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Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression. Clin Cancer Res 2017 Nov 15;23(22):7034-7046

Date

09/01/2017

Pubmed ID

28855350

Pubmed Central ID

PMC5690831

DOI

10.1158/1078-0432.CCR-17-0647

Scopus ID

2-s2.0-85034821972   25 Citations

Abstract

Purpose: VEGF-targeted therapies have modest efficacy in cancer patients, but acquired resistance is common. The mechanisms underlying such resistance are poorly understood.Experimental Design: To evaluate the potential role of immune cells in the development of resistance to VEGF blockade, we first established a preclinical model of adaptive resistance to anti-VEGF therapy. Additional in vitro and in vivo studies were carried out to characterize the role of macrophages in such resistance.Results: Using murine cancer models of adaptive resistance to anti-VEGF antibody (AVA), we found a previously unrecognized role of macrophages in such resistance. Macrophages were actively recruited to the tumor microenvironment and were responsible for the emergence of AVA resistance. Depletion of macrophages following emergence of resistance halted tumor growth and prolonged survival of tumor-bearing mice. In a macrophage-deficient mouse model, resistance to AVA failed to develop, but could be induced by injection of macrophages. Downregulation of macrophage VEGFR-1 and VEGFR-3 expression accompanied upregulation of alternative angiogenic pathways, facilitating escape from anti-VEGF therapy.Conclusions: These findings provide a new understanding of the mechanisms underlying the modest efficacy of current antiangiogenesis therapies and identify new opportunities for combination approaches for ovarian and other cancers. Clin Cancer Res; 23(22); 7034-46. ©2017 AACR.

Author List

Dalton HJ, Pradeep S, McGuire M, Hailemichael Y, Ma S, Lyons Y, Armaiz-Pena GN, Previs RA, Hansen JM, Rupaimoole R, Gonzalez-Villasana V, Cho MS, Wu SY, Mangala LS, Jennings NB, Hu W, Langley R, Mu H, Andreeff M, Bar-Eli M, Overwijk W, Ram P, Lopez-Berestein G, Coleman RL, Sood AK

Author

Sunila Pradeep PhD Assistant Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antineoplastic Agents
Cell Line, Tumor
Cell Proliferation
Cell Survival
Disease Models, Animal
Drug Resistance, Neoplasm
Female
Gene Expression Regulation, Neoplastic
Humans
Macrophages
Mice
Neoplasms
Neovascularization, Pathologic
Promoter Regions, Genetic
Receptors, Vascular Endothelial Growth Factor
Tumor Microenvironment
Xenograft Model Antitumor Assays
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a