c-Met autocrine activation induces development of malignant melanoma and acquisition of the metastatic phenotype

Toshiyuki Otsuka, Hisashi Takayama, Richard Sharp, Giulia Celli, William J. LaRochelle, Donald P. Bottaro, Nelson Ellmore, Wilfred Vieira, Jennie W. Owens, Miriam Anver, Glenn Merlino

Research output: Contribution to journalArticlepeer-review

233 Scopus citations


The molecular and genetic events that contribute to the genesis and progression of cutaneous malignant melanoma, a complex and aggressive disease with a high propensity for metastasis, are poorly understood due in large part to the dearth of relevant experimental animal models. Here we used transgenic mice ectopically expressing hepatocyte growth factor/scatter factor (HGF/SF) to show that the Met signaling pathway is an important in vivo regulator of melanocyte function, whose subversion induces malignant melanoma. Tumorigenesis occurred in stages, beginning with the abnormal accumulation of melanocytes in the epidermis and dermis and culminating in the development of metastatic melanoma. Oncogenesis in this model was driven by creation of HGF/SF-Met autocrine loops through forced expression of the transgenic ligand and apparent selection of melanocytes overexpressing endogenous receptor, rather than paracrine stimulation or mutational activation of c-met. Preference for liver as a metastatic target correlated with high HGF/SF-Met autocrine activity, consistent with the notion that such activity may influence colonization. Although basic fibroblast growth factor and its receptor were both weakly expressed in the majority of melanomas examined, high levels were found only in those rare neoplasms with low or undetectable HGF/SF and Met expression, suggesting that these two tyrosine kinase receptor autocrine loops serve a critical overlapping function in melanocytic tumorigenesis. Our data support a causal role for HGF/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 mechanisms by which human melanoma progresses to malignancy and expediting the development of efficacious therapeutic modalities designed to constrain metastasis.

Original languageEnglish (US)
Pages (from-to)5157-5167
Number of pages11
JournalCancer research
Issue number22
StatePublished - Nov 15 1998

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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