title: Interleukin-6 Stimulates Defective Angiogenesis.
abstract: The cytokine IL6 has a number of tumor-promoting activities in human and experimental cancers, but its potential as an angiogenic agent has not been fully investigated. Here, we show that IL6 can directly induce vessel sprouting in the ex vivo aortic ring model, as well as endothelial cell proliferation and migration, with similar potency to VEGF. However, IL6-stimulated aortic ring vessel sprouts had defective pericyte coverage compared with VEGF-stimulated vessels. The mechanism of IL6 action on pericytes involved stimulation of the Notch ligand Jagged1 as well as angiopoietin2 (Ang2). When peritoneal xenografts of ovarian cancer were treated with an anti-IL6 antibody, pericyte coverage of vessels was restored. In addition, in human ovarian cancer biopsies, there was an association between levels of IL6 mRNA, Jagged1, and Ang2. Our findings have implications for the use of cancer therapies that target VEGF or IL6 and for understanding abnormal angiogenesis in cancers, chronic inflammatory disease, and stroke.
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: Ganga
authors.initials: G
authors.lastname: Gopinathan
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: Carla
authors.initials: C
authors.lastname: Milagre
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: Oliver M T
authors.initials: OM
authors.lastname: Pearce
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Reynolds
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: Kairbaan
authors.initials: K
authors.lastname: Hodivala-Dilke
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Leinster
authors.affiliation: MedImmune, One MedImmune Way, Gaithersburg, Maryland.
authors.forename: Haihong
authors.initials: H
authors.lastname: Zhong
authors.affiliation: MedImmune, One MedImmune Way, Gaithersburg, Maryland.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hollingsworth
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Thompson
authors.affiliation: William Harvey Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors.forename: James R
authors.initials: JR
authors.lastname: Whiteford
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom. f.balkwill@qmul.ac.uk.
authors.forename: Frances
authors.initials: F
authors.lastname: Balkwill
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy / Q000379:methods; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009924:Organ Culture Techniques; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020286:Pericytes / Q000187:drug effects / Q000473:pathology; D017208:Rats, Wistar; D000072099:Serrate-Jagged Proteins; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology; D033921:Vesicular Transport Proteins / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D002135:Calcium-Binding Proteins; C508600:IL6 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C000606275:Jag1 protein, rat; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins; C555023:VPS51 protein, human; D042461:Vascular Endothelial Growth Factor A; D033921:Vesicular Transport Proteins