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PMID: 21490397 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The Journal of clinical investigation ·Vol. 121 ·No. 5 ·2011-05-00 ·Pages 1969-73

Welford AF, Biziato D, Coffelt SB, Nucera S, Fisher M, Pucci F, Di Serio C, Naldini L, De Palma M, Tozer GM, Lewis CE

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.

MeSH Terms
Animals Antineoplastic Agents, Phytogenic/pharmacology Cell Separation Chemokine CXCL12/metabolism Female Flow Cytometry Macrophages/metabolism Mammary Neoplasms, Animal Mice Mice, Transgenic Necrosis/pathology Neoplasm Transplantation Receptor Protein-Tyrosine Kinases/metabolism Receptor, TIE-2 Receptors, CXCR4/metabolism Stilbenes/pharmacology
Chemicals
Antineoplastic Agents, Phytogenic Chemokine CXCL12 Cxcl12 protein, mouse Receptors, CXCR4 Stilbenes Receptor Protein-Tyrosine Kinases Receptor, TIE-2 Tek protein, mouse fosbretabulin
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Welford Abigail F
Tumour Microcirculation Group, The University of Sheffield Medical School, Sheffield, UK.
Biziato Daniela
Coffelt Seth B
Nucera Silvia
Fisher Matthew
Pucci Ferdinando
Di Serio Clelia
Naldini Luigi
De Palma Michele
Tozer Gillian M
Lewis Claire E
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI44562
Published
2011-05-00
Epub
2011-00-01
Pages
1969-73
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC3083764
Subset
IM
Grants
Cancer Research UK · 13028 · United Kingdom
Cancer Research UK · 9993 · United Kingdom
Telethon · GTF07004 · Italy
Telethon · TGT11D02 · Italy
External Links
PubMed source DOI: 10.1172/JCI44562 PMC Full Text View journal details
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