Abstract 4162: Interleukin–6 stimulates defective angiogenesis

The aim of this study was to investigate the effects of IL-6 in normal and tumour angiogenesis. In previous studies we found that elevated levels of the inflammatory cytokine interleukin-6, IL-6, were linked with poor prognosis in ovarian cancer patients by influencing tumour growth, invasion, angiogenesis and chemo-resistance. A clinical trial conducted in parallel with pre-clinical studies showed an anti-IL-6 antibody to have some activity in ovarian cancer patients and in xenograft models, with systemic and local reduction in pro-inflammatory and angiogenic factors such as TNF, IL-8 and VEGF. IL-6 directly induced vessel sprouting in the ex vivo aortic ring model, as well as stimulated endothelial cell proliferation and migration, with similar potency to VEGF. However, IL-6 itself did not induce VEGF in the endothelial cells tested. In contrast to VEGF, IL-6-stimulated aortic ring vessel sprouts had defective pericyte coverage. The mechanism of the IL-6 action on pericytes involved stimulation of the Notch ligand Jagged1 as well as Angiopoietin 2. When peritoneal ovarian cancer xenografts were treated with an anti-IL-6 antibody, pericyte coverage of vessels was restored. In addition, in human ovarian cancer biopsies there was an association between levels of IL-6mRNA, Jagged1 and Angiopoeitin2. Our findings have implications for the use of cancer therapies that target VEGF or IL-6 and for understanding abnormal angiogenesis in cancers, chronic inflammatory disease and stroke. Citation Format: Ganga Gopinathan, Carla Milagre, Oliver M.T Pearce, Louise Reynolds, Kairbaan Hodivala-Dilke, Andrew Leinster, Haihong Zhong, Robert E. Hollingsworth, Richard Thompson, James R. Whiteford, Frances Balkwill. Interleukin–6 stimulates defective angiogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4162. doi:10.1158/1538-7445.AM2015-4162