The Effects of Interleukin-6 on Angiogenesis

Abstract

Elevated levels of the inflammatory cytokine interleukin-6, IL-6, have been 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, via reduction in pro-inflammatory and angiogenic factors such as TNF-α, IL-8 and VEGF. Anti-IL-6 treatment also showed significant reductions in vascular area with decreased expression of an angiogenic factor Jagged1. The aim of my study was to investigate the effects of IL-6 on normal and tumour angiogenesis. I found that recombinant IL-6 stimulates angiogenesis in mouse and rat aortic ring assays and that it can also stimulate growth and migration of endothelial cells in vitro. IL-6 has similar potency as VEGF in inducing vessel sprouting. IL-6 itself does not induce VEGF in the endothelial cells I tested. Investigation of the effects of IL-6 on vessel maturation revealed a significant reduction in pericyte coverage of vessels treated with IL-6 compared with VEGF. Collectively, these data led to my hypothesis that ‘IL-6 drives aberrant angiogenesis, independent of VEGF signalling’. Investigating the mechanism by which IL-6 drives angiogenesis and leads to defective pericyte formation, I showed a link between IL-6 and the Notch ligands, Jagged1 and DLL4. My data suggested that IL-6 could stimulate Jagged1 in endothelial cells, whereas VEGF induces DLL4, the Notch ligand known to be involved in inducing stalk phenotype. Exploring previous findings to get a better understanding of the interaction of Notch ligands and pericyte recruitment also suggested a role of Angiopoeitin-2 in relation to IL-6 signalling. These observations were extended in IGROV-1 ovarian cancer xenografts treated with an anti-IL-6 antibody and by analysis of gene expression datasets from ovarian cancer biopsies. My results suggest therapeutic potential of combining inhibitors of IL-6 and VEGF in ovarian cancer.