RRC ID 1992
Author Ueda Y, Nakagawa T, Kubota T, Ido K, Sato K.
Title Glioma cells under hypoxic conditions block the brain microvascular endothelial cell death induced by serum starvation.
Journal J. Neurochem.
Abstract Angiogenesis is one of essential components for the growth of neoplasms, including malignant gliomas. However, tumor vascularization is often poorly organized and marginally functional due to tumor structural abnormalities, inducing regional or temporal hypoxic conditions and nutritional shortages in tumor tissues. We investigated how during angiogenesis migrating endothelial cells survive in these hypoxic and reduced nutritional conditions. Human brain microvascular endothelial cells (HBMECs) underwent apoptosis and necrosis after serum withdrawal. This endothelial cell death was blocked by recombinant VEGF protein or the culture medium of U251 glioma cells exposed to hypoxia (H-CM). Hypoxic treatment increased vascular endothelial growth factor (VEGF) and tumor necrosis factor alpha (TNF-alpha) expression in U251 glioma cells. H-CM activated nuclear factor-kappaB (NFkappaB) protein and increased the gene expression of antiapoptotic factors including Bcl-2, Bcl-X(L), survivin and X-chromosome-linked inhibitor of apoptosis protein (XIAP) in endothelial cells. The survival activity of H-CM for endothelial cells was abolished by two kinds of VEGF inhibitors {Cyclopeptidic VEGF inhibitor and a VEGF receptor tyrosine kinase inhibitor (4-[(4'-chloro-2'-fluoro) phenylamino]-6, 7-dimethoxyquinazoline)} or NFkappaB inhibitors (ALLN and BAY 11-7082). These VEGF inhibitors did not block the activation of NFkappaB induced by H-CM in endothelial cells. On the contrary, TNF-alpha antagonist WP9QY enhanced the survival activity of H-CM for endothelial cells and blocked NFkappaB activation induced by H-CM under serum-starved conditions. Taken together, our data suggest that both the secretion of VEGF from glioma cells and activation of NFkappaB in endothelial cells induced by TNF-alpha are necessary for endothelial cell survival as they increase the expression of antiapoptotic genes in endothelial cells under conditions of serum starvation. These pathways may be one of the mechanisms by which angiogenesis is maintained in glioma tissues.
Volume 95(1)
Pages 99-110
Published 2005-10
DOI 10.1111/j.1471-4159.2005.03343.x
PMID 16042757
MeSH Apoptosis / drug effects Brain / blood supply* Cell Line, Tumor Cell Survival / drug effects Culture Media / pharmacology* Culture Media, Serum-Free / pharmacology* Endothelial Cells / drug effects Endothelial Cells / metabolism Endothelial Cells / pathology Endothelial Cells / physiology* Glioma / metabolism* Humans Hypoxia / metabolism* Microcirculation / drug effects NF-kappa B / antagonists & inhibitors NF-kappa B / metabolism Necrosis Recombinant Proteins / pharmacology Tumor Necrosis Factor-alpha / antagonists & inhibitors Tumor Necrosis Factor-alpha / metabolism Umbilical Veins / cytology Vascular Endothelial Growth Factor A / antagonists & inhibitors Vascular Endothelial Growth Factor A / metabolism Vascular Endothelial Growth Factor A / pharmacology
IF 4.87
Times Cited 14
Human and Animal Cells U251