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

Authors :
Abigail F. Welford
Michele De Palma
Seth B. Coffelt
Luigi Naldini
Silvia Nucera
Gillian M. Tozer
Ferdinando Pucci
Matthew Fisher
Claire E. Lewis
Daniela Biziato
Clelia Di Serio
Welford, A. F.
Biziato, D.
Coffelt, S. B.
Nucera, S.
Fisher, M.
Pucci, F.
DI SERIO, Mariaclelia
Naldini, L.
De Palma, M.
Tozer, G. M.
Lewis, C. E.
Source :
Journal of Clinical Investigation
Publication Year :
2011
Publisher :
American Society for Clinical Investigation, 2011.

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.

Details

ISSN :
00219738
Volume :
121
Database :
OpenAIRE
Journal :
Journal of Clinical Investigation
Accession number :
edsair.doi.dedup.....2a238efa208786e55b79bfbe09247e1b
Full Text :
https://doi.org/10.1172/jci44562