EXPRESSION OF TRANSFECTED TRANSFORMING GROWTH FACTOR-ALPHA INDUCES A MOTILE FIBROBLAST-LIKE PHENOTYPE WITH EXTRACELLULAR MATRIX-DEGRADING POTENTIAL IN A RAT BLADDER-CARCINOMA CELL-LINE

Acquisition of cell motility is often correlated with the malignant progression of a transformed cell. To investigate some of the mechanisms involved in the development of a migratory state, we transfected the NBTII rat carcinoma cell line, which forms stationary epithelial clusters in culture, with the gene encoding human transforming growth factor alpha (TGF-alpha). 1 Expression of TGF-alpha in NBTII cells resulted in cells of motile and vimentin-positive phenotype with internalized desmosomal components, analogous to the treatment of cells with exogenous TGF-alpha. The clones expressed a 5.2-kb TGF-alpha message and synthesized an 18-kDa form of TGF-alpha. Supernatants of TGF-alpha-producing clones induced the internalization of desmosomal components, the production of vimentin, and increased motility in untransfected epithelial NBTII cells, indicating that the factor produced by the clones was in a biologically active form. TGF-alpha-producing clones secreted significant levels of a 95-kDa gelatinolytic metalloproteinase, virtually absent in untransfected cell supernatants. In contrast, levels of inhibitors of metalloproteinases and of a plasminogen activator were similar in untransfected and TGF-alpha-transfected NBTII cells. These results suggest that expression of TGF-alpha is an epithelial tumor cell results in the development of a motile, fibroblast-like phenotype with matrix-degrading potential, which could result in a more aggressive tumor in vivo.