Glutamatergic Mechanisms in Glioblastoma and Tumor-Associated Epilepsy.
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ABSTRACT:
SUBMITTER: Lange F
PROVIDER: S-EPMC8156732 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Epilepsy is broadly characterized by aberrant neuronal excitability. Glutamate is the predominant excitatory neurotransmitter in the adult mammalian brain; thus, much of past epilepsy research has attempted to understand the role of glutamate in seizures and epilepsy. Seizures induce elevations in extracellular glutamate, which then contribute to excitotoxic damage. Chronic seizures can alter neuronal and glial expression of glutamate receptors and uptake transporters, further contributing to epileptogenesis. Evidence points to a shared glutamate pathology for epilepsy and other central nervous system (CNS) disorders, including depression, which is often a comorbidity of epilepsy. Therapies that target glutamatergic neurotransmission are available, but many have met with difficulty because of untoward adverse effects. Better understanding of this system has generated novel therapeutic targets that directly and indirectly modulate glutamatergic signaling. Thus, future efforts to manage the epileptic patient with glutamatergic-centric treatments now hold greater potential.
| S-EPMC4526718 | biostudies-literature
Project description:Glioblastoma cells produce and release high amounts of glutamate into the extracellular milieu and subsequently can trigger seizure in patients. Tumor-associated microglia/macrophages (TAMs), consisting of both parenchymal microglia and monocytes-derived macrophages (MDMs) recruited from the blood, are known to populate up to 1/3 of the glioblastoma tumor environment and exhibit an alternative, tumor-promoting and supporting phenotype. However, it is unknown how TAMs respond to the excess extracellular glutamate in the glioblastoma microenvironment. We investigated the expressions of genes related to glutamate transport and metabolism in human TAMs freshly isolated from glioblastoma resections. Quantitative real-time PCR analysis showed (i) significant increases in the expressions of GRIA2 (GluA2 or AMPA receptor 2), SLC1A2 (EAAT2), SLC1A3 (EAAT1), (ii) a near-significant decrease in the expression of SLC7A11 (cystine-glutamate antiporter xCT) and (iii) a remarkable increase in GLUL expression (glutamine synthetase) in these cells compared to adult primary human microglia. TAMs co-cultured with glioblastoma cells also exhibited a similar glutamatergic profile as freshly isolated TAMs except for a slight increase in SLC7A11 expression. We next analyzed these genes expressions in cultured human MDMs derived from peripheral blood monocytes for comparison. In contrast, MDMs co-cultured with glioblastoma cells compared to MDMs co-cultured with normal astrocytes exhibited decreased expressions in the tested genes except for GLUL. This is the first study to demonstrate transcriptional changes in glutamatergic signaling of TAMs in a glioblastoma microenvironment, and the findings here suggest that TAMs and MDMs might potentially elicit different cellular responses in the presence of excess extracellular glutamate.
| S-EPMC4623498 | biostudies-literature
Project description:BackgroundGlutamate is one of the most important excitatory neurotransmitters in the mammalian brain and is involved in a variety of neurological disorders. Increasing evidence also shows that microRNA (miRNA) and mRNA pairs are engaged in a variety of pathophysiological processes. However, the miRNA and mRNA pairs that affect the glutamatergic system in post-traumatic epilepsy (PTE) remain unknown.MethodsPTE rats were induced by injecting 0.1 mol/L, 1 μL/min FeCl2 solution. Behavioral scores and EEG monitoring were used to evaluate whether PTE was successfully induced. RNA-seq was used to obtain mRNA and miRNA expression profiles. Bioinformatics analysis was performed to screen differentially expressed mRNAs and miRNAs associated with the glutamatergic system and then predict miRNA-mRNA interaction pairs. Real-time quantitative reverse transcription PCR was used to further validate the expression of the differential miRNAs and mRNAs. The microRNA-mRNA was subject to the Pearson correlation analysis.ResultsEight of the 91 differentially expressed mRNAs were associated with the glutamatergic system, of which six were upregulated and two were downregulated. Forty miRNAs were significantly differentially expressed, with 14 upregulated and 26 downregulated genes. The predicted miRNA-mRNA interaction network shows that five of the eight differentially expressed mRNAs associated with the glutamatergic system were targeted by multiple miRNAs, including Slc17a6, Mef2c, Fyn, Slc25a22, and Shank2, while the remaining three mRNAs were not targeted by any miRNAs. Of the 40 differentially expressed miRNAs, seven miRNAs were found to have multiple target mRNAs associated with the glutamatergic system. Real-time quantitative reverse transcription PCR validation and Pearson correlation analysis were performed on these seven targeted miRNAs-Slc17a6, Mef2c, Fyn, Slc25a22, and Shank2-and six additional miRNAs selected from the literature. Real-time quantitative reverse transcription PCR showed that the expression levels of the mRNAs and miRNAs agreed with the predictions in the study. Among them, the miR-98-5p-Slc17a6, miR-335-5p-Slc17a6, miR-30e-5p-Slc17a6, miR-1224-Slc25a22, and miR-211-5p-Slc25a22 pairs were verified to have negative correlations.ConclusionsOur results indicate that miRNA-mRNA interaction pairs associated with the glutamatergic system are involved in the development of PTE and have potential as diagnostic biomarkers and therapeutic targets for PTE.
| S-EPMC9822725 | biostudies-literature
Project description:BACKGROUND:Patients with glioma exhibit a great variability in clinical symptoms apart from variations in response to therapy and survival. Many patients present with epileptic seizures at disease onset, especially in case of low-grade gliomas, but not all have seizures. A large proportion of patients develop refractory seizures. It is likely that the variability in epileptic symptoms cannot exclusively be explained by tumor-related factors, but rather reflects complex interaction between tumor-related, environmental and hereditary factors. MATERIAL AND METHODS:No data exist on susceptibility genes associated with epileptic symptoms in patients with glioma. However, an increasing number of candidate genes have been proposed for other focal epilepsies such as temporal lobe epilepsy. Some of the susceptibility candidate genes associated with focal epilepsy may contribute to epileptic symptoms also in patients with glioma. RESULTS:This review presents an update on studies on genetic polymorphisms and focal epilepsy and brings forward putative candidate genes for tumor-associated epilepsy, based on the assumption that common etiological pathways may exist for glioma development and glioma-associated seizures. Conclusion. Genes involved in the immune response, in synaptic transmission and in cell cycle control are discussed that may play a role in the pathogenesis of tumor growth as well as epileptic symptoms in patients with gliomas.
| S-EPMC6436628 | biostudies-literature
Project description:Glioblastoma is the most common and malignant primary brain tumor, defined by its highly aggressive nature. Despite the advances in diagnostic and surgical techniques, and the development of novel therapies in the last decade, the prognosis for glioblastoma is still extremely poor. One major factor for the failure of existing therapeutic approaches is the highly invasive nature of glioblastomas. The extreme infiltrating capacity of tumor cells into the brain parenchyma makes complete surgical removal difficult; glioblastomas almost inevitably recur in a more therapy-resistant state, sometimes at distant sites in the brain. Therefore, there are major efforts to understand the molecular mechanisms underpinning glioblastoma invasion; however, there is no approved therapy directed against the invasive phenotype as of now. Here, we review the major molecular mechanisms of glioblastoma cell invasion, including the routes followed by glioblastoma cells, the interaction of tumor cells within the brain environment and the extracellular matrix components, and the roles of tumor cell adhesion and extracellular matrix remodeling. We also include a perspective of high-throughput approaches utilized to discover novel players for invasion and clinical targeting of invasive glioblastoma cells.
| S-EPMC8773542 | biostudies-literature
Project description:Seizures frequently accompany gliomas and often escalate to peritumoral epilepsy. Previous work revealed the importance of tumor-derived excitatory glutamate (Glu) release mediated by the cystine-glutamate transporter (SXC) in epileptogenesis. We now show a novel contribution of GABAergic disinhibition to disease pathophysiology. In a validated mouse glioma model, we found that peritumoral parvalbumin-positive GABAergic inhibitory interneurons are significantly reduced, corresponding with deficits in spontaneous and evoked inhibitory neurotransmission. Most remaining peritumoral neurons exhibit elevated intracellular Cl(-) concentration ([Cl(-) ]i ) and consequently depolarizing, excitatory gamma-aminobutyric acid (GABA) responses. In these neurons, the plasmalemmal expression of KCC2, which establishes the low [Cl(-) ]i required for GABAA R-mediated inhibition, is significantly decreased. Interestingly, reductions in inhibition are independent of Glu release, but the presence of both decreased inhibition and decreased SXC expression is required for epileptogenesis. We suggest GABAergic disinhibition renders peritumoral neuronal networks hyper-excitable and susceptible to seizures triggered by excitatory stimuli, and propose KCC2 as a therapeutic target.
| S-EPMC4237714 | biostudies-literature
Project description:In glioblastoma (GBM), tumor-associated macrophages (TAM) represent up to one half of the cells of the tumor mass, including both infiltrating macrophages and resident brain microglia. In an effort to delineate the temporal and spatial dynamics of TAM composition during gliomagenesis, we used genetically engineered and GL261-induced mouse models in combination with CX3CR1GFP/WT;CCR2RFP/WT double knock-in mice. Using this approach, we demonstrated that CX3CR1LoCCR2Hi monocytes were recruited to the GBM, where they transitioned to CX3CR1HiCCR2Lo macrophages and CX3CR1HiCCR2- microglia-like cells. Infiltrating macrophages/monocytes constituted approximately 85% of the total TAM population, with resident microglia accounting for the approximately 15% remaining. Bone marrow-derived infiltrating macrophages/monocytes were recruited to the tumor early during GBM initiation, where they localized preferentially to perivascular areas. In contrast, resident microglia were localized mainly to peritumoral regions. RNA-sequencing analyses revealed differential gene expression patterns unique to infiltrating and resident cells, suggesting unique functions for each TAM population. Notably, limiting monocyte infiltration via genetic Ccl2 reduction prolonged the survival of tumor-bearing mice. Our findings illuminate the unique composition and functions of infiltrating and resident myeloid cells in GBM, establishing a rationale to target infiltrating cells in this neoplasm. Cancer Res; 77(9); 2266-78. ©2017 AACR.
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Project description:Glioblastoma is the most common and lethal brain tumor associated with only 12% median survival rate of patients. Despite the development of advanced surgical, radiation or use of combinations of anti-cancer drugs, treatment for glioblastoma patients is still a challenge. The major contributing factor in glioblastoma progression and resistive nature is its ability to evade the immune surveillance. Hence, modulating the immune system in glioblastoma tumors could be an important strategy for anticancer therapeutics. Penfluridol, an antipsychotic drug has been shown to have anti-cancer properties in our recently published studies. The present study evaluates the immune response of penfluridol in glioblastoma tumors. Our results demonstrated that penfluridol treatment significantly suppressed glioblastoma tumor growth. Our current results demonstrated about 72% suppression of myeloid derived suppressor cells (MDSCs) with penfluridol treatment in mouse bearing U87MG glioblastoma tumors. MDSCs are known to increase regulatory T cells (Treg), which are immunosuppressive in nature and suppresses M1 macrophages that are tumor suppressive in nature. Our results also showed suppression of regulatory T cells as well as elevation of M1 macrophages with penfluridol treatment by 58% and 57% respectively. Decrease in CCL4 as well as IFNγ with penfluridol treatment was also observed indicating decrease in overall tumor inflammation. This is the first report demonstrating immune modulations by penfluridol treatment associated with glioblastoma tumor growth suppression prompting further investigation to establish penfluridol as a treatment option for glioblastoma patients.
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Project description:Necrosis in solid tumors is commonly associated with poor prognostic but how these lesions expand remains unclear. Studies have found that neutrophils associate with and contribute to necrosis development in glioblastoma by inducing tumor cell ferroptosis through transferring myeloperoxidase-containing granules. However, the mechanism of neutrophilic granule transfer remains elusive. We performed an unbiased small molecule screen and found that statins inhibit neutrophil-induced tumor cell death by blocking the neutrophilic granule transfer. Further, we identified a novel process wherein neutrophils are engulfed by tumor cells before releasing myeloperoxidase-containing contents into tumor cells. This neutrophil engulfment is initiated by integrin-mediated adhesion, and further mediated by LC3-associated phagocytosis (LAP), which can be blocked by inhibiting the Vps34-UVRAG-RUBCN-containing PI3K complex. Myeloperoxidase inhibition or Vps34 depletion resulted in reduced necrosis formation and prolonged mouse survival in an orthotopic glioblastoma mouse model. Thus, our study unveils a critical role for LAP-mediated neutrophil internalization in facilitating the transfer of neutrophilic granules, which in turn triggers tumor cell death and necrosis expansion. Targeting this process holds promise for improving glioblastoma prognosis.
| S-SCDT-10_1038-S44318-024-00130-4 | biostudies-other
Project description:Brain tumors are common in epilepsy surgery and frequently occur in the temporal lobe, but the optimal surgical strategies to remove the tumor and epileptogenic zone remain controversial. We aim at illustrating the positron emission tomography (PET) metabolism and the stereoelectroencephalography (SEEG) epileptogenicity of temporal lobe long-term epilepsy-associated tumors (LEAT). In this study, 70 patients and 25 healthy controls were included. Our analysis leveraged group-level analysis to reveal the whole-brain metabolic pattern of temporal lobe LEATs. The SEEG-based epileptogenicity mapping was performed to verify the PET findings in the epileptic network. Compared to controls, patients with a temporal lobe LEAT showed a more widespread epileptic network based on 18FDG-PET in patients with a mesial temporal lobe LEAT than in those with a lateral temporal lobe LEAT. The significant brain clusters mainly involved the paracentral lobule (ANOVA F = 9.731, p < 0.001), caudate nucleus (ANOVA F = 20.749, p < 0.001), putamen (Kruskal-Wallis H = 19.258, p < 0.001), and thalamus (ANOVA F = 4.754, p = 0.011). Subgroup analysis and SEEG-based epileptogenicity mapping are similar to the metabolic pattern. Our findings demonstrate the metabolic and electrophysiological organization of the temporal lobe LEAT epileptic network, which may assist in a patient-specific surgical strategy.
| S-EPMC9504693 | biostudies-literature