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Endothelial cell barrier impairment induced by glioblastomas and transforming growth factor beta2 involves matrix metalloproteinases and tight junction proteins

Ishihara, Hideyuki and Kubota, Hisashi and Lindberg, Raija L. P. and Leppert, David and Gloor, Sergio M. and Errede, Mariella and Virgintino, Daniela and Fontana, Adriano and Yonekawa, Yasuhiro and Frei, Karl. (2008) Endothelial cell barrier impairment induced by glioblastomas and transforming growth factor beta2 involves matrix metalloproteinases and tight junction proteins. Journal of neuropathology and experimental neurology, Vol. 67, H. 5. pp. 435-448.

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Official URL: http://edoc.unibas.ch/dok/A6004308

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Abstract

Gliomas, particularly glioblastoma multiforme, perturb the blood-brain barrier and cause brain edema that contributes to morbidity and mortality. The mechanisms underlying this vasogenic edema are poorly understood. We examined the effects of cocultured primary cultured human glioblastoma cells and glioma-derived growth factors on the endothelial cell tight junction proteins claudin 1, claudin 5, occludin, and zonula occludens 1 of brain-derived microvascular endothelial cells and a human umbilical vein endothelial cell line. Cocultured glioblastoma cells and glioma-derived factors (e.g. transforming growth factor beta2) enhanced the paracellular flux of endothelial cell monolayers in conjunction with downregulation of the tight junction proteins. Neutralizing anti-transforming growth factor beta2 antibodies partially restored the barrier properties in this in vitro blood-brain barrier model. The involvement of endothelial cell-derived matrix metalloproteinases (MMPs) was demonstrated by quantitative reverse-transcriptase-polymerase chain reaction analysis and by the determination of MMP activities via zymography and fluorometry in the presence or absence of the MMP inhibitor GM6001. Occludin, claudin 1, and claudin 5 were expressed in microvascular endothelial cells in nonneoplastic brain samples but were significantly reduced in anaplastic astrocytoma and glioblastoma samples. Taken together, these in vitro and in vivo results indicate that glioma-derived factors may induce MMPs and downregulate endothelial tight junction protein and, thus, play a key role in glioma-induced impairment of the blood-brain barrier.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Clinical Neuroimmunology (Derfuss/Lindberg)
UniBasel Contributors:Lindberg Gasser, Raija L.P.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Lippincott Williams & Wilkins
ISSN:0022-3069
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:25 Apr 2014 08:01
Deposited On:25 Apr 2014 08:01

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