Updates on the hepatocyte growth factor/c-Met axis in hepatocellular carcinoma and its therapeutic implications

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer and is the second leading cause of cancer death. Since the diagnosis of HCC is difficult, in many cases patients with HCC are diagnosed advanced stage of development. Hepatocyte growth factor (HGF)/c-mesenchymal-epithelial transition receptor (c-Met) axis is a key signaling pathway in HCC, either via canonical or non-canonical pathways. Available treatments against HCC based upon HGF/c-Met inhibition can increase patient lifespan, but do not reach the expected therapeutic benefits. In HCC, c-Met monomers can bind other receptor monomers, activating several noncanonical signaling pathways, leading to increased cell proliferation, invasion, motility, and drug resistance. All of these processes are enhanced by the tumor microenvironment, with stromal cells contributing to boost tumor progression through oxidative stress, angiogenesis, lymphangiogenesis, inflammation, and fibrosis. Novel treatments against HCC are being explored to modulate other targets such as microRNAs, methyltransferases, and acetyltransferases, which are all involved in the regulation of gene expression in cancer. This review compiles basic knowledge regarding signaling pathways in HCC, and compounds already used or showing potential to be used in clinical trials.

Second-line cabozantinib after sorafenib treatment for advanced hepatocellular carcinoma: a subgroup analysis of the phase 3 CELESTIAL trial

“…Importantly, the improvements observed in the <3 month subgroup suggest that cabozantinib has activity in patients who are intolerant or refractory to first-line sorafenib, a subgroup who would have been ineligible for RESORCE. Cabozantinib inhibits multiple receptor tyrosine kinases implicated in HCC pathogenesis and treatment resistance (MET, AXL and VEGF receptors), [1][2][3][4][5][6] which may help to overcome both primary and secondary sorafenib resistance and could contribute to the observed efficacy across varying durations of prior sorafenib. The analysis presented here has limitations.…”

Five gene signatures were identified in the prediction of overall survival in resectable pancreatic cancer

“…4 Nomogram for predicting 1-, 3-, and 5-year OS and Calibration curves for the nomogram in validation set overexpression of HIST1H1C is associated with unfavorable prognosis in adrenocortical carcinoma [40] and nonfunctional pituitary adenomas [41]. Methyltransferase (MET) is a proto-oncogene encoding the receptor tyrosine kinase c-MET for hepatocyte growth factor (HGF) [42], which triggers cell migration, proliferation, and angiogenesis. Aberrant MET expression is commonly expressed in various malignancies [43][44][45][46][47].…”

Long non-coding RNA RP11-284P20.2 promotes cell proliferation and invasion in hepatocellular carcinoma by recruiting EIF3b to induce c-met protein synthesis

“…Growing number of studies suggests that the occurrence of HCC is associated with an aberrant activation of c-met, a transmembrane tyrosine kinase receptor of hepatocyte growth factor (HGF). The primary function of the c-met pathway is largely restricted to organ morphogenesis during development, with a limited role in damage repair and regeneration of tissue in adults [3,4]. However, abnormal activation of the HGF/c-met pathway has been found to stimulate cell proliferation, survival, migration, invasion, angiogenesis, and morphogenic differentiation.…”

“…However, abnormal activation of the HGF/c-met pathway has been found to stimulate cell proliferation, survival, migration, invasion, angiogenesis, and morphogenic differentiation. These pleiotropic effects of c-met are mainly associated with the interaction of c-met cytoplasmic domain with multiple proteins, such as epithelial growth factor receptor, chemokine receptor 4, vascular endothelial growth factor receptor 2, and fibroblast growth factor receptor [3,4].…”