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Glutamatergic Mechanisms in Glioblastoma and Tumor-Associated Epilepsy

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Glutamatergic Mechanisms in Glioblastoma and Tumor-Associated Epilepsy cells Review Glutamatergic Mechanisms in Glioblastoma and Tumor-Associated Epilepsy Falko Lange 1,2,* , Julia Hörnschemeyer 1 and Timo Kirschstein 1,2,* 1 Oscar-Langendorff-Institute of Physiology, Rostock University Medical Center, 18057 Rostock, Germany; [email protected] 2 Center for Transdisciplinary Neurosciences Rostock, University of Rostock, 18147 Rostock, Germany * Correspondence: [email protected] (F.L.); [email protected] (T.K.) 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 glutamater- gic 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. Keywords: glutamate; ionotropic glutamate receptor; metabotropic glutamate receptor; glioblastoma; epilepsy; seizures; perampanel; preclinical model Citation: Lange, F.; Hörnschemeyer, J.; Kirschstein, T. Glutamatergic Mechanisms in Glioblastoma and Tumor-Associated Epilepsy. Cells 1. Introduction 2021, 10, 1226. https://doi.org/ Glioblastomas (WHO grade IV gliomas) represent the most common tumors of the 10.3390/cells10051226 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 median age of Academic Editor: Marco G. Paggi onset is 64 years, with an increase at the age of 75–84 years [1]. Primary glioblastomas arise de novo, whereas secondary glioblastomas derive from less-malignant precursor Received: 12 April 2021 lesions [2]. The majority of glioblastomas is defined as primary, mostly with wild-type Accepted: 13 May 2021 Published: 17 May 2021 isocitrate dehydrogenase 1 (IDH1), whereas most of the secondary cases harbor mutations in IDH1 [3]. Mutations in IDH1 are associated with an increased patient survival [4]. Publisher’s Note: MDPI stays neutral Depending on the genetic and epigenetic alterations [5], four subtypes can be de- with regard to jurisdictional claims in fined [6]. Genes encoding members of the signaling pathways phosphatidylinositol-3- published maps and institutional affil- kinase (PI3K) or mitogen-activated protein kinase (MAPK) and the corresponding receptor iations. tyrosine kinases-like epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor A (PDGFRA) are altered in up to 90% of cases [7,8]. Among the tumor sup- pressors, loss of function of phosphatase and tensin homolog (PTEN) is the most frequent mutation (30–40%) [6,9]. In approximately 10% of cases, neurofibromin 1 (NF1) is mutated or deregulated [8,9]. With respect to cell cycle control, loss-of-function mutations of cyclin Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. dependent kinase inhibitor 2A/B (CDKN2A/B) can be found in half of all glioblastoma This article is an open access article specimens, and cyclin-dependent kinase 4 (CDK4) is often highly amplified. Furthermore, distributed under the terms and like in other major cancer types [10], tumor protein P53 (TP53) is also subject to mutations. conditions of the Creative Commons Despite the knowledge gained on tumorigenesis and the progression of glioblastomas Attribution (CC BY) license (https:// in the last decades, these have so far only insufficiently contributed to improving treatment creativecommons.org/licenses/by/ options. Standard therapy includes resection of the tumor mass followed by adjuvant 4.0/). irradiation and chemotherapy with the alkylating drug temozolomide (TMZ) [11]. This Cells 2021, 10, 1226. https://doi.org/10.3390/cells10051226 https://www.mdpi.com/journal/cells Cells 2021, 10, 1226 2 of 22 regimen prolongs the median overall survival to 15–18 months (versus 3–4 months with- out treatment [12]) [11,13,14]. The status of O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation is an established prognostic marker of the treatment with TMZ [13,15–17], albeit in a Spanish study including more than 300 patients, contrary to previous studies, no beneficial effect of MGMT promotor methylation status could be detected [18]. Combination of TMZ with lomustine, also an alkylating agent, may prolong the survival of patients with methylated MGMT promotors [19]. However, 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]. However, the low level of acceptance of this method has limited its widespread use [22,23]. Glioblastomas are associated with a variety of neurological symptoms and signs including headaches, changes in cognition and personality, gait imbalance, visual deficits and tumor-associated epilepsy [12]. The occurrence of seizures is not only a frequent comorbidity in the course of glioma progression [24] but is often the initial manifestation of the tumor disease [25]. In low-grade gliomas, 70–90% of the patients suffer from seizures at the time of diagnosis, whereas in glioblastoma, seizures appear to be less frequent (up to 60%) [25,26]. Epileptogenesis in the peritumoral tissue is a multifactorial process [27]. Based on numerous preclinical, but also some clinical, studies, there is increasing evidence that the neurotransmitter glutamate plays an important role in the development of seizures and also in the progression of the tumor disease. Herein, we review our current understanding of the glutamatergic processes at the molecular level that drive glioma progression and presentation of an epileptic phenotype. Based on this, open research questions are presented that could serve to reach a better understanding of the disease in the future. 2. Glutamatergic Mechanisms of Glioma Progression and Tumor-Associated Epilepsy Glioblastoma and tumor-associated epilepsy share pathophysiological mechanisms that drive both tumor progression and the generation of seizures [28]. One major patholog- ical mechanism is aberrant glutamate signaling within the tumor tissue and its microenvi- ronment. In the glioma-surrounding tissue, extracellular glutamate levels were found to be elevated up to 100-times higher than in unaffected brains [29,30]. On the one hand, high levels of glutamate stimulate proliferation and invasion of glioma cells [31–33] and, on the other hand, may lead to epileptic discharges, excitotoxicity and therefore allow for tumor bulk expansion (Figure1)[34,35]. Primarily, glutamate is released by glioblastoma cells via cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11 or xCT) [36]. To counteract oxidative stress, cystine, an essential precursor for glutathione synthesis, is imported in exchange for glutamate. In glioblastoma cells, expression of xCT is often upregulated [37–40]. This may be in part due to hypoxic conditions in fast-growing glioblastomas [41]. It was reported that the expression levels of xCT were found to be associated with seizures [42,43] and identified as an independent biomarker for glioma-associated seizures [43], also in a cohort of IDH1-wildtype glioblastoma patients [44]. With respect to glioblastoma, no correlation with survival was found [42,43]. Furthermore, the re-uptake of glutamate from the extracellular space is also impaired in glioma tissue, as expression of glutamate transporter 1 (GLT-1), also known as excitatory amino acid transporter 2 (EAAT2), is downregulated, or carriers are mislocalized, and therefore sodium-dependent re-uptake of glutamate is reduced [37,45,46]. The situation may be exacerbated by an overexpression of branched-chain amino acid transaminase 1 (BCAT1) [47]. Again, upregulation may in part be driven by hypoxic conditions, in which HIF-1α was identified as an essential transcription factor [48]. BCAT1 transfers an α-amino group from branched-chain amino acids to α-ketoglutarate, thereby producing glutamate and the respective branched-chain α-ketoacid. This mechanism may contribute Cells 2021, 10, 1226 3 of 22 to an elevated glutamate level within the cytoplasm of the tumor cells and subsequently Cells 2021, 10, x FOR PEER REVIEW 3 of 24 an increased glutamate release [47]. In glioblastomas, high expression of BCAT1 was associated with poor survival [49,50]. Figure 1. Glutamatergic interaction in health and glioma. Details of the molecular processes are described in Section2. Figure 1. Glutamatergic interaction in health and glioma. Details of the molecular processes are described in Section 2. AMPA receptor (AMPAR), alanine-serine-cysteine amino acid transporter-2 (ASCT2), branched-chain amino acid
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