Activated HGF-c-Met Axis in Head and Neck Cancer

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a highly morbid disease. Recent developments including Food and Drug Administration (FDA) approved molecular targeted agent’s pembrolizumab and cetuximab show promise but did not improve the five-year survival which is currently less than 40%. The hepatocyte growth factor receptor; also known as mesenchymal–epithelial transition factor (c-Met) and its ligand hepatocyte growth factor (HGF) are overexpressed in head and neck squamous cell carcinoma (HNSCC); and regulates tumor progression and response to therapy. The c-Met pathway has been shown to regulate many cellular processes such as cell proliferation, invasion, and angiogenesis. The c-Met pathway is involved in cross-talk, activation, and perpetuation of other signaling pathways, curbing the cogency of a blockade molecule on a single pathway. The receptor and its ligand act 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 activate protein kinase (MAPK), and wingless-related integration site (Wnt) pathways. They are also known to cross-talk with other receptors; namely epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) and specifically contribute to treatment resistance. Clinical trials targeting the c-Met axis in HNSCC have been undertaken because of significant preclinical work demonstrating a relationship between HGF/c-Met signaling and cancer cell survival. Here we focus on HGF/c-Met impact on cellular signaling in HNSCC to potentiate tumor growth and disrupt therapeutic efficacy. Herein we summarize the current understanding of HGF/c-Met signaling and its effects on HNSCC. The intertwining of c-Met signaling with other signaling pathways provides opportunities for more robust and specific therapies, leading to better clinical outcomes.

Activated hepatic stellate cells promote progression of post-heat residual hepatocellular carcinoma from autophagic survival to proliferation

“…HGF/c-Met signaling modulated the biological status of autophagy or proliferation c-Met as the only receptor of HGF is often over-expressed in cancers [25]. HGF/c-Met signaling is strongly associated with survival of cancer cells [26]. In addition, ERK1/2 is the direct downstream effector of c-Met [27].…”

Pathological roles of c‑Met in bladder cancer: Association with cyclooxygenase‑2, heme oxygenase‑1, vascular endothelial growth factor‑A and programmed death ligand�1

“…c-Met is a receptor tyrosine kinase that binds a specific ligand, namely hepatocyte growth factor (HGF). In many types of cancer, the HGF/c-Met system is important for malignant potential, cancer cell invasion, metastasis, and determining clinical outcomes (4,5). In fact, cancer cell proliferation, cell cycle, migration, and angiogenesis were previously suggested as HGF/c-Met-related pathological mechanisms, based on in vivo and in vitro studies (6)(7)(8).…”

Hepatocyte Growth Factor Receptor overexpression predicts reduced survival but its targeting is not effective in unselected HNSCC patients

“…In addition, overexpression of HGF was detected in clinical samples and associated with metastasis and prognosis . Overexpression of MET and its ligand HGF have been reported in HNSCC as well, but initial clinical trials with MET inhibitors in HNSCC patients have been disappointing . Therefore, we elected to reinvestigate the relevance of MET as a potential therapeutic target in HNSCC using the selective MET inhibitor BAY‐853474 and reevaluate the prognostic value of MET expression.…”