Endocan Is Upregulated on Tumor Vessels in Invasive Bladder Cancer Where It Mediates VEGF-A-Induced Angiogenesis
Endocan Is Upregulated on Tumor Vessels in Invasive Bladder Cancer Where It Mediates VEGF-A-Induced Angiogenesis
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DOI：
10.1158/0008-5472.can-12-1855
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发表时间：
2013-02-01
期刊：
影响因子：
11.2
通讯作者：
Detmar, Michael
中科院分区：
文献类型：
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作者：
Roudnicky, Filip;Poyet, Cedric;Detmar, Michael
肿瘤相关血管与正常血管不同，仅存在于肿瘤血管上的蛋白质可作为癌症抗血管生成治疗的生物标志物或靶点。通过比较人浸润性膀胱癌与正常膀胱组织血管内皮的转录谱，我们发现内皮细胞特异性分子内皮素（ESM1）在肿瘤血管上高度升高。侵袭性膀胱癌血管生成内皮尖端细胞的丝状伪足与Endocan相关。值得注意的是，肿瘤血管上的内啡肽表达与分期和侵袭性密切相关，预示着非侵袭性膀胱癌的无复发生存时间更短。浸润性膀胱癌患者血浆内啡肽和VEGF-A水平均高于健康人。在培养的血管内皮细胞或转基因小鼠中进行的机制研究表明，VEGF-A通过磷酸化和激活VEGFR-2来刺激内啡肽的表达，这是VEGF-A促进细胞迁移和成管所必需的。综上所述，我们的研究结果表明，破坏内源性与VEGFR-2或VEGF-A的相互作用可能为抑制肿瘤血管生成提供一种新的合理策略。此外，他们认为内啡肽可能作为一种有用的生物标志物，用于监测膀胱癌患者的疾病进展和vegf - a靶向治疗的疗效。癌症Res;73 (3);1097 - 106。(c) 2012年AACR。
Tumor-associated blood vessels differ from normal vessels and proteins present only on tumor vessels may serve as biomarkers or targets for antiangiogenic therapy in cancer. Comparing the transcriptional profiles of blood vascular endothelium from human invasive bladder cancer with normal bladder tissue, we found that the endothelial cell-specific molecule endocan (ESM1) was highly elevated on tumor vessels. Endocan was associated with filopodia of angiogenic endothelial tip cells in invasive bladder cancer. Notably, endocan expression on tumor vessels correlated strongly with staging and invasiveness, predicting a shorter recurrence-free survival time in noninvasive bladder cancers. Both endocan and VEGF-A levels were higher in plasma of patients with invasive bladder cancer than healthy individuals. Mechanistic investigations in cultured blood vascular endothelial cells or transgenic mice revealed that endocan expression was stimulated by VEGF-A through the phosphorylation and activation of VEGFR-2, which was required to promote cell migration and tube formation by VEGF-A. Taken together, our findings suggest that disrupting endocan interaction with VEGFR-2 or VEGF-A could offer a novel rational strategy to inhibit tumor angiogenesis. Furthermore, they suggest that endocan might serve as a useful biomarker to monitor disease progression and the efficacy of VEGF-A-targeting therapies in patients with bladder cancer. Cancer Res; 73(3); 1097-106. (c) 2012 AACR.