Abstract
The progression of glioblastomas is associated with a variety of neurological impairments, such as tumor-related epileptic seizures. Seizures are not only a common comorbidity of glioblastoma but often an initial clinical symptom of this cancer entity. Both, glioblastoma and tumor-associated epilepsy are closely linked to one another through several pathophysiological mechanisms, with the neurotransmitter glutamate playing a key role. Glutamate interacts with its ionotropic and metabotropic receptors to promote both tumor progression and excitotoxicity. In this review, based on its physiological functions, our current understanding of glutamate receptors and glutamatergic signaling will be discussed in detail. Furthermore, preclinical models to study glutamatergic interactions between glioma cells and the tumor-surrounding microenvironment will be presented. Finally, current studies addressing glutamate receptors in glioma and tumor-related epilepsy will be highlighted and future approaches to interfere with the glutamatergic network are discussed.
Highlights
Oscar-Langendorff-Institute of Physiology, Rostock University Medical Center, 18057 Rostock, Germany; Center for Transdisciplinary Neurosciences Rostock, University of Rostock, 18147 Rostock, Germany
The re-uptake of glutamate from the extracellular space is impaired in glioma tissue, as expression of glutamate transporter 1 (GLT-1), known as excitatory amino acid transporter 2 (EAAT2), is downregulated, or carriers are mislocalized, and sodium-dependent re-uptake of glutamate is reduced [37,45,46]
The re-uptake of to glutamate from cell the death extracellular space is conditions impaired in glioma tissue, as expression of glutamate transporter 1 (GLT-1), known as excitatory amino acid transporter 2 (EAAT2), is downregulated, or carriers are mislocalized, and sodium-dependent re-uptake of glutamate is reduced [37,45,46]
Summary
Glioblastomas (WHO grade IV gliomas) represent the most common tumors of the central nervous system, and with an overall 5-year survival of 6.8%, this tumor disease has one of the worst prognoses in the entire oncological spectrum [1]. The majority of glioblastomas is defined as primary, mostly with wild-type isocitrate dehydrogenase 1 (IDH1), whereas most of the secondary cases harbor mutations in IDH1 [3]. Combination of TMZ with lomustine, an alkylating agent, may prolong the survival of patients with methylated MGMT promotors [19]. The findings of Herrlinger et al in 2019 were based on a relatively small cohort (129 patients), and survival successes came at the price of additional side effects. Another add-on therapy is tumor-treating fields that mediate antimitotic effects by alternating electric fields, which can prolong the survival of patients with glioblastoma [20,21]. Open research questions are presented that could serve to reach a better understanding of the disease in the future
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