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Cellular & Molecular Biology Letters Dec 2023Glioma is the most pervasive intracranial tumor in the central nervous system (CNS), with glioblastoma (GBM) being the most malignant type having a highly heterogeneous... (Review)
Review
Glioma is the most pervasive intracranial tumor in the central nervous system (CNS), with glioblastoma (GBM) being the most malignant type having a highly heterogeneous cancer cell population. There is a significantly high mortality rate in GBM patients. Molecular biomarkers related to GBM malignancy may have prognostic values in predicting survival outcomes and therapeutic responses, especially in patients with high-grade gliomas. In particular, N6-methyladenine (m6A) mRNA modification is the most abundant form of post-transcriptional RNA modification in mammals and is involved in regulating mRNA translation and degradation. Cumulative findings indicate that m6A methylation plays a crucial part in neurogenesis and glioma pathogenesis. In this review, we summarize recent advances regarding the functional significance of m6A modification and its regulatory factors in glioma occurrence and progression. Significant advancement of m6A methylation-associated regulators as potential therapeutic targets is also discussed.
Topics: Animals; Humans; Glioma; Central Nervous System; Brain Neoplasms; Adenosine; Methylation; Mammals
PubMed: 38072944
DOI: 10.1186/s11658-023-00514-0 -
Neuro-oncology Oct 2023In the 5th edition of the WHO CNS tumor classification (CNS5, 2021), multiple molecular characteristics became essential diagnostic criteria for many additional CNS...
In the 5th edition of the WHO CNS tumor classification (CNS5, 2021), multiple molecular characteristics became essential diagnostic criteria for many additional CNS tumor types. For those tumors, an integrated, "histomolecular" diagnosis is required. A variety of approaches exists for determining the status of the underlying molecular markers. The present guideline focuses on the methods that can be used for assessment of the currently most informative diagnostic and prognostic molecular markers for the diagnosis of gliomas, glioneuronal and neuronal tumors. The main characteristics of the molecular methods are systematically discussed, followed by recommendations and information on available evidence levels for diagnostic measures. The recommendations cover DNA and RNA next-generation-sequencing, methylome profiling, and select assays for single/limited target analyses, including immunohistochemistry. Additionally, because of its importance as a predictive marker in IDH-wildtype glioblastomas, tools for the analysis of MGMT promoter methylation status are covered. A structured overview of the different assays with their characteristics, especially their advantages and limitations, is provided, and requirements for input material and reporting of results are clarified. General aspects of molecular diagnostic testing regarding clinical relevance, accessibility, cost, implementation, regulatory, and ethical aspects are discussed as well. Finally, we provide an outlook on new developments in the landscape of molecular testing technologies in neuro-oncology.
Topics: Humans; Brain Neoplasms; Pathology, Molecular; Mutation; Glioma; World Health Organization
PubMed: 37279174
DOI: 10.1093/neuonc/noad100 -
Frontiers in Immunology 2024Glioma is a malignant tumor of the central nervous system (CNS). Currently, effective treatment options for gliomas are still lacking. Neutrophils, as an important... (Review)
Review
Glioma is a malignant tumor of the central nervous system (CNS). Currently, effective treatment options for gliomas are still lacking. Neutrophils, as an important member of the tumor microenvironment (TME), are widely distributed in circulation. Recently, the discovery of cranial-meningeal channels and intracranial lymphatic vessels has provided new insights into the origins of neutrophils in the CNS. Neutrophils in the brain may originate more from the skull and adjacent vertebral bone marrow. They cross the blood-brain barrier (BBB) under the action of chemokines and enter the brain parenchyma, subsequently migrating to the glioma TME and undergoing phenotypic changes upon contact with tumor cells. Under glycolytic metabolism model, neutrophils show complex and dual functions in different stages of cancer progression, including participation in the malignant progression, immune suppression, and anti-tumor effects of gliomas. Additionally, neutrophils in the TME interact with other immune cells, playing a crucial role in cancer immunotherapy. Targeting neutrophils may be a novel generation of immunotherapy and improve the efficacy of cancer treatments. This article reviews the molecular mechanisms of neutrophils infiltrating the central nervous system from the external environment, detailing the origin, functions, classifications, and targeted therapies of neutrophils in the context of glioma.
Topics: Humans; Tumor Microenvironment; Glioma; Neutrophils; Immunotherapy; Brain Neoplasms; Animals; Blood-Brain Barrier; Neutrophil Infiltration
PubMed: 38779679
DOI: 10.3389/fimmu.2024.1393173 -
Nature Medicine Jun 2024Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is limited. We present an epigenetically defined neural...
Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is limited. We present an epigenetically defined neural signature of glioblastoma that independently predicts patients' survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals a high abundance of malignant stemcell-like cells in high-neural glioblastoma, primarily of the neural lineage. These cells are further classified as neural-progenitor-cell-like, astrocyte-like and oligodendrocyte-progenitor-like, alongside oligodendrocytes and excitatory neurons. In line with these findings, high-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature is associated with decreased overall and progression-free survival. High-neural tumors also exhibit increased functional connectivity in magnetencephalography and resting-state magnet resonance imaging and can be detected via DNA analytes and brain-derived neurotrophic factor in patients' plasma. The prognostic importance of the neural signature was further validated in patients diagnosed with diffuse midline glioma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant. High-neural gliomas likely require a maximized surgical resection approach for improved outcomes.
Topics: Humans; Epigenesis, Genetic; Prognosis; Glioma; Brain Neoplasms; DNA Methylation; Animals; Mice; Male; Female; Gene Expression Regulation, Neoplastic; Glioblastoma; Middle Aged; Neurons; Adult; Single-Cell Analysis; Cell Line, Tumor; Transcriptome; Neoplasm Grading
PubMed: 38760585
DOI: 10.1038/s41591-024-02969-w -
CNS Neuroscience & Therapeutics Jul 2023H3 mutated diffuse midline gliomas (DMGs) are extremely aggressive and the leading cause of cancer-related deaths in pediatric brain tumors with 5-year survival <1%.... (Review)
Review
BACKGROUND
H3 mutated diffuse midline gliomas (DMGs) are extremely aggressive and the leading cause of cancer-related deaths in pediatric brain tumors with 5-year survival <1%. Radiotherapy is the only established adjuvant treatment of H3 DMGs; however, the radio-resistance is commonly observed.
METHODS
We summarized current understandings of the molecular responses of H3 DMGs to radiotherapy and provide crucial insights into current advances in radiosensitivity enhancement.
RESULTS
Ionizing radiation (IR) can mainly inhibit tumor cell growth by inducing DNA damage regulated by the cell cycle checkpoints and DNA damage repair (DDR) system. In H3K27M DMGs, the aberrant genetic and epigenetic changes, stemness genotype, and epithelial-mesenchymal transition (EMT) disrupt the cell cycle checkpoints and DDR system by altering the associated regulatory signaling pathways, which leads to the development of radio-resistance.
CONCLUSIONS
The advances in mechanisms of radio-resistance in H3 DMGs promote the potential targets to enhance the sensitivity to radiotherapy.
Topics: Child; Humans; Glioma; Histones; Mutation; Brain Neoplasms
PubMed: 37157237
DOI: 10.1111/cns.14225 -
Cellular and Molecular Life Sciences :... Aug 2023We previously reported that TRPM7 regulates glioma cells' stemness through STAT3. In addition, we demonstrated that FOSL1 is a response gene for TRPM7, and the FOSL1...
INTRODUCTION
We previously reported that TRPM7 regulates glioma cells' stemness through STAT3. In addition, we demonstrated that FOSL1 is a response gene for TRPM7, and the FOSL1 gene serves as an oncogene to promote glioma proliferation and invasion.
METHODS
In the present study, we determined the effects of FOSL1 on glioma stem cell (GSC) markers CD133 and ALDH1 by flow cytometry, and the maintenance of stem cell activity by extreme limiting dilution assays (ELDA). To further gain insight into the mechanism by which TRPM7 activates transcription of the FOSL1 gene to contribute to glioma stemness, we constructed a FOSL1 promoter and its GAS mutants followed by luciferase reporter assays and ChIP-qPCR in a glioma cell line and glioma patient-derived xenoline. We further examined GSC markers ALDH1 and TRPM7 as well as FOSL1 by immunohistochemistry staining (IHC) in brain tissue microarray (TMA) of glioma patients.
RESULTS
We revealed that FOSL1 knockdown reduces the expression of GSC markers CD133 and ALDH1, and FOSL1 is required to maintain stem cell activity in glioma cells. The experiments also showed that mutations of - 328 to - 336 and - 378 to - 386 GAS elements markedly reduced FOSL1 promoter activity. Constitutively active STAT3 increased while dominant-negative STAT3 decreased FOSL1 promoter activity. Furthermore, overexpression of TRPM7 enhanced while silencing of TRPM7 reduced FOSL1 promoter activity. ChIP-qPCR assays revealed that STAT3, present in nuclear lysates of glioma cells stimulated by constitutively activated STAT3, can bind to two GAS elements, respectively. We demonstrated that deacetylation of FOSL1 at the Lys-116 residue located within its DNA binding domain led to an increase in FOSL1 transcriptional activity. We found that the expression of TRPM7, ALDH1, and FOSL1 protein is associated with grades of malignant glioma, and TRPM7 protein expression correlates to the expression of ALDH1 and FOSL1 in glioma patients.
CONCLUSIONS
These combined results demonstrated that TRPM7 induced FOSL1 transcriptional activation, which is mediated by the action of STAT3, a mechanism shown to be important in glioma stemness. These results indicated that FOSL1, similar to GSC markers ALDH1 and TRPM7, is a diagnostic marker and potential drug target for glioma patients.
Topics: Humans; TRPM Cation Channels; Oncogenes; Biological Assay; Brain; Glioma; Protein Serine-Threonine Kinases; STAT3 Transcription Factor
PubMed: 37642779
DOI: 10.1007/s00018-023-04921-6 -
Nature Communications Oct 2023Current diagnosis of glioma types requires combining both histological features and molecular characteristics, which is an expensive and time-consuming procedure....
Current diagnosis of glioma types requires combining both histological features and molecular characteristics, which is an expensive and time-consuming procedure. Determining the tumor types directly from whole-slide images (WSIs) is of great value for glioma diagnosis. This study presents an integrated diagnosis model for automatic classification of diffuse gliomas from annotation-free standard WSIs. Our model is developed on a training cohort (n = 1362) and a validation cohort (n = 340), and tested on an internal testing cohort (n = 289) and two external cohorts (n = 305 and 328, respectively). The model can learn imaging features containing both pathological morphology and underlying biological clues to achieve the integrated diagnosis. Our model achieves high performance with area under receiver operator curve all above 0.90 in classifying major tumor types, in identifying tumor grades within type, and especially in distinguishing tumor genotypes with shared histological features. This integrated diagnosis model has the potential to be used in clinical scenarios for automated and unbiased classification of adult-type diffuse gliomas.
Topics: Adult; Humans; Brain Neoplasms; Deep Learning; Neuropathology; Glioma
PubMed: 37821431
DOI: 10.1038/s41467-023-41195-9 -
Journal of Nanobiotechnology Jun 2024Recently, the significant benefits of cancer immunotherapy for most cancers have been demonstrated in clinical and preclinical studies. However, the efficacy of these... (Review)
Review
Recently, the significant benefits of cancer immunotherapy for most cancers have been demonstrated in clinical and preclinical studies. However, the efficacy of these immunotherapies for gliomas is limited, owing to restricted drug delivery and insufficient immune activation. As drug carriers, exosomes offer the advantages of low toxicity, good biocompatibility, and intrinsic cell targeting, which could enhance glioma immunotherapy efficacy. However, a review of exosome-based drug delivery systems for glioma immunotherapy has not been presented. This review introduces the current problems in glioma immunotherapy and the role of exosomes in addressing these issues. Meanwhile, preparation and application strategies of exosome-based drug delivery systems for glioma immunotherapy are discussed, especially for enhancing immunogenicity and reversing the immunosuppressive tumor microenvironment. Finally, we briefly describe the challenges of exosome-based drug delivery systems in clinical translation. We anticipate that this review will guide the use of exosomes as drug carriers for glioma immunotherapy.
Topics: Exosomes; Humans; Glioma; Immunotherapy; Animals; Drug Delivery Systems; Tumor Microenvironment; Drug Carriers; Brain Neoplasms
PubMed: 38890722
DOI: 10.1186/s12951-024-02611-4 -
Brain Pathology (Zurich, Switzerland) Sep 2023Fusions involving CRAF (RAF1) are infrequent oncogenic drivers in pediatric low-grade gliomas, rarely identified in tumors bearing features of pilocytic astrocytoma, and...
Fusions involving CRAF (RAF1) are infrequent oncogenic drivers in pediatric low-grade gliomas, rarely identified in tumors bearing features of pilocytic astrocytoma, and involving a limited number of known fusion partners. We describe recurrent TRAK1::RAF1 fusions, previously unreported in brain tumors, in three pediatric patients with low-grade glial-glioneuronal tumors. We present the associated clinical, histopathologic and molecular features. Patients were all female, aged 8 years, 15 months, and 10 months at diagnosis. All tumors were located in the cerebral hemispheres and predominantly cortical, with leptomeningeal involvement in 2/3 patients. Similar to previously described activating RAF1 fusions, the breakpoints in RAF1 all occurred 5' of the kinase domain, while the breakpoints in the 3' partner preserved the N-terminal kinesin-interacting domain and coiled-coil motifs of TRAK1. Two of the three cases demonstrated methylation profiles (v12.5) compatible with desmoplastic infantile ganglioglioma (DIG)/desmoplastic infantile astrocytoma (DIA) and have remained clinically stable and without disease progression/recurrence after resection. The remaining tumor was non-classifiable; with focal recurrence 14 months after initial resection; the patient remains symptom free and without further recurrence/progression (5 months post re-resection and 19 months from initial diagnosis). Our report expands the landscape of oncogenic RAF1 fusions in pediatric gliomas, which will help to further refine tumor classification and guide management of patients with these alterations.
Topics: Child; Female; Humans; Adaptor Proteins, Vesicular Transport; Astrocytoma; Brain Neoplasms; Ganglioglioma; Glioma; Oncogene Fusion
PubMed: 37399073
DOI: 10.1111/bpa.13185 -
Frontiers in Immunology 2023Brain tumors are the leading cause of morbidity and mortality related to cancer in children, where high-grade glioma harbor the worst prognosis. It has become obvious... (Review)
Review
Brain tumors are the leading cause of morbidity and mortality related to cancer in children, where high-grade glioma harbor the worst prognosis. It has become obvious that pediatric glioma differs significantly from their adult counterparts, rendering extrapolations difficult. Curative options for several types of glioma are lacking, albeit ongoing research efforts and clinical trials. As already proven in the past, inter- and intratumoral heterogeneity plays an important role in the resistance to therapy and thus implicates morbidity and mortality for these patients. However, while less studied, the tumor micro-environment (TME) adds another level of heterogeneity. Knowledge gaps exist on how the TME interacts with the tumor cells and how the location of the various cell types in the TME influences tumor growth and the response to treatment. Some studies identified the presence of several (immune) cell types as prognostic factors, but often lack a deeper understanding of the underlying mechanisms, possibly leading to contradictory findings. Although the TME in pediatric glioma is regarded as "cold", several treatment options are emerging, with the TME being the primary target of treatment. Therefore, it is crucial to study the TME of pediatric glioma, so that the interactions between TME, tumoral cells and therapeutics can be better understood before, during and after treatment. In this review, we provide an overview of the available insights into the composition and role of the TME across different types of pediatric glioma. Moreover, where possible, we provide a framework on how a particular TME may influence responses to conventional- and/or immunotherapy.
Topics: Adult; Humans; Child; Glioma; Brain Neoplasms; Immunotherapy; Tumor Microenvironment
PubMed: 37901250
DOI: 10.3389/fimmu.2023.1227126