CHRONIC EXPOSURE OF CULTURED TRANSFORMED MOUSE EPIDERMAL-CELLS TO TRANSFORMING GROWTH FACTOR-BETA(1) INDUCES AN EPITHELIAL-MESENCHYMAL TRANSDIFFERENTIATION AND A SPINDLE TUMORAL PHENOTYPE

Transformed mouse epidermal keratinocytes of the cell line PDV, when c ultured under the presence of transforming growth factor-beta(1) (TGF- beta(1)), escaped the block of growth exerted by this factor in normal keratinocytes and underwent marked changes in cell differentiation, T GF-beta(1) induced disruption of epithelial interactions, dispersion o f cells, increased local movement, and conversion to a fibroblast-like morphology. These changes were reversible and correlated with down-re gulation of epithelial protein markers such as E-cadherin and cytokera tins and upregulation of vimentin. TGF-beta(1)-treated cells with a fi broblast-like phenotype induced spindle cell carcinomas upon transplan tation in athymic nude mice, whereas untreated PDV cells or fusiform c ells reverted to the epithelial phenotype and produced well-differenti ated squamous cell carcinomas. Nontumorigenic immortalized epidermal k eratinocytes, when grown under the presence of TGF-beta(1), did not tr ansdifferentiate to a mesenchymal phenotype, their proliferation was b locked, and cells finally died. These results suggest a role for TGF-b eta(1) in the progression of squamous carcinoma cells to spindle carci nomas in mouse skin carcinogenesis.