Hepatocyte growth factor/MET in cancer progression and biomarker discovery

Abstract

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.

Targeting c‐met receptor tyrosine kinase by the DNA aptamer SL1 as a potential novel therapeutic option for myeloma

“…Phosphorylation of Y1349 and Y1356 creates a multisubstrate docking site that is necessary for the induction of downstream signaling cascades such as Ras/Raf/MAPK, PI3K/AKT/mTOR, and/or STAT3/5. These signaling cascades drive distinct biological responses including cell growth, inhibition of apoptosis, cell migration and angiogenesis . MM cells express c‐met and often simultaneously express HGF, thus creating an HGF/c‐met autocrine loop.…”

Next-generation sequencing reveals lymph node metastasis associated genetic markers in colorectal cancer

“…The combination of emerging and traditional therapies improves the level of disease-free survival, survival rate and prognosis in patients with colorectal cancer. However, disease recurrence following surgery or chemotherapy, drug resistance and deterioration remains inevitable (5,6).…”

Activation of extracellular signal‐regulated kinase is associated with hepatocellular carcinoma with aggressive phenotypes

“…The ERK pathway is activated by various stimuli, including receptor tyrosine kinase and G protein‐coupled receptors . A key role of the HGF/c‐MET axis in activation of the downstream ERK signaling pathway has been identified in a number of cancer types, including HCC . In our in vitro study, administration of HGF induced ERK activation and promoted cell proliferation.…”

“…Immunohistochemical analyses showed a positive correlation between ERK activation and c‐MET expression. Consequently, we investigated the functional role of ERK in HCC cell lines exposed to HGF, a c‐MET ligand that triggers activation of the Raf/MEK/ERK pathway . Sorafenib, a multikinase inhibitor, is universally used to treat HCC.…”