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Clin Cancer Res. 2017 Nov 15;23(22):7034-7046. doi: 10.1158/1078-0432.CCR-17-0647. Epub 2017 Aug 29.

Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression.

Author information

1
Departments of Gynecologic Oncology and Reproductive Medicine.
2
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
3
Department of Melanoma Medical Oncology.
4
Experimental Therapeutics.
5
Departamento de Biologia Celular y Genetica, Universidad Autonoma de Nuevo Leon, San Nicolas de los Garza, Nuevo Leon, Mexico.
6
Benign Hematology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas.
8
Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
9
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
10
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
11
Departments of Gynecologic Oncology and Reproductive Medicine, asood@mdanderson.org.

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.

PMID:
28855350
PMCID:
PMC5690831
DOI:
10.1158/1078-0432.CCR-17-0647
[Indexed for MEDLINE]
Free PMC Article

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