Research Assistant Professor
Hepatocyte growth factor (HGF) was originally discovered as a mitogenic protein for mature hepatocytes. HGF exerts various biological activities, including cell proliferation, 3-D morphogenesis, migration, and anti-apoptosis in diverse biological processes. The receptor for HGF is Met tyrosine kinase. HGF plays critical roles in dynamic morphogenesis and regeneration of various tissues such as the liver. In cancer tissues, however, aberrant activation of the Met/HGF receptor is tightly associated with malignant progression of cancer, i.e., 3-D invasion, metastasis, angiogenesis, and drug resistance. Thus HGF-Met system is emerging hot target in the molecular targeted therapy of cancer. Our research projects include 1) regulation of tumor invasion-metastasis via HGF-Met pathway, 2) aberrant Met activation and drug resistance in cancer cells, 3) discovery of HGF-Met inhibitory molecules (NK4 and small synthetic) and anti-cancer approach with HGF-Met inhibitors, and 4) significance of suppressive mechanisms for the HGF-dependent Met activation in 3-D epithelial morphogenesis and tissue regeneration. HGF-Met system makes a way for dynamic 3-D reconstruction of tissues via epithelial-mesenchymal interactions for regeneration of wounded tissues, whereas it is utilized for acquisition of malignancy of cancers. The simile that “cancer is never-healing wound” seems pertinent from the aspect of HGFMet.
Fig.1 Biological functions of HGF in regeneration, 3-D morphogenesis, and tumor invasionmetastasis
HGF exerts biological actions through the Met, and plays roles in tissue regeneration and 3-D morphogenesis. In cancer tissues, HGF plays a definitive role in invasion, metastasis, and drug resistance. Met activation by HGF become therapeutics for treatment of diseases, while inhibition of HGF-Met become anti-cancer therapeutics, leading to inhibition of metastasis and drug resistance.
Fig.2 3-D morphogenesis and inhibition of tumor invasion
HGF induces 3-D epithelial morphogenesis/tubulogenesis (upper). The response to HGF depends on 3-D position of cells. Mechanism for 3-D position-dependent Met activation leads to understanding of morphogenesis and tumor invasion. Our research includes drug discovery targeting HGF-Met. An inhibitory molecule for HGF-Met inhibits tumor invasion (lower). HGF-Met inhibitors are expected to suppress cancer invasion, metastasis, and drug resistance.