Expression of constitutively activated hepatocyte growth factor/scatter factor receptor (c-met) in B16 melanoma cells selected for enhanced liver colonization.

The murine melanoma B16-LS9 cell line was obtained after repeated passages in vivo through the liver of syngeneic mice, and shows an enhanced ability to colonize the liver after intravenous inoculation when compared to its parental, unselected counterpart B16-F1. We have previously shown that paracrine growth effects mainly account for better growth of B16-LS9 in the liver than at other sites, and more recently we reported hepatic transferrin as a factor contributing to efficient growth in the liver. Here we show that increased expression of constitutively activated c-met (the receptor for Hepatocyte Growth Factor/Scatter Factor) consistently occurs during selection of B16 cells through the liver. Constitutive activation of c-met seems to follow its own overexpression and not to depend on an autocrine mechanism. As a consequence, liver-selected B16 melanoma cells have higher tyrosine-kinase activity and higher amounts of tyrosine-phosphorylated proteins than parental B16-F1 or lung-specific B16-F10 cells. Overexpression of constitutively activated c-met enhances motility and invasiveness of B16-LS9 cells, presumably favoring their colonization efficiency in vivo. However, whether levels of c-met expression also determine the organ-specificity of B16 melanoma cells needs further clarification.