TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice
Abigail F. Welford, … , Gillian M. Tozer, Claire E. Lewis
Abigail F. Welford, … , Gillian M. Tozer, Claire E. Lewis
Published April 1, 2011
Citation Information: J Clin Invest. 2011;121(5):1969-1973. https://doi.org/10.1172/JCI44562.
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Brief Report Oncology

TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice

Abstract

Vascular-disrupting agents (VDAs) such as combretastatin A4 phosphate (CA4P) selectively disrupt blood vessels in tumors and induce tumor necrosis. However, tumors rapidly repopulate after treatment with such compounds. Here, we show that CA4P-induced vessel narrowing, hypoxia, and hemorrhagic necrosis in murine mammary tumors were accompanied by elevated tumor levels of the chemokine CXCL12 and infiltration by proangiogenic TIE2-expressing macrophages (TEMs). Inhibiting TEM recruitment to CA4P-treated tumors either by interfering pharmacologically with the CXCL12/CXCR4 axis or by genetically depleting TEMs in tumor-bearing mice markedly increased the efficacy of CA4P treatment. These data suggest that TEMs limit VDA-induced tumor injury and represent a potential target for improving the clinical efficacy of VDA-based therapies.

Authors

Abigail F. Welford, Daniela Biziato, Seth B. Coffelt, Silvia Nucera, Matthew Fisher, Ferdinando Pucci, Clelia Di Serio, Luigi Naldini, Michele De Palma, Gillian M. Tozer, Claire E. Lewis

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Figure 1

CA4P induced vascular damage, increased tumor hypoxia, and increased TEM numbers in MMTV-PyMT mammary tumors.

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CA4P induced vascular damage, increased tumor hypoxia, and increased TEM...
(A) H&E staining shows a marked increase in tumor necrosis (N) 24 hours after 50 mg/kg CA4P. (B) Staining with anti-PIMO shows increased hypoxia (red). (C) Tumor sections stained with anti-CD31 antibodies show reduced lumen of blood vessels (white) 24 hours after 50 mg/kg CA4P. (D) Tumors stained with DAPI (to show cell nuclei; blue), anti-F4/80 (green), and anti-TIE2 (red). Yellow arrows denote F4/80+TIE2+ TEMs; F4/80–TIE2+ structures represent blood vessels. (E) Number of all F4/80+ cells/field and F4/80+TIE2+ TEMs/field (by immunofluorescent staining; see D above) and proportion (%) of F4/80+TIE2– and F4/80+TIE2+ cells (TEMs) in viable cells obtained from dispersed tumors (by flow cytometric analysis; see Supplemental Figure 1). Scale bars: 50 μm. *P < 0.05, **P < 0.01, ***P < 0.001, compared with relevant control group. NS, no statistical difference (P > 0.05).