Gagner Jean-Pierre, Sarfraz Yasmeen, Ortenzi Valerio, Alotaibi Fawaz M, Chiriboga Luis A, Tayyib Awab T, Douglas Garry J, Chevalier Eric, Romagnoli Barbara, Tuffin Gérald, Schmitt Michel, Lemercier Guillaume, Dembowsky Klaus, Zagzag David
Microvascular and Molecular Neuro-Oncology Laboratory, New York University Langone Medical Center, New York, New York; Department of Pathology, New York University Langone Medical Center, New York, New York.
Department of Pathology, New York University Langone Medical Center, New York, New York.
Am J Pathol. 2017 Sep;187(9):2080-2094. doi: 10.1016/j.ajpath.2017.04.020. Epub 2017 Jul 20.
Resistance to antiangiogenic therapy in glioblastoma (GBM) patients may involve hypoxia-induced expression of C-X-C motif chemokine receptor 4 (CXCR4) on invading tumor cells, macrophage/microglial cells (MGCs), and glioma stem cells (GSCs). We determined whether antagonizing CXCR4 with POL5551 disrupts anti-vascular endothelial growth factor (VEGF) therapy-induced glioma growth and dissemination. Mice bearing orthotopic CT-2A or GL261 gliomas received POL5551 and/or anti-VEGF antibody B20-4.1.1. Brain tissue was analyzed for tumor volume, invasiveness, hypoxia, vascular density, proliferation, apoptosis, GSCs, and MGCs. Glioma cells were evaluated for CXCR4 expression and polymorphism and POL5551's effects on CXCR4 ligand binding, cell viability, and migration. No CXCR4 mutations were identified. POL5551 inhibited CXCR4 binding to its ligand, stromal cell-derived factor-1α, and reduced hypoxia- and stromal cell-derived factor-1α-mediated migration dose-dependently but minimally affected cell viability. In vivo, B20-4.1.1 increased hypoxic foci and invasiveness, as seen in GBM patients receiving anti-VEGF therapy. Combination of POL5551 and B20-4.1.1 reduced both glioma invasiveness by 16% to 39% and vascular density compared to B20-4.1.1 alone in both glioma models. Reduced populations of GSCs and MGCs were also seen in CT-2A tumors. POL5551 concentrations, evaluated by mass spectrometry, were higher in tumors than in neighboring brain tissues, likely accounting for the results. Inhibition of CXCR4-regulated tumoral, stem cell, and immune mechanisms by adjunctive CXCR4 antagonists may help overcome antiangiogenic therapy resistance, benefiting GBM patients.
胶质母细胞瘤（GBM）患者对抗血管生成疗法产生耐药性，可能与缺氧诱导侵袭性肿瘤细胞、巨噬细胞/小胶质细胞（MGCs）和胶质瘤干细胞（GSCs）上C-X-C基序趋化因子受体4（CXCR4）的表达有关。我们研究了用POL5551拮抗CXCR4是否会破坏抗血管内皮生长因子（VEGF）治疗诱导的胶质瘤生长和扩散。携带原位CT-2A或GL261胶质瘤的小鼠接受POL5551和/或抗VEGF抗体B20-4.1.1。分析脑组织中的肿瘤体积、侵袭性、缺氧情况、血管密度、增殖、凋亡、GSCs和MGCs。评估胶质瘤细胞的CXCR4表达和多态性以及POL5551对CXCR4配体结合、细胞活力和迁移的影响。未发现CXCR4突变。POL555抑制CXCR4与其配体基质细胞衍生因子-1α的结合，并剂量依赖性地降低缺氧和基质细胞衍生因子-1α介导的迁移，但对细胞活力影响极小。在体内，B20-4.1.1增加了缺氧灶和侵袭性，这在接受抗VEGF治疗的GBM患者中也有出现。在两种胶质瘤模型中，与单独使用B20-4.1.1相比，POL5551和B20-4.1.1联合使用可使胶质瘤侵袭性降低16%至39%，血管密度也降低。在CT-2A肿瘤中还观察到GSCs和MGCs的数量减少。通过质谱评估，肿瘤中的POL5551浓度高于邻近脑组织，这可能是导致上述结果的原因。辅助性CXCR4拮抗剂抑制CXCR4调节的肿瘤、干细胞和免疫机制，可能有助于克服抗血管生成疗法耐药性，使GBM患者受益。
