Targeting c-MET/HGF Signaling Pathway in Upper Gastrointestinal Cancers: Rationale and Progress

Abstract

Aberrant activation of receptor-tyrosine kinase c-Met/HGF pathway is shown to be associated with cell proliferation, invasion, metastasis and poor-prognosis in several tumor types, including upper gastrointestinal-malignancies. The interaction of c-Met with multiple signalling-pathways involved in tumorigenic-properties and invasive-phenotype has gained substantial attention, suggesting its role as an intriguing-target for cancer-therapy. In recent years, there have been considerable efforts in the development of effective c-Met inhibitors with potential clinical-applications and one of them, crizotinib (dual c-Met/ALK inhibitor), has recently been approved for lung-cancers with ALKrearrangement. However several important questions remain to be answered on the molecular mechanisms underlying the antitumor effects of crizotinib, as well as on its possible role in the treatment of different tumor types, including uppergastrointestinal- cancers. The aim of this review is to give an overview on critical role of the c-Met/HGF pathway in cancer, and the preclinical/clinical studies on c-Met inhibitors. There are accumulating evidences on therapeutic potential of c-Met inhibitors for the treatment of other malignancies, such as gastric and pancreatic cancers. However, further investigations are needed to identify determinants of the activity of c-Met inhibitors, through the analysis of genetic/ environmental alterations affecting c-Met and parallel pro-cancer pathways; mechanisms result in developing resistance to anti-c-Met agents; and selection of patients that might benefit from therapy. These studies will be essential to improve the selectivity/efficacy of future anticancer strategies of c-Met targeted-therapies in the treatment of upper gastrointestinal- cancers.

Nicotine Reduces Survival via Augmentation of Paracrine HGF–MET Signaling in the Pancreatic Cancer Microenvironment

“…Therefore, HGF-MET paracrine signaling is not clinically applicable in the context of isolated PC cells in vitro or injected PC cell xenografts. Our data would therefore suggest that c-Met inhibition may still be a more prominent mechanism mediating the antitumor effects of Crizotinib in an intact tumor microenvironment containing up to 80% HGF-secreting stromal cells by mass, which is supported by multiple recent investigations (41, 45–47). …”

Intermittent Hypoxia in Pancreatic beta Cells

“…Recently, enhanced metastatic ability of IH-treated human pancreatic cancer cell lines (PANC-1 and BxPC-3) was also reported [58]. As Reg family proteins and HGF were reported to be over-expressed in some cancer cells and to influence cancer patient prognosis [41,[59][60][61][62][63][64][65][66][67][68][69][70][71][72], IH may accelerate tumor proliferation and/or invasion, ultimately resulting in an adverse outcome via over-expression of Reg family and/or HGF.…”

Targeting the tumor microenvironment as a potential therapeutic approach in colorectal cancer: Rational and progress

“…Angiogenesis is a process in which new blood vessels are formed from existing blood vessels. This process is important for the transportation of oxygen and nutrients (Gholamin et al, ). Angiogenesis is composed of five steps: (i) endothelial cell activation; (ii) basement membrane degradation; (iii) endothelial cell spread; (iv) blood vessel formation; and (v) angiogenic remodeling.…”

“…A large proportion of early‐stage patients are successfully treated with aggressive surgical resection of the primary tumor (Bahrami, Aledavoud, et al, ). However, many patients with stage II/III disease have recurrent disease, and this is frequently associated with metastases (Gholamin et al, ). Patients with stage IV disease and metastases, and those with a high risk of relapse, receive cytotoxic chemotherapy (Bahrami, Khazaei, et al, ).…”