RT Journal Article
SR Electronic
T1 Targeting xCT-mediated glutamate release normalizes tumor angiogenesis in the brain
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 134924
DO 10.1101/134924
A1 Zheng Fan
A1 Thomas Broggini
A1 Eduard Yakubov
A1 Tina Sehm
A1 Sebastian Schürmann
A1 Eric P. Meyer
A1 Nevenka Dudvarski Stankovic
A1 Mirko HH. Schmidt
A1 Marco Stampanoni
A1 Marcus A. Czabanka
A1 Robert Nitsch
A1 Michael Buchfelder
A1 Oliver Friedrich
A1 Ilker Y. Eyupoglu
A1 Nicolai E. Savaskan
YR 2017
UL http://biorxiv.org/content/early/2017/05/18/134924.abstract
AB Brain tumors are among the most malignant primary tumors, hallmarked by angiogenesis, neuronal destruction and brain swelling. Inhibition of the glutamate-cystein antiporter xCT (system xc−/SLC7A11) alleviates seizures, neuronal cell death and tumor-associated brain edema. Here we show enhanced tumor vessel growth and increased brain edema in xCT-expressing brain tumors. Furthermore, xCT-mediated glutamate impacts directly on endothelial cells in an N-methyl-D-aspartate receptor (NMDAR) dependent manner with intracellular Ca2+ release. Cerebral intravital microscopy revealed that xCT-driven tumor vessels are functional and display increased permeability. Endothelial-cell-specific NMDAR1 knockout mice (GRINiΔEC) show suppressed endothelial sprouting and vascular density compared to control littermates. In addition, implanted gliomas in GRINiΔEC mice display reduced tumor vessels in contrast to gliomas in wildtype animals. Moreover, therapeutic targeting of xCT in gliomas alleviates tumor angiogenesis to normalized levels comparable to controls. Our data reveal that xCT and its substrate glutamate specifically operate on endothelial cells and promote neoangiogenesis. Thus, targeting xCT expression and glutamate secretion in gliomas provides a novel therapeutic roadmap for normalizing tumor angiogenesis.