Title:Neurodegeneration in the Brain Tumor Microenvironment: Glutamate in the Limelight
Volume: 13
Issue: 2
Author(s): Nicolai E. Savaskan, Zheng Fan, Thomas Broggini, Michael Buchfelder and Ilker Y. Eyüpoglu
Affiliation:
Keywords:
GBM, glutamate, neuron, NMDA, ROS, systemX, TRP, xCT.
Abstract: Malignant brain tumors are characterized by destructive growth and neuronal cell death making them one of the
most devastating diseases. Neurodegenerative actions of malignant gliomas resemble mechanisms also found in many
neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis. Recent data
demonstrate that gliomas seize neuronal glutamate signaling for their own growth advantage. Excessive glutamate release
via the glutamate/cystine antiporter xCT (system xc-, SLC7a11) renders cancer cells resistant to chemotherapeutics and
create the tumor microenvironment toxic for neurons. In particular the glutamate/cystine antiporter xCT takes center stage
in neurodegenerative processes and sets this transporter a potential prime target for cancer therapy. Noteworthy is the
finding, that reactive oxygen species (ROS) activate transient receptor potential (TRP) channels and thereby TRP
channels can potentiate glutamate release. Yet another important biological feature of the xCT/glutamate system is its
modulatory effect on the tumor microenvironment with impact on host cells and the cancer stem cell niche. The EMA and
FDA-approved drug sulfasalazine (SAS) presents a lead compound for xCT inhibition, although so far clinical trials on
glioblastomas with SAS were ambiguous. Here, we critically analyze the mechanisms of action of xCT antiporter on
malignant gliomas and in the tumor microenvironment. Deciphering the impact of xCT and glutamate and its relation to
TRP channels in brain tumors pave the way for developing important cancer microenvironmental modulators and
drugable lead targets.
