Artikel
Inhibition of glioma-induced cell death and subsequent reduction of perifocal edema by targeted xCT interference
Hemmung des Gliom-induzierten Zelltods und entsprechende Reduktion des perifokalen Ödems durch Modulation des xCT-Rezeptors
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Veröffentlicht: | 11. April 2007 |
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Gliederung
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Objective: A hallmark of invasive brain tumors such as glioblastoma multiforme is the massive cell death that occurs in adjacent brain parenchyma. The mechanism by which malignant gliomas cause cell death along the growing tumor margins is unclear. However, it is thought that extracellular neurotoxic factors play an important role in this process.
Methods: HPLC was used to measure glutamate levels in media. To identify neuronal cell death rat entorhino-hippocampal slice cultures were prepared and eGFP transfected F98 glioma cells were implanted into the entorhinal cortex. Expressions of receptors were identified by real-time PCR and Western blotting. xCT knocked down glioma cells were characterized by MTT cell growth assay, measurement of ROS and FACS analysis. For in vivo experiments implantation of glioma cells into the right basal ganglia of Wistar rats were performed. Tumor growth was identified by a 1.5 Tesla MRI.
Results: Here, we identified that the excitatory neurotransmitter glutamate is released by glioma cells at neurotoxic concentrations during brain invasion. In line with these results, abrogation of glutamate secretion from glioma cells or inhibition of glutamate receptors in living brain slice cultures blocked neuronal cell death. Analysis of glutamate transporters revealed further that the cystine-glutamate exchanger xCT (SLC7A11) is mainly expressed in glioma cells. Moreover, siRNA-mediated knock down of the cystine/glutamate transporter xCT in glioma cells (kd_xCT) implanted into brain slice cultures prevented peritumoral cell death. In vivo experiments using kd_xCT glioma cells implanted into Wistar rats resulted in a significant increase of animal survival. Subsequent 1.5 Tesla MRI depicted a significantly reduced perifocal edema which may be at least in parts responsible for the prolonged survival of kd_xCT implanted animals.
Conclusions: These results show that xCT is indispensable for malignant glioma progression. The data support the concept that peritumoral cell death is dependent upon xCT-mediated glutamate secretion and is consecutively responsible for perifocal edema. Therefore, xCT presents a potential prime target for therapeutic intervention of brain malignancies.