title: 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.affiliation: Tumour Microcirculation Group, The University of Sheffield Medical School, Sheffield, UK.
authors.forename: Abigail F
authors.initials: AF
authors.lastname: Welford
authors.forename: Daniela
authors.initials: D
authors.lastname: Biziato
authors.forename: Seth B
authors.initials: SB
authors.lastname: Coffelt
authors.forename: Silvia
authors.initials: S
authors.lastname: Nucera
authors.forename: Matthew
authors.initials: M
authors.lastname: Fisher
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Pucci
authors.forename: Clelia
authors.initials: C
authors.lastname: Di Serio
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
authors.forename: Michele
authors.initials: M
authors.lastname: De Palma
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Tozer
authors.forename: Claire E
authors.initials: CE
authors.lastname: Lewis
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002469:Cell Separation; D054377:Chemokine CXCL12 / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D008264:Macrophages / Q000378:metabolism*; D015674:Mammary Neoplasms, Animal; D051379:Mice; D008822:Mice, Transgenic; D009336:Necrosis / Q000473:pathology; D009368:Neoplasm Transplantation; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D042787:Receptor, TIE-2; D019718:Receptors, CXCR4 / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D013267:Stilbenes; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; C058728:fosbretabulin