IL-8 associates with a pro-angiogenic and mesenchymal subtype in glioblastoma
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Siobhan Conroy1,2, Frank A.E. Kruyt3, Michiel Wagemakers4, Krishna P.L. Bhat2,* and Wilfred F.A. den Dunnen1,*
1Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
2Department of Translational Molecular Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA
3Department of Neurosurgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
4Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
*These authors share senior authorship
Wilfred F.A. den Dunnen, email: email@example.com
Keywords: glioblastoma; subclasses; angiogenesis; IL-8
Received: September 07, 2017 Accepted: February 10, 2018 Epub: February 28, 2018 Published: March 20, 2018
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.
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