Conroy Siobhan, Kruyt Frank A E, Wagemakers Michiel, Bhat Krishna P L, den Dunnen Wilfred F A
Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Translational Molecular Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA.
Oncotarget. 2018 Feb 28;9(21):15721-15731. doi: 10.18632/oncotarget.24595. eCollection 2018 Mar 20.
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 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.
胶质母细胞瘤（GBM）是一种高度侵袭性的脑肿瘤，其特征是血管化程度高。然而，通过抗血管内皮生长因子（VEGF）治疗对脉管系统进行治疗靶向一直令人失望，血管生成素-2（Ang-2）上调在一定程度上对此负有责任。因此，在本研究中，我们探讨了Ang-2和VEGFA的相互作用及其对GBM中血管生成的影响，特别是在分子亚类的背景下。在一个大型患者队列中，我们发现特别是Ang-2和VEGFA的联合高表达预示着GBM患者的总体生存率较差。这两种因子的高表达也与GBM组织中IL-8表达增加有关，但用Ang-2和/或VEGFA刺激并未显示出肿瘤或内皮细胞特异性的IL-8反应。与神经干细胞样（PN）胶质母细胞瘤干细胞（GSCs）相比，间充质（MES）亚型的胶质母细胞瘤干细胞显示出显著更高的IL8表达。源自MES GSCs的分泌型IL-8诱导内皮细胞增殖和管形成，并且MES GBMs中增殖内皮细胞的数量增加。我们的结果突出了IL-8在MES GBMs中的关键促血管生成作用。
