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 3

Conditional depletion of TEMs increases the efficacy of CA4P treatment.

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Conditional depletion of TEMs increases the efficacy of CA4P treatment. ...
(A) N202 tumors excised 24 hours after the last of 3 daily i.p. injections of CA4P or saline in the presence or absence of GCV to deplete TEMs were stained with DAPI (blue), anti-F4/80 (green), anti-TIE2 (red), and anti-MMP9 (white). TEMs are highlighted with yellow arrows; non-TAMs that express MMP9 are shown with white arrows. Scale bar: 50 μm. (B and C) Changes in TEM numbers and tumor necrotic area 24 hours and 72 hours after last CA4P injection. n = 6 mice per group. *P < 0.05.