Glutamatergic Mechanisms in Glioblastoma and Tumor-Associated Epilepsy

Lange, Falko; Hörnschemeyer, Julia; Kirschstein, Timo

doi:10.3390/cells10051226

Cited by 53 publications

(48 citation statements)

References 191 publications

(240 reference statements)

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“…While glutamate export has previously been linked to nucleotide synthesis (15), our model does not predict any advantage of such a behavior in the TME. Glutamate is also a central signaling molecule, and glutamate secretion in glioblastoma has been linked to signaling effects, leading to a growth advantage (37,38).…”

Section: Resultsmentioning

confidence: 99%

Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth

Gustafsson

Roshanzamir

Hagnestål³

et al. 2022

Preprint

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Metabolism within the tumor microenvironment, where a complex mixture of different cell types resides in a nutrient-deprived surrounding, is not fully understood due to difficulties in measuring metabolic fluxes and exchange of metabolites between different cell types in vivo. Genome-scale metabolic modeling enables estimation of such exchange fluxes as well as an opportunity to gain insight into the metabolic behavior of individual cell types. Here, we estimated the availability of nutrients and oxygen within the tumor microenvironment using concentration measurements from blood together with a metabolite diffusion model. In addition, we developed an approach to efficiently apply enzyme usage constraints in a comprehensive metabolic model of human cells. The combined modeling reproduced severe hypoxic conditions and the Warburg effect, and we found that limitations in enzymatic capacity contribute to cancer cells' preferential use of glutamine as a substrate to the citric acid cycle. Furthermore, we investigated the common belief that some stromal cells are exploited by cancer cells to produce metabolites useful for the cancer cells. We identified a total of 233 potential metabolites that could support collaboration between cancer cells and cancer associated fibroblasts, but when limiting to metabolites previously identified to participate in such collaboration, no growth advantage was observed. Our work highlights the importance of enzymatic capacity limitations for cell behaviors and exemplifies the utility of enzyme constrained models for accurate prediction of metabolism in cells and tumor microenvironments.

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Section: Resultsmentioning

confidence: 99%

Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth

Gustafsson

Roshanzamir

Hagnestål³

et al. 2022

Preprint

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show abstract

“…α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors are highly expressed in glioblastoma and play a pivotal role in mediating the glutamate-related effects in gliomas. Experimental models show that high-grade gliomas release excitotoxic concentrations of glutamate, which has been shown to enhance tumor proliferation and migration ( 14 ). Stimulated AMPAr generates the cytoskeletal reorganization of glioma cells and has been shown to improve the detachment of cells from the extracellular matrix and glioma invasion ( 15 ).…”

Section: Discussionmentioning

confidence: 99%

Levetiracetam Prophylaxis Therapy for Brain Tumor-Related Epilepsy (BTRE) Is Associated With a Higher Psychiatric Burden

et al. 2022

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Purpose: Brain tumor-related epilepsy (BTRE) is a condition characterized by the development of seizures in the context of an undergoing oncological background. Levetiracetam (LEV) is a third-generation anti-seizure medication (ASM) widely used in BTRE prophylaxis. The study evaluated LEV neuropsychiatric side effects (SEs) in BTRE prophylaxis.Method: Twenty-eight patients with brain tumors were retrospectively selected and divided into two groups. In one group, we evaluated patients with a BTRE diagnosis using LEV (BTRE-group). The other group included patients with brain tumors who never had epilepsy and used a prophylactic ASM regimen with LEV (PROPHYLAXIS-group). Neuropsychiatric SEs of LEV were monitored using the Neuropsychiatric Inventory Questionnaire (NPI-Q) at the baseline visit and the 6- and 12-month follow-up.Results: Eighteen patients of the BTRE-group and 10 patients of the PROPHYLAXIS-group were included. Compared to the BTRE-group, the PROPHYLAXIS-group showed a higher severity of neuropsychiatric symptoms. According to Linear Mixed Models (LMM), a multiplicative effect was observed for the interaction between group treatment and time. For the caregiver distress score (CDS), only a time-effect was observed.Conclusion: Prophylactic ASM with LEV is associated with an increased frequency of neuropsychiatric SE. Accurate epileptological evaluations in patients with brain tumors are mandatory to select who would benefit most from ASM.

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“…Moreover, the high glutamate levels in tumor tissue are also a consequence of both increased release of a glutamate agonist in the synaptic cleft, induced by mutation of IDH 1/2 (isocitrate dehydrogenase 1 and 2) ( 9 ), and a reduced glutamate removal from extracellular space, caused by the downregulation of excitatory aminoacidic transporter EAAT2 ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

“…Anatomically, low-grade gliomas (LGGs) infiltrate the cortex and subcortical white matter and slowly disrupt functional networks. Glioma-related glutamatergic activity has been demonstrated to promote epileptic discharges in tumor-surrounding tissue and simultaneously stimulate tumoral cell proliferation, migration, and invasion of health brain parenchyma, inducing neuronal death via calcium excitotoxicity ( 8 , 9 ).…”

Section: Introductionmentioning

confidence: 99%

Pre- and Post-surgical Poor Seizure Control as Hallmark of Malignant Progression in Patients With Glioma?

et al. 2022

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BackgroundRegarding brain tumor-related epilepsy (BTRE), there is an increasing number of evidence about a relationship between epileptogenesis and oncogenesis. A recent study suggests a role of post-surgery seizure outcome on the survival of patients with low-grade glioma (LGG), underlying the need for a targeted and aggressive epilepsy treatment.ObjectiveThis study aims at investigating the possible correlation between pre- and post-surgical seizure control and tumor progression in patients who underwent surgery for LGG.MethodsWe performed a retrospective analysis of patients affected by LGGs and BTRE, in a single high-volume neurosurgical center. Seizure control was assessed before surgery and at 3 years of follow-up. Patients with histological progression in high-grade glioma (HGG) have been evaluated. Clinical features, pre-surgical electroencephalograms (EEGs), and electrocorticography (ECoG) have been analyzed.ResultsAmong 154 subjects, we collected 32 patients who presented a tumor progression in HGG during the follow-up period. The majority had poor seizure control both pre- and post-surgery, never being in Engel class Ia throughout the whole history of their disease. Almost all patients with poor seizure control had pathological ECoG recording. Clinical features of seizures did not correlate with seizure outcome. On the univariate analysis, the age, the post-operative Engel class, and the extent of resection (EOR) were the prognostic factors significantly associated with oncological outcome; nevertheless, on multivariate analysis, Engel class significance was not confirmed, and the only predicting factor were age and EOR.ConclusionsAlthough not confirmed on multivariate analysis, post-surgical seizure control could be a relevant factor to consider during follow-up of BRTE, in particular, when gross total resection is not achieved. Pathological findings on the ECoG may suggest a “hidden” propensity to malignant progression, strictly related to the persistent neuronal hyper-excitability. Further studies with longer follow-up period are needed to confirm our observations.

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Glutamatergic Mechanisms in Glioblastoma and Tumor-Associated Epilepsy

Cited by 53 publications

References 191 publications

Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth

Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth

Levetiracetam Prophylaxis Therapy for Brain Tumor-Related Epilepsy (BTRE) Is Associated With a Higher Psychiatric Burden

Pre- and Post-surgical Poor Seizure Control as Hallmark of Malignant Progression in Patients With Glioma?

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