Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma
Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma
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DOI：
10.1073/pnas.1014480108
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发表时间：
2011-03-01
影响因子：
11.1
通讯作者：
Niclou, Simone P.
中科院分区：
文献类型：
--
作者：
Keunen, Olivier;Johansson, Mikael;Niclou, Simone P.
贝伐单抗是一种抗血管内皮生长因子（VEGF）的抗体，是一种很有前途的，但仍有争议的治疗人类胶质母细胞瘤（GBM）的药物。其对肿瘤负荷、复发和血管生理学的影响尚不清楚。因此，我们在源自患者肿瘤球状体的临床相关颅内GBM异种移植模型中，在表型、生理和分子水平上确定了肿瘤对贝伐珠单抗的反应。使用解剖和生理磁共振成像（MRI），我们表明，贝伐单抗导致对比度增强强烈下降，而对肿瘤生长只有轻微的影响。有趣的是，动态对比增强MRI显示血管供应显著减少，如肿瘤内血流量和血容量减少所证明的，在形态学水平上，大中型血管显著减少。电子显微镜显示在治疗的肿瘤细胞中线粒体较少。重要的是，这伴随着脑实质中浸润肿瘤细胞增加68%。在分子水平上，我们观察到乳酸和丙氨酸代谢产物的增加，以及缺氧诱导因子1 α的诱导和磷脂酰肌醇-3-激酶途径的激活。这些数据强烈表明，抗VEGF治疗诱导的血管重塑导致更缺氧的肿瘤微环境。这有利于肿瘤细胞朝向糖酵解的代谢变化，这导致肿瘤细胞侵入正常大脑的增强。目前的工作强调需要结合联合收割机抗血管生成治疗GBM与药物靶向特定的信号或代谢途径，糖酵解表型。
Bevacizumab, an antibody against vascular endothelial growth factor (VEGF), is a promising, yet controversial, drug in human glioblastoma treatment (GBM). Its effects on tumor burden, recurrence, and vascular physiology are unclear. We therefore determined the tumor response to bevacizumab at the phenotypic, physiological, and molecular level in a clinically relevant intracranial GBM xenograft model derived from patient tumor spheroids. Using anatomical and physiological magnetic resonance imaging (MRI), we show that bevacizumab causes a strong decrease in contrast enhancement while having only a marginal effect on tumor growth. Interestingly, dynamic contrast-enhanced MRI revealed a significant reduction of the vascular supply, as evidenced by a decrease in intratumoral blood flow and volume and, at the morphological level, by a strong reduction of large- and medium-sized blood vessels. Electron microscopy revealed fewer mitochondria in the treated tumor cells. Importantly, this was accompanied by a 68% increase in infiltrating tumor cells in the brain parenchyma. At the molecular level we observed an increase in lactate and alanine metabolites, together with an induction of hypoxia-inducible factor 1 alpha and an activation of the phosphatidyl-inositol-3-kinase pathway. These data strongly suggest that vascular remodeling induced by anti-VEGF treatment leads to a more hypoxic tumor microenvironment. This favors a metabolic change in the tumor cells toward glycolysis, which leads to enhanced tumor cell invasion into the normal brain. The present work underlines the need to combine anti-angiogenic treatment in GBMs with drugs targeting specific signaling or metabolic pathways linked to the glycolytic phenotype.