The HGF-Met Signaling Axis: Emerging Themes and Targets of Inhibition

The Met tyrosine kinase receptor is the only known receptor for hepatocyte growth factor (HGF). Downstream Met signaling is essential for embryonic development; however, aberrant Met signaling promotes tumor progression by facilitating cell proliferation, survival, migration, invasion, and metastasis. Tumor cell invasion is considered an important step in distant metastatic foci formation. Several recent reviews have focused on the pleiotropic effects of Met signaling in both tumor cells and in the surrounding stromal cells. This review will summarize the currently described mechanisms driving Met induced tumor cell progression and invasion, the role played by cells in the tumor stroma, and therapeutic approaches to block receptor activity. In addition, this review will also highlight two new areas of development: 1) attenuation of Met signaling via multiple mechanisms of action targeting tumor cells and cells in the surrounding stroma using plant-derived polyphenols and 2) the induction by HGF of atypical lysosome trafficking, leading to increased protease secretion and tumor cell invasion. These new areas of research will help to uncover novel therapeutic targets to block the HGF/Met signaling axis to slow cancer progression.