REGULATION OF UVEAL MELANOMA INTERCONVERTED PHENOTYPE BY HEPATOCYTE GROWTH-FACTOR SCATTER FACTOR (HGF SF)/

Human uveal melanoma disseminates initially and preferentially to the liver. This study describes the relationship between the expression of the c-met proto-oncogene (receptor for hepatocyte growth factor/scatt er factor (HGF/SF)) in interconverted uveal melanoma cells (co-express ing vimentin and keratin intermediate filaments) and the regulation of their motogenic response to HGF/SF, a key step in local invasion and targeted dissemination to the liver. Expression of c-met in uveal mela noma cell lines correlates with both the appearance of an interconvert ed phenotype and invasive ability (measured in vitro). Using chemotact ic checkerboard analysis, the greatest motogenic response to HGE/SF wa s achieved by invasive, interconverted, c-met-positive uveal melanoma cells. C-met was observed histologically in a uveal melanoma containin g interconverted cells but was absent in a tumor composed of non-inter converted cells (vimentin positive/keratin negative). The c-met ligand , HGF/SF, although not expressed by uveal melanoma cell lines, was loc alized in tissue sections of primary uveal melanomas and metastatic me lanoma to the liver. In the primary tumor, staining for HGF/SF was mos t intense at the level of the choriocapillaris, a finding that is sign ificant because 1) highly remodeled neovascular loops and networks, wh ich appear in tumors likely to disseminate, can be traced to the chori ocapillaris and the draining vortex veins and 2) HGF/SF plays a role i n tumor angiogenesis. Foci of metastatic melanoma to the liver stain d iffusely for HGF/SF. Regulation of the uveal melanoma interconverted p henotype by HGF/SF may play an important role in the dissemination of this tumor.