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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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 2

Inhibition of tumor recruitment of CXCR4+ TEMs increases the therapeutic efficacy of CA4P.

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Inhibition of tumor recruitment of CXCR4+ TEMs increases the therapeutic...
(A) CXCL12 expression, determined by immunofluorescence staining (see Supplemental Figure 3), was increased in MMTV-PyMT tumors 24 hours after injection with 50 mg/kg CA4P. (B and C) Flow cytometric analysis of dispersed MMTV-PyMT tumors shows that (B) the majority of F4/80+TIE2+ TEMs express CXCR4 and the MFI for CXCR4 is higher for TEMs than TIE2– TAMs and (C) CXCR4 expression/TEM is upregulated after CA4P treatment. (D) The CXCR4 inhibitor, AMD-3100, inhibits recruitment of TEMs, but not TIE2– TAMs, to MMTV-PyMT tumors and increases CA4P-induced tumor necrosis. n > 5 mice per group. *P < 0.05; **P < 0.01. (E) Twice daily i.p. injections of 5 mg/kg AMD-3100 (for the period indicated) enhanced the effects of 3 daily i.p. injections of 50 mg/kg CA4P on the growth of N202 tumors. Statistical analysis in E employed the nonlinear mixed effects model described in the Supplemental Methods.