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

Publication ,  Journal Article
Dalton, HJ; Pradeep, S; McGuire, M; Hailemichael, Y; Ma, S; Lyons, Y; Armaiz-Pena, GN; Previs, RA; Hansen, JM; Rupaimoole, R; Cho, MS; Wu, SY ...
Published in: Clin Cancer Res
November 15, 2017

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.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

November 15, 2017

Volume

23

Issue

22

Start / End Page

7034 / 7046

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Microenvironment
  • Receptors, Vascular Endothelial Growth Factor
  • Promoter Regions, Genetic
  • Oncology & Carcinogenesis
  • Neovascularization, Pathologic
  • Neoplasms
  • Mice
  • Macrophages
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
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Dalton, H. J., Pradeep, S., McGuire, M., Hailemichael, Y., Ma, S., Lyons, Y., … Sood, A. K. (2017). Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression. Clin Cancer Res, 23(22), 7034–7046. https://doi.org/10.1158/1078-0432.CCR-17-0647
Dalton, Heather J., Sunila Pradeep, Michael McGuire, Yared Hailemichael, Shaolin Ma, Yasmin Lyons, Guillermo N. Armaiz-Pena, et al. “Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression.Clin Cancer Res 23, no. 22 (November 15, 2017): 7034–46. https://doi.org/10.1158/1078-0432.CCR-17-0647.
Dalton HJ, Pradeep S, McGuire M, Hailemichael Y, Ma S, Lyons Y, et al. Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression. Clin Cancer Res. 2017 Nov 15;23(22):7034–46.
Dalton, Heather J., et al. “Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression.Clin Cancer Res, vol. 23, no. 22, Nov. 2017, pp. 7034–46. Pubmed, doi:10.1158/1078-0432.CCR-17-0647.
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. Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression. Clin Cancer Res. 2017 Nov 15;23(22):7034–7046.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

November 15, 2017

Volume

23

Issue

22

Start / End Page

7034 / 7046

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Microenvironment
  • Receptors, Vascular Endothelial Growth Factor
  • Promoter Regions, Genetic
  • Oncology & Carcinogenesis
  • Neovascularization, Pathologic
  • Neoplasms
  • Mice
  • Macrophages
  • Humans