Plasmalemmal vesicle associated protein-1 is a novel marker implicated in brain tumor angiogenesis
Plasmalemmal vesicle associated protein-1 is a novel marker implicated in brain tumor angiogenesis
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DOI：
10.1158/1078-0432.ccr-05-1099
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发表时间：
2005-11-01
影响因子：
11.5
通讯作者：
Walter, KA
中科院分区：
文献类型：
--
作者：
Carson-Walter, EB;Hampton, J;Walter, KA
目的：质膜囊泡相关蛋白-1（PV-1）在人脑胶质母细胞瘤内皮细胞中表达上调。我们试图进一步描述PV-1在人脑肿瘤中的表达模式，并询问其在脑肿瘤血管生成中的作用。实验设计：定量逆转录- PCR和原位杂交用于测量PV-1在46例人脑肿瘤和相关病理状态中的表达。Matrigel tubulogenesis测定和细胞迁移测定被用来显示PV-1在原代人内皮细胞（HMVEC）基因敲低conditions.Results的功能：PV-1是选择性上调，在各种高级别的人脑肿瘤，包括胶质母细胞瘤和转移癌，以及其他脑疾病与血脑屏障破坏，如急性缺血。在低级别肿瘤中表达水平降低;然而，与室管膜和脉络丛相关的肿瘤（PV-1表达的已知部位）也表现出稳健的表达。脑内PV-1 mRNA表达仅限于内皮细胞。通过暴露于U87 MG和U251 MG人脑肿瘤细胞系的条件培养基以及添加外源性血管内皮生长因子或分散因子/肝细胞生长因子的培养基，在体外诱导HMVEC细胞中PV-1表达。RNA干扰介导的抑制PV-1在HMVEC细胞中的诱导阻断了Matrigel诱导的小管形成，并抑制了条件培养基或血管生成生长因子诱导的细胞迁移。PV-1表达的抑制与体外内皮分化失败相关。PV-1代表了脑肿瘤血管生成和血脑屏障完整性的新标志物，是潜在的治疗靶点。
Purpose: Plasmalemmal vesicle associated protein-1 (PV-1) is up-regulated in the endothelium of human glioblastoma. We sought to further characterize the expression pattern of PV-1 in human brain tumors and interrogate its role in brain tumor angiogenesis.Experimental Design: Quantitative reverse transcription- PCR and in situ hybridization were used to measure PV-1 expression in a panel of 46 human brain tumors and related pathologic states. Matrigel tubulogenesis assays and cell migration assays were used to show function of PV-1 in primary human endothelial cells (HMVEC) under gene knockdown conditions.Results: PV-1 is selectively up-regulated in a variety of high-grade human brain tumors, including glioblastoma and metastatic carcinoma, as well as other cerebral disorders associated with bloodbrain barrier disruption, such as acute ischemia. Expression levels were reduced in low-grade neoplasia; however, tumors associated with the ependyma and choroid plexus, known sites of PV-1 expression, also exhibited robust expression. Cerebral expression of PV-1 mRNA was confined to endothelial cells in all cases. PV-1 expression was induced in HMVEC cells in vitro by exposure to medium conditioned by U87MG and U251MG human brain tumor cell lines and by medium supplemented with exogenous vascular endothelial growth factor or scatter factor/hepatocyte growth factor. RNA interference -mediated inhibition of PV-1 induction in HMVEC cells blocked Matrigel -induced tubulogenesis and inhibited cell migration induced by conditioned medium or angiogenic growth factors.Conclusions: Our results confirm that PV-1 is preferentially induced in the endothelium of highgrade human brain tumors. Inhibition of PV-1 expression is associated with failure of endothelial differentiation in vitro. PV-1 represents a novel marker of brain tumor angiogenesis and integrity of the blood-brain barrier and is a potential therapeutic target.