Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme

The aim of the study was to characterize the interendothelial junctions in tumor microvessels of five cases of human glioblastoma multiforme. In addit ion to morphological analysis, tumors were screened for the expression of j unctional proteins, such as occludin, claudin-1, ZO-1 and catenins. The exp ression 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 analys is, under the conditions of tumor growth tight junction particles of endoth elial cells were almost exclusively associated with the exocytoplasmic frac ture face, providing evidence for a switch of the particles from the protop lasmic to the external leaflet of the endothelial membrane. These results s uggest a relationship between claudin-1 suppression and the alteration of t ight 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 junctio ns, was not detectable in most microvessels, whereas beta-catenin was abund antly labeled. In this context, it is of particular interest that the major ity of microvascular pericytes were negative for alpha-smooth muscle actin, which is a marker of differentiated pericytes, although pericytes were fre quently 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 dysregul ation of junctional proteins.