IL-8 associates with a pro-angiogenic and mesenchymal subtype in glioblastoma

// Siobhan Conroy 1, 2 , Frank A.E. Kruyt 3 , Michiel Wagemakers 4 , Krishna P.L. Bhat 2, * and Wilfred F.A. den Dunnen 1, * 1 Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 2 Department of Translational Molecular Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA 3 Department of Neurosurgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 4 Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands * These authors share senior authorship Correspondence to: Wilfred F.A. den Dunnen, email: w.f.a.den.dunnen@umcg.nl Keywords: glioblastoma; subclasses; angiogenesis; IL-8 Received: September 07, 2017      Accepted: February 10, 2018      Epub: February 28, 2018      Published: March 20, 2018 ABSTRACT Glioblastoma (GBM) is a highly aggressive brain tumor characterized by a high rate of vascularization. However, therapeutic targeting of the vasculature through anti-vascular endothelial growth factor (VEGF) treatment has been disappointing, for which Angiopoietin-2 (Ang-2) upregulation has partly been held accountable. In this study we therefore explored the interplay of Ang-2 and VEGFA and their effect on angiogenesis in GBM, especially in the context of molecular subclasses. In a large patient cohort we identified that especially combined high expression of Ang-2 and VEGFA predicted poor overall survival of GBM patients. The high expression of both factors was also associated with increased IL-8 expression in GBM tissues, but in vitro stimulation with Ang-2 and/or VEGFA did not indicate tumor or endothelial cell-specific IL-8 responses. Glioblastoma stem cells (GSCs) of the mesenchymal (MES) subtype showed dramatically higher expression of IL8 when compared to proneural (PN) GSCs. Secreted IL-8 derived from MES GSCs induced endothelial proliferation and tube formation, and the MES GBMs had increased counts of proliferating endothelial cells. Our results highlight a critical pro-angiogenic role of IL-8 in MES GBMs.