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 growth factor/scatter factor receptor (HGF/SFr), the product of the c-met proto-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 activities (uPA and gelatinase), in correlation with a stronger invasive and motility response to HGF/SF treatment. However, HGF/SF treatment inhibits growth of B16 cells, which might appear in contradiction with the observation that c-met overexpression and constitutive activation seems to be required for efficient liver colonization. However, this apparent 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 motility 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 effects exerted by HGF/SF stimulation on motility and invasion, while the negative effects on growth are counteracted by other paracrine factor(s).
Friedrich Miescher Institute, Basel, Switzerland. rusciano@fmi.ch
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Rusciano
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Lin
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Lorenzoni
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Casella
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Burger
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D017364:Collagenases / Q000096:biosynthesis; D004789:Enzyme Activation; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000556:secondary*; D008168:Lung / Q000378:metabolism / Q000502:physiology; D020780:Matrix Metalloproteinase 9; D008546:Melanoma, Experimental / Q000201:enzymology / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis
D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D014568:Urokinase-Type Plasminogen Activator; D017364:Collagenases; D020780:Matrix Metalloproteinase 9