Inducible expression of transforming growth factor beta 1 in papillomas causes rapid metastasis

Transforming growth factor beta1 (TGF-beta1) acts as a tumor suppressor at early stages of carcinogenesis, however, it has also been suggested to prom ote tumor progression at late stages. To determine at which stage and by wh at mechanisms this functional switch occurs, we have generated gene-switch- TGF-beta1 mice in which TGF-beta1 transgene expression can be induced in sk in tumors at specific stages. These mice were exposed to a chemical carcino genesis protocol, which allows tumorigenesis to develop in progressive stag es from benign papillomas to malignant carcinomas. Remarkably, TGF-beta1 tr ansgene induction in papillomas rapidly induced metastasis. This function i s in sharp contrast to its tumor suppressive effect when TGF-beta1 transgen e expression was induced early in the protocol. Transgenic papillomas exhib ited down-regulation of TGF-beta receptors and their signal transducer, the Smads, and loss of the invasion suppressor E-cadherin/catenin complex in t he cell membrane. These molecules were lost only in malignant carcinomas in control mice at a much later stage. Furthermore, transgenic papillomas exh ibited elevated expression of matrix metalloproteinases and increased angio genesis. Our study suggests that TGF-beta1 overexpression may directly indu ce tumor metastasis by initiating events necessary for invasion. Down-regul ation of TGF-beta signaling components in tumor epithelia selectively aboli shes growth inhibition, thus, switching the role of TGF-beta1 to a metastas is promoter.