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

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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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.

Original languageEnglish
Pages (from-to)1969-1973
Number of pages5
JournalJournal of Clinical Investigation
Volume121
Issue number5
DOIs
Publication statusPublished - May 2 2011

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Welford, A. F., Biziato, D., Coffelt, S. B., Nucera, S., Fisher, M., Pucci, F., Di Serio, C., Naldini, L., De Palma, M., Tozer, G. M., & Lewis, C. E. (2011). TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice. Journal of Clinical Investigation, 121(5), 1969-1973. https://doi.org/10.1172/JCI44562