The blood-brain barrier (BBB), mediated by endothelial tight junctions, isdefective in malignantgliomas such as glioblastoma, resulting in cerebral edema and contrastenhancement uponneuroradiological examination. The mechanisms underlying BBB breakdown areessentiallyunknown. Since non-neoplastic astrocytes are required to induce BBB featuresof cerebralendothelial cells, it is conceivable that malignant astrocytes have lost thisability due todedifferentiation. Alternatively, glioma cells might actively degradepreviously intact BBB tightjunctions. To examine the latter hypothesis, we have employed atransepithelial electricalresistance breakdown assay using monolayers of the C7 subclone of Madin-Darbycanine kidney(MDCK-C7) cells forming tight junctions similar to those of BBB endothelialcells. We found thatglioblastoma primary cells co-cultured with the MDCK-C7 monolayer (withoutdirect contact ofthe two cell types) resulted in marked breakdown of electrical resistance,whereas primary culturesderived from low-grade gliomas (fibrillary astrocytoma, oligoastrocytoma)showed delayed or noeffects. These results suggest that malignant gliomas have acquired theability to actively degradetight junctions by secreting soluble factors, eventually leading to BBBdisruption within invadedbrain tissue.
