Current View of the Role of Transforming Growth Factor |[beta]| 1 in Skin Carcinogenesis

摘要

Previously, we have shown that transforming growth factor 1 (TGF1) overexpression in suprabasal epidermis suppresses skin carcinogenesis at early stages, but promotes tumor invasion at later stages. To elucidate the role of TGF1 overexpression in naturally occurring human squamous cell carcinomas (SCC), we screened TGF1 expression patterns in human skin SCC samples and found that TGF1 was overexpressed with two distinct patterns: either predominantly in suprabasal layers or throughout tumor epithelia including basal proliferative cells. To determine the effect of TGF1 overexpression in basal keratinocytes, we generated transgenic mice expressing wild-type TGF1 in basal keratinocytes and hair follicles using the K5 promoter (K5.TGF1wt). Surprisingly, these mice developed a severe inflammatory skin disorder. Inflammation was also observed in head and neck tissue when TGF1 transgene expression was inducibly expressed in head and neck epithelia in our gene-switch-TGF1 transgenic mice. Given the importance of inflammation in cancer development, our data suggest that TGF1-induced inflammation may override its tumor-suppressive effect even at early stages of skin carcinogenesis. This notion is further suggested by our recent study that Smad3 knockout mice were resistant to skin chemical carcinogenesis at least in part via abrogation of endogenous TGF1-induced inflammation.