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 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.
Liebner
S
S
Institute of Pathology, University of Tübingen, Germany.
Fischmann
A
A
Rascher
G
G
Duffner
F
F
Grote
E H
EH
Kalbacher
H
H
Wolburg
H
H
D001808:Blood Vessels / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D001812:Blood-Brain Barrier / Q000502:physiology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D062445:Claudin-1; D062507:Claudin-5; D003598:Cytoskeletal Proteins / Q000378:metabolism; D051180:Desmoplakins; D015536:Down-Regulation / Q000502:physiology; D004727:Endothelium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D062793:Occludin; D010750:Phosphoproteins / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D015534:Trans-Activators; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin; D051185:gamma Catenin
C568108:CLDN1 protein, human; C107466:CLDN5 protein, human; C495270:CTNNB1 protein, human; D062445:Claudin-1; D062507:Claudin-5; D003598:Cytoskeletal Proteins; D051180:Desmoplakins; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D010750:Phosphoproteins; C569042:TJP1 protein, human; D015534:Trans-Activators; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin; D051185:gamma Catenin