C-MET AUTOCRINE ACTIVATION INDUCES DEVELOPMENT OF MALIGNANT-MELANOMA AND ACQUISITION OF THE METASTATIC PHENOTYPE

The molecular and genetic events that contribute to the genesis and pr ogression of cutaneous malignant melanoma, a complex and aggressive di sease with a high propensity for metastasis, are poorly understood due in large part to the dearth of relevant experimental animal models. H ere we used transgenic mice ectopically expressing hepatocyte growth f actor/scatter factor (HGF/SF) to show that the Met signaling pathway i s an important in vivo regulator of melanocyte function, whose subvers ion induces malignant melanoma. Tumorigenesis occurred in stages, begi nning with the abnormal accumulation of melanocytes in the epidermis a nd dermis and culminating in the development of metastatic melanoma. O ncogenesis in this model was driven by creation of HGF/SF-Met autocrin e loops through forced expression of the transgenic ligand and apparen t selection of melanocytes overexpressing endogenous receptor, rather than paracrine stimulation or mutational activation of c-met. Preferen ce for liver as a metastatic target correlated with high HGF/SF-Met au tocrine activity, consistent with the notion that such activity may in fluence colonization. Although basic fibroblast growth factor and its receptor were both weakly expressed In the majority of melanomas exami ned, high levels were found only in those rare neoplasms with low or u ndetectable HGF/SF and Met expression, suggesting that these two tyros ine kinase receptor autocrine loops serve a critical overlapping funct ion in melanocytic tumorigenesis, Our data support a causal role for H GF/SF-Met signaling in the development of melanoma and acquisition of the metastatic phenotype, Moreover, this transgenic mouse should serve as a highly useful model, facilitating our understanding of mechanism s by which human melanoma progresses to malignancy and expediting the development of efficacious therapeutic modalities designed to constrai n metastasis.