TGF beta 1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice

TGF beta 1 has been implicated in cell cycle control and carcinogenesis. To address the exact function of TGF beta 1 in skin carcinogenesis in vivo, mice with TGF beta 1 expression targeted to keratinocytes were subjected to long-term chemical carcinogenesis treatment. TGF beta 1 showed biphasic action during multistage skin carcinogenesis, acting early as a tumor suppressor but later enhancing the malignant phenotype. The transgenics were more resistant to induction of benign skin tumors than controls, but the malignant conversion rate was vastly increased. There was also a higher incidence of spindle cell carcinomas, which expressed high levels of endogenous TGF beta 3, suggesting that TGF beta 1 elicits an epithelial-mesenchymal transition in vivo and that TGF beta 3 might be involved in maintenance of the spindle cell phenotype. The action of TGF beta 1 in enhancing malignant progression may mimic its proposed function in modulating epithelial cell plasticity during embryonic development.