Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts

Christina L. Roland, Sean P. Dineen, Kristi D. Lynn, Laura A. Sullivan, Michael T. Dellinger, Leila Sadegh, James P. Sullivan, David S. Shames, Rolf A. Brekken

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

Vascular endothelial growth factor (VEGF) is a primary stimulant of angiogenesis and is a macrophage chemotactic protein. Inhibition of VEGF is beneficial in combination with chemotherapy for some breast cancer patients. However, the mechanism by which inhibition of VEGF affects tumor growth seems to involve more than its effect on endothelial cells. In general, increased immune cell infiltration into breast tumors confers a worse prognosis. We have shown previously that 2C3, a mouse monoclonal antibody that prevents VEGF from binding to VEGF receptor 2 (VEGFR2), decreases tumor growth, angiogenesis, and macrophage infiltration into pancreatic tumors and therefore hypothesized that r84, a fully human IgG that phenocopies 2C3, would similarly affect breast tumor growth and immune cell infiltration. In this study, we show that anti-VEGF therapy with bevacizumab, 2C3, or r84 inhibits the growth of established orthotopic MDA-MB-231 breast tumors in severe combined immunodeficiency (SCID) mice, reduces tumor microvessel density, limits the infiltration of tumor-associated macrophages, but is associated with elevated numbers of tumor-associated neutrophils. In addition, we found that treatment with r84 reduced the number of CD11b+Gr1+ double-positive cells in the tumor compared with tumors from control-treated animals. These results show that selective inhibition of VEGFR2 with an anti-VEGF antibody is sufficient for effective blockade of the protumorigenic activity of VEGF in breast cancer xenografts. These findings further define the complex molecular interactions in the tumor microenvironment and provide a translational tool that may be relevant to the treatment of breast cancer.

Original languageEnglish (US)
Pages (from-to)1761-1771
Number of pages11
JournalMolecular Cancer Therapeutics
Volume8
Issue number7
DOIs
StatePublished - Jul 1 2009

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Heterografts
Vascular Endothelial Growth Factor A
Breast Neoplasms
Neoplasms
Macrophages
Growth
Severe Combined Immunodeficiency
Vascular Endothelial Growth Factor Receptor-2
Vascular Endothelial Growth Factor Receptor
Tumor Microenvironment
Microvessels
Combination Drug Therapy
Neutrophils
Therapeutics
Endothelial Cells
Immunoglobulin G
Monoclonal Antibodies
Antibodies
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts. / Roland, Christina L.; Dineen, Sean P.; Lynn, Kristi D.; Sullivan, Laura A.; Dellinger, Michael T.; Sadegh, Leila; Sullivan, James P.; Shames, David S.; Brekken, Rolf A.

In: Molecular Cancer Therapeutics, Vol. 8, No. 7, 01.07.2009, p. 1761-1771.

Research output: Contribution to journalArticle

Roland, Christina L. ; Dineen, Sean P. ; Lynn, Kristi D. ; Sullivan, Laura A. ; Dellinger, Michael T. ; Sadegh, Leila ; Sullivan, James P. ; Shames, David S. ; Brekken, Rolf A. / Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts. In: Molecular Cancer Therapeutics. 2009 ; Vol. 8, No. 7. pp. 1761-1771.
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