Molecular mechanism(s) of regulation(s) of c-MET/HGF signaling in head and neck cancer

Abstract

Head and neck cancer is the sixth most common cancer across the globe. This is generally associated with tobacco and alcohol consumption. Cancer in the pharynx majorly arises through human papillomavirus (HPV) infection, thus classifying head and neck squamous cell carcinoma (HNSCC) into HPV-positive and HPV-negative HNSCCs. Aberrant, mesenchymal-epithelial transition factor (c-MET) signal transduction favors HNSCC progression by stimulating proliferation, motility, invasiveness, morphogenesis, and angiogenesis. c-MET upregulation can be found in the majority of head and neck squamous cell carcinomas. c-MET pathway acts on several downstream effectors including phospholipase C gamma (PLCγ), cellular Src kinase (c-Src), phosphotidylinsitol-3-OH kinase (PI3K), alpha serine/threonine-protein kinase (Akt), mitogen-activated protein kinase (MAPK), and wingless-related integration site (Wnt) pathways. c-MET also establishes a crosstalk pathway with epidermal growth factor receptor (EGFR) and contributes towards chemoresistance in HNSCC. In recent years, the signaling communications of c-MET/HGF in metabolic dysregulation, tumor-microenvironment and immune modulation in HNSCC have emerged. Several clinical trials have been established against c-MET/ hepatocyte growth factor (HGF) signaling network to bring up targeted and effective therapeutic strategies against HNSCC. In this review, we discuss the molecular mechanism(s) and current understanding of c-MET/HGF signaling and its effect on HNSCC.

Keywords: C-MET; Chemoresistance; EGFR; Head and neck squamous cell carcinoma; Hepatocyte growth factor; Monoclonal antibody.

Fig. 1

Different downstream signaling pathways activated through c-MET and its interactive other membrane receptors. HGF released through tumor associated fibroblast cells in microenvironment binds to c-MET and activates it through autophosphorylation of tyrosines Y1234 and Y1235 within the activation loop of the kinase domain and subsequent phosphorylation of tyrosines Y1349 and Y1356 near the -COOH terminus. Major adapter proteins and direct kinase substrates activated downstream in the c-MET pathway include growth factor receptor-bound protein 2 (GRB2), Grb2-associated adaptor protein 1 (GAB1), phosphatidylinositol 3-kinase (PI3K), son of sevenless (SOS), rat sarcoma oncogene homolog (RAS), mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3/5 (STAT 3/5), SRC, SRC homology protein tyrosine phosphatase 2 (SHP2), SRC homology domain c-terminal adaptor homolog (SHC), phospholipase c-γ (PLC), Ras-related C3 botulinum toxin substrate 1 (RAC1), p21-activated kinase (PAK), focal adhesion kinase (FAK), AKT, and mammalian target of rapamycin (mTOR). Crosstalk between c-MET and various membrane protein partners, including the epidermal growth factor receptor (EGFR), the plexin B family, α6β4 integrin, and CD44, results in additional signaling response modulation

Fig. 2

Chemotherapy resistant acquired in cancer cells via altered MET signaling. This includes overexpression of MET, activation sustained by HGF secreted by CAFs (cancer associated fibroblasts), constitutive activation of MET and secretion of HGF which is not normally expressed by epithelial cells, leading to an autocrine activation loop. This diagram illustrates the effect of EGFR inhibition through monoclonal antibodies alter/ activate MET signaling in cancer cells and causes the chemoresistance in cancer cells through c-MET activation which simultaneously cause reduced apoptosis, increased proliferation, enhanced DNA repair, upregulation of drug efflux and stimulation of epithelial-mesenchymal transition. All these changes contribute to the development of chemotherapy resistance

Fig. 3

MET therapeutic strategies in the inhibition of cancer survival. Aberrant HGF stimulation of MET in human cancer through paracrine signaling activates the receptor. MET activation results in the recruitment and activation of downstream adaptor proteins and kinase targets resulting in a multitude of effects such as increased cell proliferation, cell cycle progression, scattering, motility, survival, extracellular matrix remodeling, and changes in metabolism. Therapeutic intervention strategies to block and inhibit MET receptor oncogenic signaling cascade include blocking ligand-receptor interaction, preventing receptor dimerization, blocking MET kinase intrinsic activity, and inhibiting specific downstream signal transducers