ENHANCED TUMORIGENICITY AND INVASION-METASTASIS BY HEPATOCYTE GROWTH-FACTOR SCATTER FACTOR-MET SIGNALING IN HUMAN-CELLS CONCOMITANT WITH INDUCTION OF THE UROKINASE PROTEOLYSIS NETWORK

Hepatocyte growth factor/scatter factor (HGF/SF) is a pleiotropic effe ctor of cells expressing the Met tyrosine kinase receptor. Although HG F/SF is synthesized by mesenchymal cells and acts predominantly on epi thelial cells, we have recently demonstrated that human sarcoma cell l ines often inappropriately express high levels of Met and respond mito genically to HGF/SF. In the present report we show that HGF/SF-Met sig nalling in the human leiomyosarcoma cell line SK-LMS-1 enhances its in vivo tumorigenicity, an effect for which the mitogenicity of this sig nalling pathway is likely to play a role. In addition, we found that H GF/SF-Met signalling dramatically induces the in vitro invasiveness an d in vivo metastatic potential of these cells. We have studied the mol ecular basis by which HGF/SF-Met signalling mediates the invasive phen otype. A strong correlation has previously been demonstrated between t he activation of the urokinase plasminogen activator (uPA) proteolysis network and the acquisition of the invasive-metastatic phenotype, and we show here that HGF/SF-Met signalling significantly increases the p rotein levels of both uPA and its cellular receptor in SK-LMS-1 cells. This results in elevated levels of cell-associated uPA and enhanced p lasmin generating ability by these cells. These studies couple HGF/SF- Met signalling to the activation of proteases that mediate dissolution of the extracellular matrix basement membrane, an important property for cellular invasion-metastasis.