TRANSFORMING-GROWTH-FACTOR-BETA IS ESSENTIAL FOR SPINDLE-CELL CONVERSION OF MOUSE SKIN CARCINOMA IN-VIVO - IMPLICATIONS FOR TUMOR INVASION

Transforming growth factor beta 1 (TGF-beta 1) regulates both cell gro wth and cellular plasticity and is therefore important in the molecula r control of both the developmental and neoplastic processes, It has b een suggested that TGF-beta 1 may be a positive or negative regulator of tumorigenesis. Stimulation of tumorigenesis could be due to its act ion as an immunosuppressor or as an inducer of angiogenesis, or by its direct action on the cell in promoting cellular plasticity. In the cu rrent study, we provide evidence that TGF-beta 1 can act directly on k eratinocytes in vivo to induce the reversible epithelial-mesenchymal c onversion of a malignant metastatic keratinocyte cell line. Two squamo us clones from the cell line were shown to undergo a reversible conver sion to a fibroblastoid phenotype after culture in 1 ng/ml TGF-beta 1. The morphological conversion became apparent at 24 h post-TGF-beta tr eatment and was complete after another 24 h. The conversion was charac terized by a rapid delocalization of E-cadherin within 6-12 h posttrea tment, followed by down-regulation of E-cadherin levels by 72 h, These squamous clones spontaneously converted to a fibroblastoid phenotype after s.c. injection in nude mice. Importantly, four of four clones th at had been stably transfected with a dominant negative TGF-beta type II receptor were unable to undergo this mesenchymal switch in vivo, de spite the fact that all clones stably transfected with neomyocin resis tance alone retained their spindle characteristics in vivo. This demon strates that the epithelial-mesenchymal conversion event is mediated d irectly via the TGF-beta signaling pathway of the tumor cell per se, a nd that it is sufficient to significantly enhance tumorigenicity and t he malignant and invasive characteristics of the tumor in vivo.