HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-12, Vol.70 (24), p.10090-10100
• Main Authors: Shojaei, Farbod, Lee, Joseph H, Simmons, Brett H, Wong, Anthony, Esparza, Carlos O, Plumlee, Pamela A, Feng, Junli, Stewart, Albert E, Hu-Lowe, Dana D, Christensen, James G
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - pharmacology; Animals; Drug Resistance, Neoplasm; Hepatocyte Growth Factor - biosynthesis; Hepatocyte Growth Factor - genetics; Hepatocyte Growth Factor - metabolism; Humans; Indoles - pharmacology; Mice; Mice, Nude; Neoplasms, Experimental - blood supply; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - genetics; Neoplasms, Experimental - metabolism; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; NIH 3T3 Cells; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - biosynthesis; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Pyrroles - pharmacology; Signal Transduction; Transfection
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-0489

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.