The c-Met receptor: Implication for targeted therapies in colorectal cancer

Abstract

c-Met (mesenchymal-epithelial transition factor) is a tyrosine kinase receptor activated by hepatocyte growth factor and regulates multiple biological processes, such as cell scattering, survival, and proliferation. Aberrant c-Met signaling has been implicated in a variety of cancer types, including colorectal cancer. c-Met is genetically altered through various mechanisms that is associated with colorectal cancer progression and metastasis. Especially, in colorectal cancer, preclinical evidence for the aberrant activation of the c-Met signaling exists. Accordingly, molecular targeting of c-Met receptor could be a promising strategy, in the treatment of colorectal cancer patients. Recently, it was also shown that crosstalk between c-Met and other cell surface receptors attributes to tumorigenesis and development of therapeutic resistance. Characterization of the molecular mechanisms through which c-Met crosstalks with other receptors in favor of tumor formation and progression remains to explore. This review will describe the mechanisms of aberrant c-Met signaling in colorectal cancer and discuss on additional roles for c-Met receptor through crosstalk with other tyrosine kinase receptors and cell surface proteins in colorectal cancer. Novel therapeutic approaches for c-Met pathway targeting will also be discussed.

Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities

“…SEMA is the site where HGF binds directly to c-Met, and PSI can stabilize this interaction. Ser-975 and Tyr-1003 sites at the juxtamembrane domain play an important role in the negative regulation of c-Met [ 14 , 22 , 23 ]. When HGF binds c-Met, Tyr-1234 and Tyr-1235 in the intracellular tyrosine kinase domain undergo autophosphorylation, which results in autophosphorylation of Tyr-1349 and Tyr-1356 in the C-terminal docking site.…”

“…The HGF/c-Met axis, which can interact and cooperate with other types of tyrosine kinases, can stimulate various downstream signaling pathways in tumor cells, such as PI3K/AKT, JAK/STAT, Ras/MAPK, SRC, and Wnt/β-catenin, among others [ 10 – 13 ]. These aforementioned phenomena regulate multiple biological processes such as tumor proliferation, invasion, metastasis, anti-apoptosis, EMT, and angiogenesis [ 14 – 17 ]. It has been determined that c-Met gene mutations, overexpression, and amplification also occur in a variety of human tumor types, and these events are closely related to the aberrant activation of the HGF/c-Met signaling pathway [ 18 , 19 ].…”

The potential therapeutic and prognostic impacts of the c‐MET/HGF signaling pathway in colorectal cancer

“…It has been found that miRNAs can play a role in cancer biology as tumor suppressors or oncogenes are associated with c‐MET/HGF signaling pathway. Some miRNAs including miR‐1, miR‐34, miR‐141, miR‐199, and miR‐206 have been identified to be able to affect the c‐MET/HGF signaling pathway . Reid et al investigated miRNAs’ expression in untreated CRC patients .…”

“…c‐MET (mesenchymal–epithelial transition factor) is a tyrosine kinase cell surface receptor that upon binding of its ligand, hepatocyte growth factor (HGF), activates downstream effector pathways . Activation of the c‐MET/HGF signaling pathway regulates a variety of biological processes including cell motility and proliferation, angiogenesis, the epithelial‐to‐mesenchymal transition, and also the development and progression of cancer cells .…”

Phase I Study of Ramucirumab Plus Merestinib in Previously Treated Metastatic Colorectal Cancer: Safety, Preliminary Efficacy, and Pharmacokinetic Findings

“…Evidence to support such an approach includes the demonstration of cross talk between hepatocyte growth factor/c‐MET signaling and VEGFR in endothelial cells mediating angiogenesis [5], which may play a role in CRC progression. In addition, c‐MET has been implicated in mediating resistance to antiangiogenic therapy [6]. Specifically, an increase in tumor hypoxia (due to an antiangiogenic‐associated decrease in tumor vascularization) has been shown to increase c‐MET expression and, consequently, metastatic potential [7].…”