HEPATOCYTE GROWTH-FACTOR RELEASES EPITHELIAL AND ENDOTHELIAL-CELLS FROM GROWTH ARREST INDUCED BY TRANSFORMING GROWTH-FACTOR-BETA-1

Human lung fibroblasts and Mv1Lu mink lung epithelial cells were used as a model to study the role of extracellular matrix in epithelial-mes enchymal interactions. Extracellular matrices of fibroblasts were foun d to contain growth promoting activity that reduced the sensitivity of Mv1Lu cells to the growth inhibitory effects of transforming growth f actor-beta (TGF-beta). The majority of the activity was identified as hepatocyte growth factor/scatter factor (HGF) by inhibition with speci fic antibodies and by reconstitution of the effect by recombinant HGF. HGF induced cell proliferation when contact-inhibited Mv1Lu cells wer e trypsinized and plated in the presence of TGF-beta 1. The effect was valid also in assays where Madin-Darby canine kidney epithelial cells or bovine capillary endothelial cells were used. The multiplication o f chronically TGF-beta 1 inhibited Mv1Lu cells was also induced by HGF . In addition, HGF induced anchorage independent growth of Mv1Lu cells that was refractory to TGF-beta 1 growth inhibition. Immunoprecipitat ion analysis indicated that HGF prevented the suppression of Cdk4 and Cdk2, but not the induction of p21, by TGF-beta 1. Since both TGF-beta 1 and HGF require proteolysis for activation, the results imply that proteolytic activity of epithelial and endothelial cells directs their responses to signals from mesenchymal-type extracellular matrices, an d that during development, matrix-bound growth and invasion promoting and suppressing factors are activated in a coordinated manner.