TUMOR-STROMA INTERACTIONS AND STROMAL CELL-DENSITY REGULATE HEPATOCYTE GROWTH-FACTOR PROTEIN-LEVELS - A ROLE FOR TRANSFORMING GROWTH-FACTOR-BETA ACTIVATION

Hepatocyte growth factor/scatter factor (HGF/SF), a fibroblast-derived mediator of epithelial and endothelial growth and motility, is regula ted by factors present in media conditioned by breast tumor cell lines . Both inhibitory and stimulatory effects were observed dependent on c ulture conditions. The present work shows that breast tumor cell condi tioned medium contains a latent HGF/SF inhibitory activity, which can be activated by a variety of treatments known to activate latent trans forming growth factor-beta. Using blocking antibodies and other criter ia, we show that transforming growth factor-beta present in epithelial cell conditioned medium is primarily responsible for mediating the do wn-regulation of fibroblast HGF/SF. Epithelial cell conditioned medium also contains a trypsin-sensitive and heat-stable stimulatory activit y. Stromal cell density but not proliferation rate markedly alters HGF /SF expression. These results indicate that the expression of at least one epithelial morphogen, HGF/SF, is interdependently regulated by me senchymal condensation and by factors released by neighboring epitheli al and carcinoma cells.