HGF/c-Met Acts as an Alternative Angiogenic Pathway in Sunitinib-Resistant Tumors

Abstract

Molecular and cellular mechanisms underlying resistance/low responsiveness to antiangiogenic compounds are under extensive investigations. Both populations of tumor and stroma (nontumor compartment) seem to contribute in inherent/acquired resistance to antiangiogenic therapy. Here, investigating in vivo efficacy of sunitinib in experimental models resulted in the identification of tumors that were resistant/ sensitive to the therapy. Analysis of tumor protein lysates indicated a greater concentration of hepatocyte growth factor (HGF) in resistant tumors than in sensitive ones. In addition, using flow cytometry, c-Met expression was found to be significantly higher in endothelial cells than in tumor cells, suggesting that HGF might target the vascular endothelial cells in resistant tumors. Combination of sunitinib and a selective c-Met inhibitor significantly inhibited tumor growth compared with sunitinib or c-Met inhibitor alone in resistant tumors. Histology and in vitro analyses suggested that combination treatment mainly targeted the vasculature in the resistant tumors. Conversely, systemic injection of HGF in the sensitive tumor models conferred resistance to sunitinib through maintenance of tumor angiogenesis. In conclusion, our study indicates a role for HGF/c-Met pathway in development of resistance to antiangiogenic therapy and suggests a potential strategy to circumvent resistance to vascular endothelial growth factor receptor tyrosine kinase inhibitor in the clinic.

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective

“…Several studies have suggested that factors such as FGF2 or platelet-derived growth factor, produced by either cancer or stromal cells, can contribute to the onset of resistance ( 57 , 61 ). Shojaei and colleagues ( 62 ) have shown that HGF production by the tumor stroma can also contribute to resistance to treatment with sunitinib, a multikinase inhibitor targeting the VEGF pathway. Indeed, they found that resistant tumors displayed a greater concentration of HGF and a high MET expression level in endothelial cells.…”

Arf6 regulates tumour angiogenesis and growth through HGF-induced endothelial β1 integrin recycling

“…Expression of both cMet and HGF is induced by hypoxiainducible factor 1a, further providing evidence for an important role of the HGF/cMet axis in adverse microenvironment conditions to promote tumour angiogenesis 14,15 . Importantly, it has been reported in a preclinical model that HGF/cMet signalling can act as an alternative angiogenic pathway in sunitinib-resistant tumours 16 . These observations indicate that targeting HGF/cMet signalling pathway in endothelial cells might be an effective approach to overcome the evasive resistance of cancer cells in the context of angiogenesis redundancy.…”

Development of a Novel c-MET–Based CTC Detection Platform

“…We have reproducibly isolated c-MET CTCs from patients with metastatic, treatment-refractory RCC, gastroesophageal, and colorectal adenocarcinomas. Patients were selected for high tumor burdens and treatment refractoriness to VEGF or EGFR/HER2-based therapies, where c-MET may play a role in mediating resistance (14,20). Surprisingly, c-MET CTCs were not detected in the majority of patients, indicating that this assay may not detect c-MET overexpressing, nonamplified CTCs.…”

“…Patients were enrolled for each of the following: prostate adenocarcinoma (10 patients), RCC (10 patients), colorectal adenocarcinoma (10 patients), urothelial carcinoma (8 patients), gastroesophageal adenocarcinoma (7 patients), and pancreatic adenocarcinoma (7 patients). Efforts were made to enroll patients with resistant disease to VEGF (RCC) or EGFR (colon) inhibitors, or for men with bone metastatic CRPC (prostate) to enrich for c-MET expression (13,14,20). All patients had metastatic disease with predominantly lymph node, liver, lung, and bone metastases (Table 1).…”