INFLUENCE OF HEPATOCYTE GROWTH-FACTOR SCATTER FACTOR ON THE METASTATIC PHENOTYPE OF B16 MELANOMA-CELLS

B16 melanoma cells selected in mice for liver-specific metastasis (B16 -LS9) overexpress a constitutively active form of the hepatocyte growt h factor/scatter factor receptor (HGF/SFr), the product of the c-met p roto-oncogene. HGF/SF can affect both invasion and growth of receptive cells. In fact, we show that overexpression of c-met in B16-LS9 cells results in a higher inducibility of two different proteolytic activit ies (uPA and gelatinase), in correlation with a stronger invasive and motility response to HGF/SF treatment. However, HGF/SF treatment inhib its growth of B16 cells, which might appear in contradiction with the observation that c-met overexpression and constitutive activation seem s to be required for efficient liver colonization. However, this appar ent discrepancy is resolved by the finding that liver-derived, but not lung-derived factor(s), can efficiently rescue B16-LS9 cells from the growth inhibitory effects of HGF/SF, while not changing their motilit y response. Therefore, overexpression of c-met in B16-LS9 cells might give a specific advantage in liver colonization, because specifically at this site B16-LS9 cells can take full advantage of the positive eff ects exerted by HGF/SF stimulation on motility and invasion, while the negative effects on growth are counteracted by other paracrine factor (s).