Distinct mechanisms of TGF-β1–mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis

In the present study, we demonstrated that human skin cancers frequently overexpress TGF-β1 but exhibit decreased expression of the TGF-β type II receptor (TGF-βRII). To understand how this combination affects cancer prognosis, we generated a transgenic mouse model that allowed inducible expression of TGF-β1 in keratinocytes expressing a dominant negative TGF-βRII (∆βRII) in the epidermis. Without ∆βRII expression, TGF-β1 transgene induction in late-stage, chemically induced papillomas failed to inhibit tumor growth but increased metastasis and epithelial-to-mesenchymal transition (EMT), i.e., formation of spindle cell carcinomas. Interestingly, ∆βRII expression abrogated TGF-β1–mediated EMT and was accompanied by restoration of membrane-associated E-cadherin/catenin complex in TGF-β1/∆βRII compound tumors. Furthermore, expression of molecules thought to mediate TGF-β1–induced EMT was attenuated in TGF-β1/∆βRII–transgenic tumors. However, TGF-β1/∆βRII–transgenic tumors progressed to metastasis without losing expression of the membrane-associated E-cadherin/catenin complex and at a rate higher than those observed in nontransgenic, TGF-β1–transgenic, or ∆βRII-transgenic mice. Abrogation of Smad activation by ∆βRII correlated with the blockade of EMT. However, ∆βRII did not alter TGF-β1–mediated expression of RhoA/Rac and MAPK, which contributed to increased metastasis. Our study provides evidence that TGF-β1 induces EMT and invasion via distinct mechanisms. TGF-β1–mediated EMT requires functional TGF-βRII, whereas TGF-β1–mediated tumor invasion cooperates with reduced TGF-βRII signaling in tumor epithelia.