Year: 2015
Type: article
Abstract: The excitatory amino acid glutamate has been previously shown to play an important role in tumor-associated seizures in glioma patients. The release of glutamate by tumor cells causes excitotoxicity and cell killing of surrounding neurons, thus making room for tumor expansion. Therefore, understanding mechanisms involved in glutamate release is crucial not only for the control of seizures, but also from a therapeutic standpoint for glioma patients. Robert et al have recently identified a mechanism for glutamate release via up-regulation of a cysteine/glutamate exchanger, System Xc- (SXC). The increased uptake of extracellular cystine needed for intracellular glutathione (GSH) synthesis is driven by glutamate release as a byproduct. The authors first compared the expression of SLC7A11, the catalytic subunit of SXC, in malignant gliomas via immunohistochemistry. They found that nearly 50% of the cases showed elevated expression of SLC7A11 relative to the peritumoral area. The expression of SLC7A11 in patient-derived primary tumor cells maintained as xenografts showed correlation of expression with SLC7A11 activity, which was blocked by an SXC inhibitor. Cortical neurons showed increased intracellular Ca2+ when exposed to conditioned media from SXC-expressing glioma cells. Implantation of SXC-expressing glioma cells intracranially into mice caused a dramatic reduction in the number of peritumoral neurons without harming surrounding GFAP+ astrocytes. The SXC-expressing gliomas showed reduced survival and the tumors were more diffuse compared with non-SXC expressing gliomas.
Source: Neuro-Oncology
Authors: Krishna Bhat, Whitney Pope, Jason Huse, Monika Hegi, Kenneth Aldape
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4253899561