Glioblastoma cells release factors that disrupt blood-brain barrier features

Abstract

The blood-brain barrier (BBB), mediated by endothelial tight junctions, is defective in malignant gliomas such as glioblastoma, resulting in cerebral edema and contrast enhancement upon neuroradiological examination. The mechanisms underlying BBB breakdown are essentially unknown. Since non-neoplastic astrocytes are required to induce BBB features of cerebral endothelial cells, it is conceivable that malignant astrocytes have lost this ability due to dedifferentiation. Alternatively, glioma cells might actively degrade previously intact BBB tight junctions. To examine the latter hypothesis, we have employed a transepithelial electrical resistance breakdown assay using monolayers of the C7 subclone of Madin-Darby canine kidney (MDCK-C7) cells forming tight junctions similar to those of BBB endothelial cells. We found that glioblastoma primary cells co-cultured with the MDCK-C7 monolayer (without direct contact of the two cell types) resulted in marked breakdown of electrical resistance, whereas primary cultures derived from low-grade gliomas (fibrillary astrocytoma, oligoastrocytoma) showed delayed or no effects. These results suggest that malignant gliomas have acquired the ability to actively degrade tight junctions by secreting soluble factors, eventually leading to BBB disruption within invaded brain tissue.

Biochemical, Cellular, and Biophysical Characterization of a Potent Inhibitor of Mutant Isocitrate Dehydrogenase IDH1

“…The integrity of the compound is expected to be stable during the cell assays described herein. Although there was no observed penetration of the blood brain barrier in these normal healthy mice, there could still be penetration in a glioma setting in which the blood brain barrier may be compromised (23), and this compound could provide a good starting point for further optimization to improve drug-like properties and potency.…”

Reduced Glioma Infiltration in Src-deficient Mice

“…Like most solid tumors, gliomas express and secrete vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) that induces proliferation and migration of neighboring endothelial cells [32][33][34][35][36]. Remodeling of the BBB vasculature by VEGF disrupts the formation of tight junctions, increases vascular permeability (VP), and results in a disordered vasculature characteristic of tumor-induced angiogenesis [34,[37][38][39]. Our previous studies have demonstrated that the non-receptor tyrosine kinase, Src, is essential for the maintenance of the BBB [40].…”

Identification of a peptide that interacts with Nestin protein expressed in brain cancer stem cells

“…Indeed, our intravenous injection of the Q-GSCT peptide into tumor-bearing mice reveals that this peptide can easily penetrate brain tumor-blood barriers and specifically accumulate in tumor tissues by targeting Nestin-positive GSCs, although the underlying mechanism remains to be clarified. However, we infer that the ability of GSCT peptide to penetrate tumor vessels would be attributable to its low molecular weight [24] and the looseness of the tumor bloodebrain barrier [25,26].…”