Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme
Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme
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DOI：
10.1007/s004010000180
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发表时间：
2000-09-01
影响因子：
12.7
通讯作者：
Wolburg, H
中科院分区：
文献类型：
--
作者：
Liebner, S;Fischmann, A;Wolburg, H
本研究的目的是研究5例人多形性胶质母细胞瘤微血管内皮细胞间连接的特征。除形态分析外，还筛查肿瘤连接蛋白的表达，如occludin、claudin-1、ZO-1和catenins。紧密连接蛋白claudin-1在大多数肿瘤微血管中表达缺失，而claudin-5和occludin仅在增生性血管中显著下调。冷冻断口分析表明，在肿瘤生长条件下，内皮细胞紧密连接的颗粒几乎完全与胞浆断裂面有关，这为内皮细胞颗粒从原生质膜向外叶转移提供了证据。这些结果提示，claudin-1的抑制与紧密连接形态的改变有关，这可能与内皮通透性的增加有关。突显肿瘤微血管未分化状态的是，白蛋白是成熟内皮细胞连接的关键蛋白，在大多数微血管中检测不到，而β-连环蛋白被大量标记。在这一背景下，特别有趣的是，大多数微血管周细胞的α-平滑肌肌动蛋白呈阴性，这是分化的周细胞的标志，尽管周细胞经常在电子显微镜下被发现。总之，这些数据表明，人类胶质瘤中微血管通透性的增加，导致了临床上严重的脑水肿症状，是连接蛋白调节失调的结果。
The aim of the study was to characterize the interendothelial junctions in tumor microvessels of five cases of human glioblastoma multiforme. In addition to morphological analysis, tumors were screened for the expression of junctional proteins, such as occludin, claudin-1, ZO-1 and catenins. The expression of the tight junction protein claudin-1 was lost in the majority of tumor microvessels, whereas claudin-5 and occludin were significantly down-regulated only in hyperplastic vessels. As shown by freeze-fracture analysis, under the conditions of tumor growth tight junction particles of endothelial cells were almost exclusively associated with the exocytoplasmic fracture face, providing evidence for a switch of the particles from the protoplasmic to the external leaflet of the endothelial membrane. These results suggest a relationship between claudin-1 suppression and the alteration of tight junction morphology, which is likely to correlate with the increase of endothelial permeability. Underlining the undifferentiated state of tumor microvessels, plakoglobin, a crucial protein for mature endothelial junctions, was not detectable in most microvessels, whereas beta-catenin was abundantly labeled. In this context, it is of particular interest that the majority of microvascular pericytes were negative for alpha-smooth muscle actin, which is a marker of differentiated pericytes, although pericytes were frequently found in electron micrographs. In conclusion, the data suggest that the increase in microvascular permeability in human gliomas, contributing to the clinically severe symptoms of brain edema, is a result of a dysregulation of junctional proteins.