Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas

Abstract

Malignant glioma represents one of the most aggressive and lethal human neoplasias. A hallmark of gliomas is their rapid proliferation and destruction of vital brain tissue, a process in which excessive glutamate release by glioma cells takes center stage. Pharmacologic antagonism with glutamate signaling through ionotropic glutamate receptors attenuates glioma progression in vivo, indicating that glutamate release by glioma cells is a prerequisite for rapid glioma growth. Glutamate has been suggested to promote glioma cell proliferation in an autocrine or paracrine manner, in particular by activation of the (RS)-a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrate (AMPA) subtype of glutamate receptors. Here, we dissect the effects of glutamate secretion on glioma progression. Glioma cells release glutamate through the amino-acid antiporter system X c À , a process that is mechanistically linked with cystine incorporation. We show that disrupting glutamate secretion by interfering with the system X c À activity attenuates glioma cell proliferation solely cystine dependently, whereas glutamate itself does not augment glioma cell growth in vitro. Neither AMPA receptor agonism nor antagonism affects glioma growth in vitro. On a molecular level, AMPA insensitivity is concordant with a pronounced transcriptional downregulation of AMPA receptor subunits or overexpression of the fully edited GluR2 subunit, both of which block receptor activity. Strikingly, AMPA receptor inhibition in tumorimplanted brain slices resulted in markedly reduced tumor progression associated with alleviated neuronal cell death, suggesting that the ability of glutamate to promote glioma progression strictly requires the tumor microenvironment. Concerning a potential pharmacotherapy, targeting system X c À activity disrupts two major pathophysiological properties of glioma cells, that is, the induction of excitotoxic neuronal cell death and incorporation of cystine required for rapid proliferation.

Histone deacetylases inhibition by SAHA/Vorinostat normalizes the glioma microenvironment via xCT equilibration

“…In exchange, cysteine is taken up into tumor cells via the same transporter as antiport34. Further, suppressed transporter expression leads to reduced glutamate export and levels in the extracellular space, and glutamate accumulates intracellular in tumor cells.…”

“…Since these target genes are often ubiquitously expressed, the problem naturally lies in the ability to modulate them in a specific manner in cancer cells without disturbing generally the physiological homeostasis. We identified xCT as a target gene playing a decisive role in the progression of malignant gliomas1734. Due to its ubiquitous expression, it falls under the restrictions attendant to target genes and would therefore have limited therapeutic scope.…”

Brain Tumor–Induced Angiogenesis: Approaches and Bioassays

“…We describe here a bridge technique, i.e. the organotypic glioma invasion model (OGIM), which combines the advantages of in vitro assays with that of the organotypic brain environment as an in vivo situation [98]. The OGIM is a robust in vitro assay enabling the investigation of key events of tumor angiogenesis within the brain.…”

“…Moreover a high-density microvessel network is produced via tumor-induction. The organotypic brain slice model represents the tumor microenvironment in vitro in a three-dimensional culture [98], which is biologically more relevant, but technically more challenging than migration, proliferation and cytotoxic assays being an appropriate possibility to test and optimize anti-cancer compounds.…”

Increased expression of glutamate transporter GLT-1 in peritumoral tissue associated with prolonged survival and decreases in tumor growth in a rat model of experimental malignant glioma

“…10 It should be noted, however, that other studies showed no effect of cell proliferation when glioma cells were treated with AMPA receptor antagonists. 41,47 Despite these contradictory results, it is possible that protection from glutamate transporter overexpression in the peritumoral tissue could be due to decreased tumor AMPA receptor activation in addition to protection against AMPA and NMDA receptor–mediated excitotoxic cell death in noncancerous tissue. This hypothesis is further confirmed by the study described above showing increased survival in patients treated with AMPA receptor antagonist talampanel when combined with radiation therapy and chemotherapy (temozolomide).…”