mice carrying the cDNA for a TGF-be ta related molecule, bone morphogenetic protein-4 (BMP-4), under the c ontrol of the regulatory elements of the cytokeratin IV gene in a ski n carcinogenesis protocol. Control non-transgenic littermates and BMP- 4 transgenic mice were treated with a single dose of a carcinogen, N-m ethyl-N'-nitrosoguanidine (MNNG), and biweekly with the tumor promoter TPA for 9 months. In control littermates TPA induced epidermal hyperp roliferation, atypia with ''dark'' cells, and dermal inflammation, res ulting in papillomas and SCCs in 13 of 26 animals tested. In BMP-4 tra nsgenic mice, TPA treatment induced the expression of the BMP-4 transg ene in interfollicular epidermis but only minimal epidermal thickening , hyperproliferation, and inflammation were noted after the initial do se of TPA. Furthermore, the mitotic indices in transgenic epidermis af ter 9 months of TPA treatment were significantly lower than the corres ponding indices from untreated transgenic epidermis. Consequently, non e of the 22 transgenic animals tested developed papillomas or SCCs. In conclusion, we have shown that the TPA induced expression of the BMP- 4 transgene blocks proliferation and inflammation in skin, steps that are critical to the subsequent formation of papillomas and SCCs and we characterized an inducible promotersystem which expresses polypeptide s in interfollicular epidermis after exogenous stimulation. (C) 1995 W iley-Liss, Inc.