-
Nitric Oxide : Biology and Chemistry Sep 2023Gliomas represent the most prevalent form of brain tumors, among which glioblastomas are the most malignant subtype. Despite advances in comprehending their biology and... (Review)
Review
INTRODUCTION
Gliomas represent the most prevalent form of brain tumors, among which glioblastomas are the most malignant subtype. Despite advances in comprehending their biology and treatment strategies, median survival remains disappointingly low. Inflammatory processes involving nitric oxide (NO), critically contribute to glioma formation. The inducible isoform of NO synthase (iNOS) is highly overexpressed in gliomas and has been linked to resistance against temozolomide (TMZ) treatment, neoplastic transformation, and modulation of immune response. While both in vitro and in vivo studies showed the potential of iNOS inhibitors as effective treatments for gliomas, no clinical trials on gliomas have been published. This review aims to summarize the available evidence regarding iNOS as a target for glioma treatment, focusing on clinically relevant data.
METHODS
Following PRISMA guidelines, we conducted a systematic review by searching PubMed/Medline, and Embase databases in May 2023. We included studies that investigated the impact of NOS inhibitors on glioma cells using L-NMMA, CM544, PBN, 1400W or l-NAME either alone or combined with TMZ. We extracted data on the NOS inhibitor used, subtype, study setting, animal model or cell lines employed, obtained results, and safety profile. Our inclusion criteria encompassed original articles in English or Spanish, studies with an untreated control group, and a primary outcome focused on the biological effects on glioma cells.
RESULTS
Out of 871 articles screened from the aforementioned databases, 37 reports were assessed for eligibility. After excluding studies that did not utilize glioma cells or address the designated outcome, 11 original articles satisfied the inclusion and exclusion criteria. Although no NOS inhibitor has been tested in a published clinical trial, three inhibitors have been evaluated using in vivo models of intracranial gliomas. l-NAME, 1400W, and CM544 were tested in vitro. Co-administration of l-NAME, or CM544 with TMZ showed superior results in vitro compared to individual agent testing.
CONCLUSION
Glioblastomas remain a challenging therapeutic target. iNOS inhibitors exhibit substantial potential as treatment options for oncologic lesions, and they have demonstrated a safe toxicity profile in humans for other pathological conditions. Research endeavors should be focused on investigating their potential effects on brain tumors.
Topics: Animals; Humans; Glioblastoma; NG-Nitroarginine Methyl Ester; Glioma; Temozolomide; Brain Neoplasms; Enzyme Inhibitors; Nitric Oxide Synthase; Nitric Oxide
PubMed: 37279819
DOI: 10.1016/j.niox.2023.06.002 -
Antioxidants & Redox Signaling Nov 2023Targeting tumor metabolism may improve the outcomes for patients with glioblastoma (GBM). To further preclinical efforts targeting metabolism in GBM, we tested the... (Review)
Review
Targeting tumor metabolism may improve the outcomes for patients with glioblastoma (GBM). To further preclinical efforts targeting metabolism in GBM, we tested the hypothesis that brain tumors can be stratified into distinct metabolic groups with different patient outcomes. Therefore, to determine if tumor metabolites relate to patient survival, we profiled the metabolomes of human gliomas and correlated metabolic information with clinical data. We found that isocitrate dehydrogenase-wildtype (IDHwt) GBMs are metabolically distinguishable from IDH mutated (IDHmut) astrocytomas and oligodendrogliomas. Survival of patients with IDHmut gliomas was expectedly more favorable than those with IDHwt GBM, and metabolic signatures can stratify IDHwt GBMs subtypes with varying prognoses. Patients whose GBMs were enriched in amino acids had improved survival, while those whose tumors were enriched for nucleotides, redox molecules, and lipid metabolites fared more poorly. These findings were recapitulated in validation cohorts using both metabolomic and transcriptomic data. Our results suggest the existence of metabolic subtypes of GBM with differing prognoses, and further support the concept that metabolism may drive the aggressiveness of human gliomas. Our data show that metabolic signatures of human gliomas can inform patient survival. These findings may be used clinically to tailor novel metabolically targeted agents for GBM patients with different metabolic phenotypes. . 39, 942-956.
Topics: Humans; Mutation; Glioma; Astrocytoma; Glioblastoma; Brain Neoplasms; Isocitrate Dehydrogenase
PubMed: 36852494
DOI: 10.1089/ars.2022.0085 -
Biology Direct Jan 2024Human Deltex 2 (DTX2) is a ubiquitin E3 ligase that functions as an oncogene and has been shown to participate in many human cancers. However, the role of DTX2 in glioma...
BACKGROUND
Human Deltex 2 (DTX2) is a ubiquitin E3 ligase that functions as an oncogene and has been shown to participate in many human cancers. However, the role of DTX2 in glioma progression has remained obscure. In this study, we explore the mechanism underlying the function of DTX2 in glioma progression.
METHODS
The associations between DTX2 expression and clinical characteristics of glioma were determined by bioinformatic analysis of data from The Cancer Genome Atlas and Human Protein Atlas. The expression of DTX2 in glioma tissues was detected using immunohistochemistry and western blotting. Lentivirus-mediated gene knockdown and overexpression were used to determine the effects of DTX2 and helicase-like transcription element (HLTF) on glioma cell proliferation and migration with CCK-8, cell colony formation, transwell, and wound healing assays; flow cytometry in vitro; and animal models in vivo. The interaction of the DTX2 and HLTF proteins was verified by immunoprecipitation assay and confocal microscopy.
RESULTS
DTX2 was highly expressed in glioma samples, and this was correlated with worse overall survival. Silencing of DTX2 suppressed glioma cell viability, colony formation, and migration and induced cell apoptosis. In vitro ubiquitination assays confirmed that DTX2 could downregulate HLTF protein levels by increasing ubiquitination of the HLTF protein. We also observed that HLTF inhibited proliferation and migration of glioma cells. Subcutaneous xenografts with DTX2-overexpressing U87 cells showed significantly increased tumor volumes and weights.
CONCLUSIONS
We have identified DTX2/HLTF as a new axis in the development of glioma that could serve as a prognostic or therapeutic marker.
Topics: Animals; Humans; Cell Line, Tumor; Glioma; Cell Proliferation; Cell Movement; Gene Expression Regulation, Neoplastic; Apoptosis; DNA-Binding Proteins; Transcription Factors
PubMed: 38163902
DOI: 10.1186/s13062-023-00447-w -
Journal of Cancer Research and Clinical... Oct 2023Glioma is the most common and fatal type of brain tumour. Owing to its aggressiveness and lethality, early diagnosis and prediction of patient survival are very...
PURPOSE
Glioma is the most common and fatal type of brain tumour. Owing to its aggressiveness and lethality, early diagnosis and prediction of patient survival are very important. This study aimed to identify key genes and biomarkers for glioma that can guide clinicians in making rapid diagnosis and prognostication.
METHODS
Data mining of The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Repository of Molecular Brain Neoplasia Data, and Genotype-Tissue Expression Project brain expression data revealed significantly differentially expressed genes (DEGs), and the risk scores of individual patients were calculated. WGCNA was utilized to screen for genes most related to clinical diagnosis. Prognostic genes associated with glioma were selected via combining the LASSO regression with univariate and multivariate Cox regression and protein-protein interaction network analyses. Then, a nomogram was constructed. And CGGA dataset was utilized to validated. The protein expression levels of the signature were detected using the human protein atlas. Drug response prediction was carried out using the package "pRRophetic".
RESULTS
A six-gene signature (KLF6, CHI3L1, SERPINE1, ANGPT2, TGFBR1, and PTX3) was identified and used to stratify patients into low- and high-risk groups. Survival, ROC curve, and Cox analyses clarified that the six hub genes were a favourable independent prognostic factor for patients with glioma. A nomogram was set up by integrating clinical parameters with risk signatures, showing high precision for predicting 2-, 3-, 4-, 5-years survival. In addition, the expression of most genes was consistent with protein expression. Furthermore, the sensitivity to the top ten drugs in the GDSC database of the high-risk group was significantly higher than the low-risk group.
CONCLUSION
Based on genetic profiles and clinicopathological features, including age, grade, isocitrate dehydrogenase mutation status, we constructed a comprehensive prognostic model for patients with glioma. These signatures can be regarded as biomarkers to predict the prognosis of gliomas, possibly providing more therapeutic strategies for future clinical research.
Topics: Humans; Brain Neoplasms; Glioma; Nomograms; Prognosis
PubMed: 37439825
DOI: 10.1007/s00432-023-05082-6 -
World Neurosurgery Oct 2023Sonodynamic therapy (SDT) has emerged as an encouraging noninvasive technique that uses ultrasound to activate targeted agents to induce antitumor effects for the... (Review)
Review
Sonodynamic therapy (SDT) has emerged as an encouraging noninvasive technique that uses ultrasound to activate targeted agents to induce antitumor effects for the treatment of glioma. With extensive variation in the types of sonosensitizers, protocols for sonication, and model systems, a comprehensive overview of existing preclinical data on the efficacy of SDT in glioma treatment is warranted. Here, we conduct a systematic review of preclinical and early clinical literature on implementing SDT to treat in vitro and in vivo models of glioma. Our findings suggest that coupling sonosensitizers such as 5-aminolevulinic acid, hematoporphyrin monomethyl ether, and sinoporphyrin sodium with focused ultrasound induces robust cytotoxic activity in tumor cells (in vitro and in vivo). These effects are likely mediated by the oxidative stress induced by reactive oxygen species production, apoptotic signaling cascades, and intracellular calcium overload. Future research is needed to better understand the biochemical and mechanistic properties of SDT, and ongoing trials may help elucidate the clinical feasibility of glioma treatment with optimized sonically activated treatments.
Topics: Humans; Ultrasonic Therapy; Glioma; Aminolevulinic Acid; Apoptosis; Reactive Oxygen Species; Antineoplastic Agents; Cell Line, Tumor
PubMed: 37454909
DOI: 10.1016/j.wneu.2023.07.030 -
Clinical Neuropathology 2024Chordoid glioma is a rare well-circumscribed glial neoplasm arising in adults and predominantly affects females. Tanycytes of the third ventricle have been proposed as...
BACKGROUND
Chordoid glioma is a rare well-circumscribed glial neoplasm arising in adults and predominantly affects females. Tanycytes of the third ventricle have been proposed as the cell of origin owing to its location. It is characterized by chordoid features with myxoid and inflammatory stroma and recurrent missense mutation.
CASE REPORT
We present two cases (30-year-old female and 45-year-old male) with similar complaints of behavioral change and headache. Midline suprasellar homogeneously enhancing mass was seen on contrast-enhanced magnetic resonance imaging. Histopathology and immunohistochemistry was characteristic of chordoid glioma with cords and clusters of epithelioid cells arranged in a solid pattern. There were variable amounts of myxoid stroma and lymphoplasmacytic infiltrate. No mitosis, necrosis, or brain invasion was noted. The cells expressed strong diffuse positivity for glial fibrillary acid protein (GFAP) and weak nuclear thyroid transcription factor (TTF-1). Epithelial membrane antigen (EMA)and brachyury were negative. Subsequently, the lady underwent gross total excision and died soon after the operation. The male patient received radiotherapy and is currently doing well after 6 months of follow-up.
CONCLUSION
The rare occurrence as well as the radiological and morphological overlaps in chordoid gliomas make them a true masquerader. Combination of GFAP and TTF-1 in the immunohistochemical panel can be useful in differential diagnosis. Mainstay of treatment is complete surgical excision, with adjuvant radiotherapy becoming increasingly important.
Topics: Adult; Female; Humans; Male; Glioma; Cerebral Ventricle Neoplasms; Immunohistochemistry; Third Ventricle; Magnetic Resonance Imaging
PubMed: 37675487
DOI: 10.5414/NP301577 -
IL4I1 in M2-like macrophage promotes glioma progression and is a promising target for immunotherapy.Frontiers in Immunology 2023Glioma is the prevailing malignant intracranial tumor, characterized by an abundance of macrophages. Specifically, the infiltrating macrophages often display the M2...
BACKGROUND
Glioma is the prevailing malignant intracranial tumor, characterized by an abundance of macrophages. Specifically, the infiltrating macrophages often display the M2 subtype and are known as tumor-associated macrophages (TAMs). They have a critical role in promoting the oncogenic properties of tumor cells. Interleukin-4-induced-1 (IL4I1) functions as an L-phenylalanine oxidase, playing a key part in regulating immune responses and the progression of various tumors. However, there is limited understanding of the IL4I1-mediated cross-talk function between TAMs and glioma cell in the glioma microenvironment.
METHODS
TCGA, GTEx, and HPA databases were applied to assess the IL4I1 expression, clinical characteristics, and prognostic value of pan-cancer. The link between IL4I1 levels and the prognosis, methylation, and immune checkpoints (ICs) in gliomas were explored through Kaplan-Meier curve, Cox regression, and Spearman correlation analyses. The IL4I1 levels and their distribution were investigated by single-cell analysis and the TIMER 2 database. Additionally, validation of IL4I1 expression was performed by WB, RT-qPCR, IHC, and IF. Co-culture models between glioma cells and M2-like macrophages were used to explore the IL4I1-mediated effects on tumor growth, invasion, and migration of glioma cells. Moreover, the function of IL4I1 on macrophage polarization was evaluated by ELISA, RT-qPCR, WB, and siRNA transfection.
RESULTS
Both transcriptome and protein levels of IL4I1 were increased obviously in various tumor types, and correlated with a dismal prognosis. Specifically, IL4I1 was implicated in aggressive progression and a dismal prognosis for patients with glioma. A negative association was noticed between the glioma grade and DNA promoter methylation of IL4I1. Enrichment analyses in glioma patients suggested that IL4I1 was linked to cytokine and immune responses, and was positively correlated with ICs. Single-cell analysis, molecular experiments, and assays showed that IL4I1 was significantly expressed in TAMs. Importantly, co-culture models proved that IL4I1 significantly promoted the invasion and migration of glioma cells, and induced the polarization of M2-like macrophages.
CONCLUSION
IL4I1 could be a promising immunotherapy target for selective modulation of TAMs and stands as a novel macrophage-related prognostic biomarker in glioma.
Topics: Humans; Macrophages; Glioma; Tumor-Associated Macrophages; Brain Neoplasms; Immunotherapy; Tumor Microenvironment; L-Amino Acid Oxidase
PubMed: 38250074
DOI: 10.3389/fimmu.2023.1338244 -
Cancer Imaging : the Official... Mar 2024The specific genetic subtypes that gliomas exhibit result in variable clinical courses and the need to involve multidisciplinary teams of neurologists, epileptologists,... (Review)
Review
The specific genetic subtypes that gliomas exhibit result in variable clinical courses and the need to involve multidisciplinary teams of neurologists, epileptologists, neurooncologists and neurosurgeons. Currently, the diagnosis of gliomas pivots mainly around the preliminary radiological findings and the subsequent definitive surgical diagnosis (via surgical sampling). Radiomics and radiogenomics present a potential to precisely diagnose and predict survival and treatment responses, via morphological, textural, and functional features derived from MRI data, as well as genomic data. In spite of their advantages, it is still lacking standardized processes of feature extraction and analysis methodology among different research groups, which have made external validations infeasible. Radiomics and radiogenomics can be used to better understand the genomic basis of gliomas, such as tumor spatial heterogeneity, treatment response, molecular classifications and tumor microenvironment immune infiltration. These novel techniques have also been used to predict histological features, grade or even overall survival in gliomas. In this review, workflows of radiomics and radiogenomics are elucidated, with recent research on machine learning or artificial intelligence in glioma.
Topics: Humans; Artificial Intelligence; Radiomics; Glioma; Machine Learning; Magnetic Resonance Imaging; Tumor Microenvironment
PubMed: 38486342
DOI: 10.1186/s40644-024-00682-y -
Current Neurology and Neuroscience... Feb 2024The response assessment in Neuro-Oncology (RANO) criteria and its versions were developed by expert opinion consensus to standardize response evaluation in glioma... (Review)
Review
PURPOSE OF REVIEW
The response assessment in Neuro-Oncology (RANO) criteria and its versions were developed by expert opinion consensus to standardize response evaluation in glioma clinical trials. New patient-based data informed the development of updated response assessment criteria, RANO 2.0.
RECENT FINDINGS
In a recent study of patients with glioblastoma, the post-radiation brain MRI was a superior baseline MRI compared to the pretreatment MRI, and confirmation scans were only beneficial within the first 12 weeks of completion of radiation in newly diagnosed disease. Nonenhancing disease evaluation did not improve the correlation between progression-free survival and overall survival in newly diagnosed and recurrent settings. RANO 2.0 recommends a single common response criteria for high- and low-grade gliomas, regardless of the treatment modality being evaluated. It also provides guidance on the evaluation of nonenhancing tumors and tumors with both enhancing and nonenhancing components.
Topics: Humans; Brain Neoplasms; Glioma; Magnetic Resonance Imaging; Glioblastoma; Neuroimaging
PubMed: 38170429
DOI: 10.1007/s11910-023-01329-4 -
European Journal of Medicinal Chemistry Sep 2023Glioma is one of the most common types of brain tumors, and its high recurrence and mortality rates threaten human health. In 2008, the frequent isocitrate dehydrogenase... (Review)
Review
Glioma is one of the most common types of brain tumors, and its high recurrence and mortality rates threaten human health. In 2008, the frequent isocitrate dehydrogenase 1 (IDH1) mutations in glioma were reported, which brought a new strategy in the treatment of this challenging disease. In this perspective, we first discuss the possible gliomagenesis after IDH1 mutations (mIDH1). Subsequently, we systematically investigate the reported mIDH1 inhibitors and present a comparative analysis of the ligand-binding pocket in mIDH1. Additionally, we also discuss the binding features and physicochemical properties of different mIDH1 inhibitors to facilitate the future development of mIDH1 inhibitors. Finally, we discuss the possible selectivity features of mIDH1 inhibitors against WT-IDH1 and IDH2 by combining protein-based and ligand-based information. We hope that this perspective can inspire the development of mIDH1 inhibitors and bring potent mIDH1 inhibitors for the treatment of glioma.
Topics: Humans; Isocitrates; Ligands; Isocitrate Dehydrogenase; Glioma; Brain Neoplasms; Mutation
PubMed: 37235998
DOI: 10.1016/j.ejmech.2023.115464