-
Frontiers in Immunology 2022Glioma is a type of brain and spinal cord tumor that begins in glial cells that support the nervous system neurons functions. Age, radiation exposure, and family... (Review)
Review
Glioma is a type of brain and spinal cord tumor that begins in glial cells that support the nervous system neurons functions. Age, radiation exposure, and family background of glioma constitute are risk factors of glioma initiation. Gliomas are categorized on a scale of four grades according to their growth rate. Grades one and two grow slowly, while grades three and four grow faster. Glioblastoma is a grade four gliomas and the deadliest due to its aggressive nature (accelerated proliferation, invasion, and migration). As such, multiple therapeutic approaches are required to improve treatment outcomes. Recently, studies have implicated the significant roles of immune cells in tumorigenesis and the progression of glioma. The energy demands of gliomas alter their microenvironment quality, thereby inducing heterogeneity and plasticity change of stromal and immune cells the pathway, which ultimately results in epigenetic modifications that facilitates tumor growth. PI3K is utilized by many intracellular signaling pathways ensuring the proper functioning of the cell. The activation of regulates the plasma membrane activities, contributing to the phosphorylation reaction necessary for transcription factors activities and oncogenes hyperactivation. The pleiotropic nature of makes its activity unpredictable during altered cellular functions. Modification of cancer cell microenvironment affects many cell types, including immune cells that are the frontline cells involved in inflammatory cascades caused by cancer cells high cytokines synthesis. Typically, the evasion of immunosurveillance by gliomas and their resistance to treatment has been attributed to epigenetic reprogramming of immune cells in the tumor microenvironment, which results from cancer metabolism. Hence, it is speculative that impeding cancer metabolism and/or circumventing the epigenetic alteration of immune cell functions in the tumor microenvironment might enhance treatment outcomes. Herein, from an oncological and immunological perspective, this review discusses the underlying pathomechanism of cell-cell interactions enhancing glioma initiation and metabolism activation and tumor microenvironment changes that affect epigenetic modifications in immune cells. Finally, prospects for therapeutic intervention were highlighted.
Topics: Cell Transformation, Neoplastic; Epigenesis, Genetic; Glioma; Humans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Tumor Microenvironment
PubMed: 35392088
DOI: 10.3389/fimmu.2022.831636 -
International Journal of Molecular... Jun 2023H3K27M mutant (mut) diffuse midline glioma (DMG) is a lethal cancer with no effective cure. The glycosphingolipids (GSL) metabolism is altered in these tumors and could...
H3K27M mutant (mut) diffuse midline glioma (DMG) is a lethal cancer with no effective cure. The glycosphingolipids (GSL) metabolism is altered in these tumors and could be exploited to develop new therapies. We tested the effect of the glucosylceramide synthase inhibitors (GSI) miglustat and eliglustat on cell proliferation, alone or in combination with temozolomide or ionizing radiation. Miglustat was included in the therapy protocol of two pediatric patients. The effect of H3.3K27 trimethylation on GSL composition was analyzed in ependymoma. GSI reduced the expression of the ganglioside GD2 in a concentration and time-dependent manner and increased the expression of ceramide, ceramide 1-phosphate, sphingosine, and sphingomyelin but not of sphingosine 1-phosphate. Miglustat significantly increased the efficacy of irradiation. Treatment with miglustat according to dose recommendations for patients with Niemann-Pick disease was well tolerated with manageable toxicities. One patient showed a mixed response. In ependymoma, a high concentration of GD2 was found only in the presence of the loss of H3.3K27 trimethylation. In conclusion, treatment with miglustat and, in general, targeting GSL metabolism may offer a new therapeutic opportunity and can be administered in close proximity to radiation therapy. Alterations in H3K27 could be useful to identify patients with a deregulated GSL metabolism.
Topics: Humans; Child; Ceramides; Glioma; Ependymoma
PubMed: 37373053
DOI: 10.3390/ijms24129905 -
Journal of Translational Medicine Mar 2023This study aimed to characterize the genetic profile of patients with glioma and discuss the impact of next-generation sequencing in glioma diagnosis and treatment.
BACKGROUND
This study aimed to characterize the genetic profile of patients with glioma and discuss the impact of next-generation sequencing in glioma diagnosis and treatment.
METHODS
Between 2019 and 2022, we analyzed the genetic profile of 99 patients with glioma through the Oncomine Focus Assay. The assay enables the detection of mutations in 52 driver genes, including single nucleotide variants (SNVs), copy number variants (CNVs), and gene fusions. We also collected and analyzed patients' clinic characteristics and treatment outcomes.
RESULTS
Over a period of 35 months, 700 patients with glioma followed by our neuro-oncology unit were screened, and 99 were enrolled in the study; most of the patients were excluded for inadequate non-morphological MRI or lack/inadequacy of the tissue samples. Based on our findings, most patients with glioma present mutations, such as SNVs, CNVs or gene fusions. Our data were similar to those reported by The Cancer Genome Atlas Program in terms of frequency of SNVs and CNVs, while we observed more cases of gene fusions. Median overall survival, progression-free survival, and time to progression were significantly lower for patients with grade VI glioblastoma than those with other gliomas. Only four patients were offered a targeted treatment based on the mutation detected; however, only one received treatment, the others could not receive the selected treatment because of worsening clinical status.
CONCLUSION
Routine timely molecular profiling in patients with glioma should be implemented to offer patients an individualized diagnostic approach and provide them with advanced targeted therapy options if available.
Topics: Humans; Glioma; Glioblastoma; Mutation; High-Throughput Nucleotide Sequencing; DNA Copy Number Variations; Brain Neoplasms
PubMed: 36959606
DOI: 10.1186/s12967-023-04057-y -
Neuro-oncology Sep 2022
Topics: Cell Lineage; Energy Metabolism; Glioma; Humans; Imidazoles; Pyridines; Pyrimidines
PubMed: 35460424
DOI: 10.1093/neuonc/noac103 -
The Oncologist Jun 2006Low-grade gliomas are a heterogeneous group of neoplasms usually encountered in younger patient populations. These tumors represent a unique challenge because most... (Review)
Review
Low-grade gliomas are a heterogeneous group of neoplasms usually encountered in younger patient populations. These tumors represent a unique challenge because most patients will survive a decade or more and may be at a higher risk for treatment-related complications. Clinical observations over the years have identified a subset of low-grade gliomas that tends to manifest more aggressive clinical behavior and require earlier, more aggressive intervention. Clinical and molecular parameters may allow better assessment of prognosis and application of risk-adjusted management strategies that may include resection, radiation, or chemotherapy. Improved methods of long-term cognitive and functional assessment are desperately needed in this patient population.
Topics: Brain Neoplasms; Glioma; Humans; Prognosis
PubMed: 16794247
DOI: 10.1634/theoncologist.11-6-681 -
Computational and Mathematical Methods... 2018Glioma constitutes the most common type of primary brain tumor with a dismal survival, often measured in terms of months or years. The thin line between treatment... (Review)
Review
Glioma constitutes the most common type of primary brain tumor with a dismal survival, often measured in terms of months or years. The thin line between treatment effectiveness and patient harm underpins the importance of tailoring clinical management to the individual patient. Randomized trials have laid the foundation for many neuro-oncological guidelines. Despite this, their findings focus on group-level estimates. Given our current tools, we are limited in our ability to guide patients on what therapy is best for them as individuals, or even how long they should expect to survive. Machine learning, however, promises to provide the analytical support for personalizing treatment decisions, and deep learning allows clinicians to unlock insight from the vast amount of unstructured data that is collected on glioma patients. Although these novel techniques have achieved astonishing results across a variety of clinical applications, significant hurdles remain associated with the implementation of them in clinical practice. Future challenges include the assembly of well-curated cross-institutional datasets, improvement of the interpretability of machine learning models, and balancing novel evidence-based decision-making with the associated liability of automated inference. Although artificial intelligence already exceeds clinical expertise in a variety of applications, clinicians remain responsible for interpreting the implications of, and acting upon, each prediction.
Topics: Brain Neoplasms; Glioblastoma; Glioma; Humans; Machine Learning; Neoplasm Recurrence, Local; Precision Medicine
PubMed: 30008798
DOI: 10.1155/2018/8572058 -
Journal of Cellular and Molecular... Feb 2021Glioma is the most common intracranial malignant tumour. A clear diagnosis and molecular targeted therapy are of great significance for improving the survival time and...
Glioma is the most common intracranial malignant tumour. A clear diagnosis and molecular targeted therapy are of great significance for improving the survival time and quality of life of patients with low-grade glioma. 5-methylcytosine methylation is one of the ways of RNA modification, but there are limited studies on the role of m C methylation of low-grade glioma. Single-nucleotide variant, RNA expression matrix and corresponding clinical data of low-grade glioma came from public database. The single-nucleotide variant and expression of m C regulators were estimated. A prognostic model based on m C regulators was constructed by Cox regression. Potential functions of these molecules were assessed by gene set enrichment analysis. DNMT3A mutation was the most frequent among the m C regulators in low-grade glioma. NSUN3, TET2, TRDMT1, ALYREF, DNMT3B, DNMT1, NOP2 and NSUN2 were up-regulated. One prognostic model was constructed which had a strong predictive power for the overall survival of low-grade glioma. We studied the expression and prognostic characteristics of m C regulators in low-grade glioma, supplied biomarkers for the diagnosis and prognosis and provided the foundation for the study of the pathogenesis of low-grade glioma.
Topics: 5-Methylcytosine; Biomarkers, Tumor; Computational Biology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioma; Humans; Methylation; Neoplasm Grading; Prognosis; RNA; ROC Curve; Transcriptome
PubMed: 33400376
DOI: 10.1111/jcmm.16221 -
American Society of Clinical Oncology... Jan 2019Following the identification of key molecular alterations that provided superior prognostication and led to the updated 2016 World Health Organization (WHO) Central... (Review)
Review
Following the identification of key molecular alterations that provided superior prognostication and led to the updated 2016 World Health Organization (WHO) Central Nervous System (CNS) Tumor Classification, the understanding of glioma behavior has rapidly evolved. Mutations in isocitrate dehydrogenase 1 and 2 are present in the majority of adult grade 2 and 3 gliomas, and when used in conjunction with codeletion for classification, the prognostic distinction between grade 2 versus grade 3 is diminished. As such, the previously often used term of "low-grade glioma," which referred to grade 2 gliomas, has now been replaced by the phrase "lower-grade glioma" to encompass both grade 2 and 3 tumors. Additional molecular characterization is ongoing to even further classify this heterogeneous group of tumors. With such a colossal shift in the understanding of lower-grade gliomas, management of disease is being redefined in the setting of emerging molecular-genetic biomarkers. In this article, we review recent progress and future directions regarding the surgical, radiotherapeutic, chemotherapeutic, and long-term management of adult lower-grade gliomas.
Topics: Biomarkers, Tumor; Combined Modality Therapy; Disease Management; Glioma; Humans; Neoplasm Grading; Neoplasm Staging; Nervous System Diseases
PubMed: 31099638
DOI: 10.1200/EDBK_238353 -
International Journal of Molecular... Oct 2021Glioma is the most common and aggressive tumor of the central nervous system. The uncontrolled proliferation, cellular heterogeneity, and diffusive capacity of glioma... (Review)
Review
Glioma is the most common and aggressive tumor of the central nervous system. The uncontrolled proliferation, cellular heterogeneity, and diffusive capacity of glioma cells contribute to a very poor prognosis of patients with high grade glioma. Compared to normal cells, cancer cells exhibit a higher rate of glucose uptake, which is accompanied with the metabolic switch from oxidative phosphorylation to aerobic glycolysis. The metabolic reprogramming of cancer cell supports excessive cell proliferation, which are frequently mediated by the activation of oncogenes or the perturbations of tumor suppressor genes. Recently, a growing body of evidence has started to reveal that long noncoding RNAs (lncRNAs) are implicated in a wide spectrum of biological processes in glioma, including malignant phenotypes and aerobic glycolysis. However, the mechanisms of diverse lncRNAs in the initiation and progression of gliomas remain to be fully unveiled. In this review, we summarized the diverse roles of lncRNAs in shaping the biological features and aerobic glycolysis of glioma. The thorough understanding of lncRNAs in glioma biology provides opportunities for developing diagnostic biomarkers and novel therapeutic strategies targeting gliomas.
Topics: Aerobiosis; Biomarkers, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Glioma; Glycolysis; Humans; Neoplastic Stem Cells; Prognosis; RNA, Long Noncoding; Signal Transduction
PubMed: 34681857
DOI: 10.3390/ijms222011197 -
Neuro-oncology Sep 2019
Topics: Biomarkers; Brain Neoplasms; Glioblastoma; Glioma; Heterografts; Humans
PubMed: 31271213
DOI: 10.1093/neuonc/noz120