Hepatocyte growth factor/MET in cancer progression and biomarker discovery.

Signaling driven by hepatocyte growth factor (HGF) and MET receptor facilitates conspicuous biological responses such as epithelial cell migration, 3-D morphogenesis, and survival. The dynamic migration and promotion of cell survival induced by MET activation are bases for invasion-metastasis and resistance, respectively, against targeted drugs in cancers. Recent studies indicated that MET in tumor-derived exosomes facilitates metastatic niche formation and metastasis in malignant melanoma. In lung cancer, gene amplification-induced MET activation and ligand-dependent MET activation in an autocrine/paracrine manner are causes for resistance to epidermal growth factor receptor tyrosine kinase inhibitors and anaplastic lymphoma kinase inhibitors. Hepatocyte growth factor secreted in the tumor microenvironment contributes to the innate and acquired resistance to RAF inhibitors. Changes in serum/plasma HGF, soluble MET (sMET), and phospho-MET have been confirmed to be associated with disease progression, metastasis, therapy response, and survival. Higher serum/plasma HGF levels are associated with therapy resistance and/or metastasis, while lower HGF levels are associated with progression-free survival and overall survival after treatment with targeted drugs in lung cancer, gastric cancer, colon cancer, and malignant melanoma. Urinary sMET levels in patients with bladder cancer are higher than those in patients without bladder cancer and associated with disease progression. Some of the multi-kinase inhibitors that target MET have received regulatory approval, whereas none of the selective HGF-MET inhibitors have shown efficacy in phase III clinical trials. Validation of the HGF-MET pathway as a critical driver in cancer development/progression and utilization of appropriate biomarkers are key to development and approval of HGF-MET inhibitors for clinical use.

Matsumoto K ，Umitsu M ，De Silva DM ，Roy A ，Bottaro DP ... -  《-》

Fibroblast-secreted hepatocyte growth factor mediates epidermal growth factor receptor tyrosine kinase inhibitor resistance in triple-negative breast cancers through paracrine activation of Met.

Mueller KL ，Madden JM ，Zoratti GL ，Kuperwasser C ，List K ，Boerner JL ... -  《-》

HGF-induced formation of the MET-AXL-ELMO2-DOCK180 complex promotes RAC1 activation, receptor clustering, and cancer cell migration and invasion.

The MET proto-oncogene-encoded receptor tyrosine kinase (MET) and AXL receptor tyrosine kinase (AXL) are independently operating receptor tyrosine kinases (RTKs) that are functionally associated with aggressive and invasive cancer cell growth. However, how MET and AXL regulate the migratory properties of cancer cells remains largely unclear. We report here that the addition of hepatocyte growth factor (HGF), the natural ligand of MET, to serum-starved human glioblastoma cells induces the rapid activation of both MET and AXL and formation of highly polarized MET-AXL clusters on the plasma membrane. HGF also promoted the formation of the MET and AXL protein complexes and phosphorylation of AXL, independent of AXL's ligand, growth arrest-specific 6 (GAS6). The HGF-induced MET-AXL complex stimulated rapid and dynamic cytoskeleton reorganization by activating the small GTPase RAC1, a process requiring both MET and AXL kinase activities. We further found that HGF also promotes the recruitment of ELMO2 and DOCK180, a bipartite guanine nucleotide exchange factor for RAC1, to the MET-AXL complex and thereby stimulates the RAC1-dependent cytoskeleton reorganization. We also demonstrated that the MET-AXL-ELMO2-DOCK180 complex is critical for HGF-induced cell migration and invasion in glioblastoma or other cancer cells. Our findings uncover a critical HGF-dependent signaling pathway that involves the assembly of a large protein complex consisting of MET, AXL, ELMO2, and DOCK180 on the plasma membrane, leading to RAC1-dependent cell migration and invasion in various cancer cells.

Li W ，Xiong X ，Abdalla A ，Alejo S ，Zhu L ，Lu F ，Sun H ... -  《-》

Co-expression of hepatocyte growth factor and c-Met predicts peritoneal dissemination established by autocrine hepatocyte growth factor/c-Met signaling in gastric cancer.

Epithelial-mesenchymal transition (EMT) promotes and facilitates migration and invasion of epithelial tumor cells. EMT is induced by factors such as hepatocyte growth factor (HGF). This study aimed to establish whether the HGF/c-Met pathway is associated with gastric cancer metastasis; especially peritoneal dissemination. HGF and c-Met expression and EMT-related molecules were evaluated using real-time PCR and immunohistochemistry. The role of the HGF/c-Met pathway in EMT and anoikis was determined, and kinase inhibitor SU11274 was tested for its ability to block HGF-induced biological effects. In HGF(-) /c-Met(+) gastric cancer cells, recombinant HGF promoted an EMT phenotype that was characterized by morphology, impaired E-cadherin and induction of vimentin. HGF promoted cell growth, invasiveness and migration and inhibition of anoikis. SU11274 blocked HGF-induced EMT and biological effects in vitro. In HGF(+) /c-Met(+) gastric cancer cells, HGF did not affect the biological outcome of EMT and anoikis, but SU11274 exerted the same inhibitory effects as in HGF(-) /c-Met(+) cells. In vivo, HGF(+) /c-Met(+) gastric cancer cells only established peritoneal dissemination and SU11274 inhibited tumor growth. Clinically, HGF expression was significantly correlated with c-Met expression in gastric cancer. Increased HGF and c-Met had a significant association with poor prognosis and predicted peritoneal dissemination. We demonstrated that the HGF/c-Met pathway induces EMT and inhibition of anoikis in gastric cancer cells. Co-expression of HGF and c-Met has the potential to promote peritoneal dissemination in gastric cancer. Blockade of the autocrine HGF/c-Met pathway could be clinically useful for the treatment of peritoneal dissemination in gastric cancer.

Toiyama Y ，Yasuda H ，Saigusa S ，Matushita K ，Fujikawa H ，Tanaka K ，Mohri Y ，Inoue Y ，Goel A ，Kusunoki M ... -  《-》

Increased HGF Expression Induces Resistance to c-MET Tyrosine Kinase Inhibitors in Gastric Cancer.

Increased expression of hepatocyte growth factor (HGF) and MET proto-oncogene (c-MET) is associated with poor prognosis in various cancer types. Recently, it was reported that the expression of HGF induces resistance to tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor, human epidermal receptor receptor 2, and b-raf proto-oncogene. Here, we investigated the effects of HGF overexpression in gastric cancer cells in the absence or presence of c-MET TKIs. The effects of c-MET TKIs in gastric cancer cells with and without c-MET overexpression were determined in gastric cancer cell lines with various cell biology methods. Compared to the control, cells with induced expression of HGF showed increase in anchorage-independent colony formation (p<0.001). The c-MET TKIs inhibited HGF/c-MET downstream signaling, cell proliferation, migration and invasion, and triggered cell-cycle arrest in Hs746T cells. However, HGF-transfected cells were less affected. c-MET TKIs had inhibitory effects only on cells overexpressing c-MET. Furthermore, overexpression of HGF resulted in resistance to c-MET TKIs through an autocrine manner in gastric cancer cells.

Ahn SY ，Kim J ，Kim MA ，Choi J ，Kim WH ... -  《-》