Glutamate and the biology of gliomas
Article first published online: 29 DEC 2010
Copyright © 2010 Wiley-Liss, Inc.
Special Issue: Glioma
Volume 59, Issue 8, pages 1181–1189, August 2011
How to Cite
de Groot, J. and Sontheimer, H. (2011), Glutamate and the biology of gliomas. Glia, 59: 1181–1189. doi: 10.1002/glia.21113
- Issue published online: 2 JUN 2011
- Article first published online: 29 DEC 2010
- Manuscript Accepted: 29 OCT 2010
- Manuscript Received: 20 SEP 2010
- NIH. Grant Number: RO1-NS052634
Several important and previously unrecognized roles for the neurotransmitter glutamate in the biology of primary brain tumors have recently been elucidated. Glutamate is produced and released from glioma cells via the system xc− cystine glutamate transporter as a byproduct of glutathione synthesis. Glutamate appears to play a central role in the malignant phenotype of glioma via multiple mechanisms. By binding to peritumoral neuronal glutamate receptors, glutamate is responsible for seizure induction and similarly causes excitotoxicity, which aids the expansion of tumor cells into the space vacated by destroyed tissue. Glutamate also activates ionotropic and metabotropic glutamate receptors on glioma cells in a paracrine and autocrine manner. α-Amino-3-hydroxy-5-methyl-4-isoaxazolepropionate acid (AMPA) glutamate receptors lack the GluR2 subunit rendering them Ca2+ permeable and capable of activating the AKT and MAPK pathways. Furthermore, these receptors are critical in aiding the invasion of glioma cells into normal brain. AMPA-Rs accumulate at focal adhesion sites where they may indirectly mediate interactions between the extracellular matrix and integrins. Glutamate receptor stimulation results in activation of focal adhesion kinase, which is critical to the regulation of growth factor and integrin-stimulated cell motility and invasion. The multitude of effects of glutamate on glioma biology supports the rationale for pharmacological targeting of glutamate receptors and transporters. Several ongoing and recently completed clinical trials are exploring the therapeutic potential of interrupting glutamate-mediated brain tumor growth. © 2010 Wiley-Liss, Inc.