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Data from HGF/c-Met Acts as an Alternative Angiogenic Pathway in Sunitinib-Resistant Tumors
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Data from HGF/c-Met Acts as an Alternative Angiogenic Pathway in Sunitinib-Resistant Tumors
Data from HGF/c-Met Acts as an Alternative Angiogenic Pathway in Sunitinib-Resistant Tumors
FS
Farbod Shojaei
Farbod Shojaei
JL
Joseph H. Lee
Joseph H. Lee
BS
Brett H. Simmons
Brett H. Simmons
AW
Anthony Wong
Anthony Wong
CE
Carlos O. Esparza
Carlos O. Esparza
PP
Pamela A. Plumlee
Pamela A. Plumlee
JF
Junli Feng
Junli Feng
AS
Albert E. Stewart
Albert E. Stewart
DH
Dana D. Hu-Lowe
Dana D. Hu-Lowe
JC
James G. Christensen
James G. Christensen
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30 March 2023
other
Published by
American Association for Cancer Research (AACR)
https://doi.org/10.1158/0008-5472.c.6501192
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. Cancer Res; 70(24); 10090–100. ©2010 AACR.
Keywords
MODELS
RESISTANT TUMORS
RESISTANCE TO SUNITINIB
EFFICACY
RESISTANCE TO ANTIANGIOGENIC THERAPY
HGF/C MET
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Open Access