gms | German Medical Science

Objective: Brain tumors are hallmarked by the increased angiogenesis, neuronal destruction and brain swelling. We could show that interference with the glutamate antiporter xCT/SLC7A11 reduces neuronal cell death and alleviates tumor-associated brain edema. However, the underlying mechanisms of xCT mediated brain swelling, i.e. cytotoxic or vasogenic effects remain to be uncovered.

Method: We treated male nude mice and rats bearing wild type gliomas or xCT knockdown or overexpressing glioma (n = 5 - 9 per group) or glioma cells grown in vascular organotypic brain slice cultures. We generated inducible endothelial-cell-specific NMDAR1 knockout mice (GRINiE∆C) for the analysis of glutamate signaling in endothelial cells. Using intravital imaging, micro CT scanning, molecular techniques and histological analysis we determined tumor growth, tumor angiogenesis, glioma proliferation, neurodegeneration and glutamate signaling in endothelia. Data were analyzed with two sided unpaired t-test.

Results: Here we show that diminished glutamate secretion through xCT silencing normalizes tumor vasculature and tumor-induced angiogenesis. Consistent with this, xCT overexpressing brain tumors enhance tumor vessels and increase cell death. Moreover, glioma-derived glutamate impacts directly on endothelial cells in a glutamate receptor-dependent manner. Glutamate attenuates Avastin-mediated anti-angiogenesis. xCT expressing tumors form functional vessels whereas xCT knock down in gliomas normalizes vessel function as revealed by intravital microscopy. By using inducible loss-of-function genetics in vivo, we demonstrate that endothelial-cell-specific glutamate knockout mice show suppressed endothelial sprout formation and vascular density. Thus, our data reveal that the transporter xCT and its substrate glutamate operate on endothelial cells promoting angiogenesis.

Conclusions: We propose that targeting glutamate receptors in endothelial cells and xCT in gliomas provide a therapeutic roadmap for normalizing the tumor microenvironment and angiogenesis.