Met-HGF/SF: Tumorigenesis, invasion and metastasis

Hepatocyte growth factor/scatter factor (HGF/SF) is synthesized by mesenchymal cells and is a paracrine effector of cells, predominantly epithelial, that, express the Met tyrosine kinase receptor. We have demonstrated that autocrine Met-HGF/SF expression in mouse fibroblasts results in transformation and tumorigenesis. HGF/SF-treatcd cells expressing Met can respond in a variety of ways: mitogenically, bv scattering (motility), and by forming branching tubules in gel matrices (branching morphogenesis). HGF/SF also induces in fitro invasiveness and is angiogenic in in riro assays. A human cell line and several mouse cell lines that we have constructed to express Met HGF/SF in an autocrine fashion are tumorigcnic, invasive and metastatic in athymic nude mice. Thus, the very complex process of invasion and metastasis can be mediated bv a ligand receptor signalling pathway, and the cell lines we have developed provide important model systems for identifying the signalling molecules that mediate these phenotypes: For example Met HGF/SF signalling activates the urokinase-plasminogen proteolysis network, thus coupling this signal transduction pathway to the proteases that mediate dissolution of the extracellular matrix. Branching morphogenesis, mediated bv Met HGF/SF signalling, is dependent on this process, as well as the formation of cell cell ¡unctions and interaction with the extracellular matrix. We have proposed a hypothesis for the role of Met and downstream signalling molecules in generating normal ducts and lumenal structures, as well as a model for how interruption of this signalling leads to abonormal malignant progression. Is Met involved in human cancer? Human sarcomas often inappropriately express Met, suggesting that it is an important oncogene in these cancers, and an increasing number of reports have implicated Met HGF/SF signalling in a variety of human cancers.