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 regulated by factors present in media conditioned by breast tumor cell lines. Both inhibitory and stimulatory effects were observed dependent on culture conditions. The present work shows that breast tumor cell conditioned medium contains a latent HGF/SF inhibitory activity, which can be activated by a variety of treatments known to activate latent transforming growth factor-beta. Using blocking antibodies and other criteria, we show that transforming growth factor-beta present in epithelial cell conditioned medium is primarily responsible for mediating the down-regulation of fibroblast HGF/SF. Epithelial cell conditioned medium also contains a trypsin-sensitive and heat-stable stimulatory activity. 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 mesenchymal condensation and by factors released by neighboring epithelial and carcinoma cells.