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-beta(1) but exhibit decreased expression of the TGF-beta type II receptor (TGF-beta RII). To understand how this combination affects cancer prognosis, we generated a transgenic mouse model that allowed inducible expression of TGF-beta(1) in keratinocytes expressing a dominant negative TGF-beta RII (Delta beta RII) in the epidermis. Without Delta beta RII expression, TGF-beta(1) 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, Delta beta RII expression abrogated TGF-beta(1)-mediated EMT and was accompanied by restoration of membrane-associated E-cadherin/catenin complex in TGF-beta(1)/Delta beta RII compound tumors. Furthermore, expression of molecules thought to mediate TGF-beta(1)-induced EMT was attenuated in TGF-beta(1)/Delta beta RII-transgenic tumors. However, TGF-beta(1)/Delta beta RII-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-beta(1)-transgenic, or Delta beta RII-transgenic mice. Abrogation of Smad activation by Delta beta RII correlated with the blockade of EMT. However, Delta beta RII did not alter TGF-beta(1)-mediated expression of RhoA/Rac and MAPK, which contributed to increased metastasis. Our study provides evidence that TGF-beta(1) induces EMT and invasion via distinct mechanisms. TGF-beta(1)-mediated EMT requires functional TGF-beta RII, whereas TGF-beta(1)-mediated tumor invasion cooperates with reduced TGF-beta RII signaling in tumor epithelia.