Relationship between survival and edema in malignant gliomas: Role of vascular endothelial growth factor and neuronal pentraxin 2
Relationship between survival and edema in malignant gliomas: Role of vascular endothelial growth factor and neuronal pentraxin 2
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DOI：
10.1158/1078-0432.ccr-06-2772
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发表时间：
2007-05-01
影响因子：
11.5
通讯作者：
Cloughesy, Timothy F.
中科院分区：
文献类型：
--
作者：
Carlson, Marc R. J.;Pope, Whitney B.;Cloughesy, Timothy F.
目的：血管内皮生长因子（VEGF）是一种强有力的血管通透性介质。VEGF抑制剂在一些恶性胶质瘤患者中减少水肿和肿瘤负荷，而其他患者则无反应。实验设计：我们使用DNA微阵列分析，检测了71例新诊断的恶性胶质瘤中VEGF和相关基因的表达，并分析了其与水肿和生存的关系。95%可信区间（95%CI），2.61-18.1; P < 0.0001]，但在有广泛水肿的肿瘤中没有。几个促血管生成基因的表达，包括肾上腺髓质素（相关系数0.80），缺氧诱导因子-1A（0.51）和血管生成素-2（0.44），与VEGF表达相关（均P < 0.0001），而几个抗血管生成基因呈负相关。与无VEGF表达增加的非水肿性肿瘤相比，水肿性肿瘤中有6个基因的表达增加了3倍以上。与VEGF相比，增加最多的神经元正五聚蛋白2（NPTX 2，7倍变化）预测具有最高水平水肿的肿瘤的存活（风险比，2.73; 95%Cl，1.49-5.02; P = 0.049）。NPTX 2与水通道蛋白3的表达密切相关（0.74，P < 0.0001）。这些结果表明，有VEGF依赖性和VEGF非依赖性的神经胶质瘤水肿的生产途径，并可能解释为什么水肿是不减少在一些患者抗VEGF治疗后。
Purpose: Vascular endothelial growth factor (VEGF) is a potent mediator of vascular permeability. VEGF inhibition reduces edema and tumor burden in some patients with malignant glioma, whereas others show no response. The role of VEGF expression in edema production and the relationship to survival is not well understood.Experimental Design: Using DNA microarray analysis, we examined VEGF and related gene expression in 71 newly diagnosed malignant gliomas and analyzed the relationship to edema and survival.Results and Conclusions: VEGF expression was predictive of survival in tumors with little or no edema [Cox proportional hazard model, 6.88; 95% confidence interval (95% CI), 2.61-18.1; P < 0.0001], but not in tumors with extensive edema. The expression of several proangiogenic genes, including adrenomedullin (correlation coefficient, 0.80), hypoxia-inducible factor-1A (0.51), and angiopoietin-2 (0.44), was correlated with VEGF expression (all with P < 0.0001), whereas that of several antiangiogenic genes was inversely correlated. The expression of six genes was increased greater than 3-fold in edematous versus nonedematous tumors in the absence of increased VEGF expression. The most increased, neuronal pentraxin 2 (NPTX2, 7-fold change), was predictive of survival in tumors with the highest levels of edema, in contrast to VEGF (hazard ratio, 2.73; 95% Cl, 1.49-5.02; P = 0.049). NPTX2 was tightly correlated with expression of the water channel aquaporin-3 (0.74, P < 0.0001). These results suggest that there are both VEGF-dependent and VEGF-independent pathways of edema production in gliomas and may explain why edema is not reduced in some patients following anti-VEGF treatment.