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Neuro-oncology Aug 2012Microglia, which contribute substantially to the tumor mass of glioblastoma, have been shown to play an important role in glioma growth and invasion. While a large... (Review)
Review
Microglia, which contribute substantially to the tumor mass of glioblastoma, have been shown to play an important role in glioma growth and invasion. While a large number of experimental studies on functional attributes of microglia in glioma provide evidence for their tumor-supporting roles, there also exist hints in support of their anti-tumor properties. Microglial activities during glioma progression seem multifaceted. They have been attributed to the receptors expressed on the microglia surface, to glioma-derived molecules that have an effect on microglia, and to the molecules released by microglia in response to their environment under glioma control, which can have autocrine effects. In this paper, the microglia and glioma literature is reviewed. We provide a synopsis of the molecular profile of microglia under the influence of glioma in order to help establish a rational basis for their potential therapeutic use. The ability of microglia precursors to cross the blood-brain barrier makes them an attractive target for the development of novel cell-based treatments of malignant glioma.
Topics: Animals; Brain Neoplasms; Glioma; Humans; Microglia
PubMed: 22573310
DOI: 10.1093/neuonc/nos116 -
Annals of Medicine 2023Adult glioma progresses rapidly and has a poor clinical outcome. The focal adhesion protein Kindlin-3 (encoded by the gene) participates in tumor development, drug...
BACKGROUND
Adult glioma progresses rapidly and has a poor clinical outcome. The focal adhesion protein Kindlin-3 (encoded by the gene) participates in tumor development, drug resistance, and progression. However, the relationship between Kindlin-3 and glioma prognosis or immune microenvironment is poorly understood.
METHODS
We comprehensively analyzed the expression, prognostic value, mutation landscape, functional enrichment, immune infiltration, and therapeutic role of in glioma using multiple datasets and validated Kindlin-3 expression in clinical tissue specimens by immunohistochemistry and multiple immunofluorescence staining.
RESULTS
is an independent predictor of glioma prognosis and is highly expressed in glioblastoma tissues. Functional enrichment analyses indicated that participates in multiple immune-related pathways such as immune response and cytokine production. Furthermore, expression was positively correlated with the infiltration of several immune cells, immune scores, and the expression of genes related to immune checkpoints. Further analyses revealed that overexpression of was linked to a better response to anti-PD1 therapy. Data from single-cell RNA-seq reveal that was largely expressed in microglial cells and tissue-resident macrophages. Multiple immunofluorescence staining confirmed the overexpression of Kindlin-3 in the glioma-associated microglia/macrophages (GAMs).
CONCLUSION
The findings of this study provide a new perspective on the role of Kindlin-3 in glioma and may have a significant impact on the discovery of novel biomarkers and targeting of GAMs in the future.
Topics: Adult; Humans; Prognosis; Glioma; Immunotherapy; Tumor Microenvironment
PubMed: 37795794
DOI: 10.1080/07853890.2023.2264325 -
Immunology Feb 2023The draining of brain interstitial fluid (ISF) to cerebrospinal fluid (CSF) and the subsequent draining of CSF to meningeal lymphatics is well-known. Nonetheless, its... (Review)
Review
The draining of brain interstitial fluid (ISF) to cerebrospinal fluid (CSF) and the subsequent draining of CSF to meningeal lymphatics is well-known. Nonetheless, its role in the development of glioma is a remarkable finding that has to be extensively understood. The glymphatic system (GS) collects CSF from the subarachnoid space and brain ISF through aquaporin-4 (AQP4) water channels. The glial limiting membrane and the perivascular astrocyte-end-feet membrane both have elevated levels of AQP4. CSF is thought to drain through the nerve sheaths of the olfactory and other cranial nerves as well as spinal meningeal lymphatics via dorsal or basal lymphatic vessels. Meningeal lymphatic vessels (MLVs) exist below the skull in the dorsal and basal regions. In this view, MLVs offer a pathway to drain macromolecules and traffic immunological cells from the CNS into cervical lymph nodes (CLNs), and thus can be used as a candidate curing strategy against glioma and other associated complications, such as neuro-inflammation. Taken together, the lymphatic drainage system could provide a route or approach for drug targeting of glioma and other neurological conditions. Nevertheless, its pathophysiological role in glioma remains elusive, which needs extensive research. The current review aims to explore the lymphatic drainage system, its role in glioma progression, and possible therapeutic techniques that target MLVs in the CNS.
Topics: Humans; Lymphatic System; Lymphatic Vessels; Brain; Meninges; Glioma
PubMed: 35719015
DOI: 10.1111/imm.13517 -
Annual Review of Pathology 2010The ongoing characterization of the genetic and epigenetic alterations in the gliomas has already improved the classification of these heterogeneous tumors and enabled... (Review)
Review
The ongoing characterization of the genetic and epigenetic alterations in the gliomas has already improved the classification of these heterogeneous tumors and enabled the development of rodent models for analysis of the molecular pathways underlying their proliferative and invasive behavior. Effective application of the targeted therapies that are now in development will depend on pathologists' ability to provide accurate information regarding the genetic alterations and the expression of key receptors and ligands in the tumors. Here we review the mechanisms that have been implicated in the pathogenesis of the gliomas and provide examples of the cooperative nature of the pathways involved, which may influence the initial therapeutic response and the potential for development of resistance.
Topics: Animals; Cell Proliferation; Disease Models, Animal; Epigenesis, Genetic; Glioma; Humans; Signal Transduction
PubMed: 19737106
DOI: 10.1146/annurev-pathol-121808-102109 -
The Oncologist Dec 2014The current progressive aging of the population is resulting in a continuous increase in the incidence of gliomas in elderly people, especially the most frequent... (Review)
Review
The current progressive aging of the population is resulting in a continuous increase in the incidence of gliomas in elderly people, especially the most frequent subtype, glioblastoma (GBM). This sociohealth shift, known as the "silver tsunami," has prompted the neuro-oncology community to investigate the role of specific antitumor treatments, such as surgery, radiotherapy, chemotherapy, and other targeted therapies, for these traditionally undertreated patients. Advanced age, a widely recognized poor prognostic factor in both low-grade glioma (LGG) and high-grade glioma patients, should no longer be the sole reason for excluding such older patients from receiving etiologic treatments. Far from it, results from recent prospective trials conducted on elderly patients with GBM demonstrate that active management of these patients can have a positive impact on survival without impairing either cognition or quality of life. Although prospective studies specifically addressing the management of grade 2 and 3 gliomas are lacking and thus needed, the aforementioned tendency toward acknowledging a therapeutic benefit for GBM patients might also apply to the treatment of patients with LGG and anaplastic gliomas. In order to optimize such etiologic treatment in conjunction with symptomatic management, neuro-oncology multidisciplinary boards must individually consider important features such as resectability of the tumor, functional and cognitive status, associated comorbidities, and social support.
Topics: Aged; Aged, 80 and over; Brain Neoplasms; Disease Progression; Glioma; Humans; Prognosis; Quality of Life
PubMed: 25342314
DOI: 10.1634/theoncologist.2014-0170 -
Frontiers in Immunology 2023Gliomas, the most prevalent primary malignant tumors of the central nervous system in adults, exhibit slow growth in lower-grade gliomas (LGG). However, the majority of...
BACKGROUND
Gliomas, the most prevalent primary malignant tumors of the central nervous system in adults, exhibit slow growth in lower-grade gliomas (LGG). However, the majority of LGG cases progress to high-grade gliomas, posing challenges for prognostication. The tumor microenvironment (TME), characterized by telomere-related genes and immune cell infiltration, strongly influences glioma growth and therapeutic response. Therefore, our objective was to develop a Telomere-TME (TM-TME) classifier that integrates telomere-related genes and immune cell landscape to assess prognosis and therapeutic response in glioma.
METHODS
This study encompassed LGG patients from the TCGA and CCGA databases. TM score and TME score were derived from the expression signatures of telomere-related genes and the presence of immune cells in LGG, respectively. The TM-TME classifier was established by combining TM and TME scores to effectively predict prognosis. Subsequently, we conducted Kaplan-Meier survival estimation, univariate Cox regression analysis, and receiver operating characteristic curves to validate the prognostic prediction capacity of the TM-TME classifier across multiple cohorts. Gene Ontology (GO) analysis, biological processes, and proteomaps were performed to annotate the functional aspects of each subgroup and visualize the cellular signaling pathways.
RESULTS
The TM_low+TME_high subgroup exhibited superior prognosis and therapeutic response compared to other subgroups (P<0.001). This finding could be attributed to distinct tumor somatic mutations and cancer cellular signaling pathways. GO analysis indicated that the TM_low+TME_high subgroup is associated with the neuronal system and modulation of chemical synaptic transmission. Conversely, the TM_high+TME_low subgroup showed a strong association with cell cycle and DNA metabolic processes. Furthermore, the classifier significantly differentiated overall survival in the TCGA LGG cohort and served as an independent prognostic factor for LGG patients in both the TCGA cohort (P<0.001) and the CGGA cohort (P<0.001).
CONCLUSION
Overall, our findings underscore the significance of the TM-TME classifier in predicting prognosis and immune therapeutic response in glioma, shedding light on the complex immune landscape within each subgroup. Additionally, our results suggest the potential of integrating risk stratification with precision therapy for LGG.
Topics: Adult; Humans; Prognosis; Biomarkers; Telomere; Glioma; Central Nervous System; Tumor Microenvironment
PubMed: 37662954
DOI: 10.3389/fimmu.2023.1220100 -
Neurologia Medico-chirurgica 2015The current World Health Organization (WHO) classification of tumors of the central nervous system (CNS) is essentially a lineage-oriented classification based on a... (Review)
Review
The current World Health Organization (WHO) classification of tumors of the central nervous system (CNS) is essentially a lineage-oriented classification based on a presumable developmental tree of CNS. A four-tiered WHO grading scheme has been successfully applied to a spectrum of diffusely infiltrative astrocytomas, but it is not fully applicable to other gliomas, including oligodendrogliomas and ependymomas. Recent genetic studies have revealed that the major categories of gliomas, such as circumscribe astrocytomas, infiltrating astrocytomas/oligodendrogliomas, and glioblastoma, roughly correspond to major genetic alterations, including isocitrate dehydrogenases (IDHs) 1/2 mutations, TP53 mutations, co-deletion of chromosome arms 1p/19q, and BRAF mutation/fusion. These genetic alterations are clinically significant in terms of the response to treatment(s) and/or the prognosis. It is, thus, rational that future classification of gliomas should be based on genotypes, rather than phenotypes, although the genetic features of each tumor are not sufficiently understood at present to draw a complete map of the gliomas, and genetic testing is not yet available worldwide, particularly in Asian and African countries. This review summarizes the current concepts of the WHO classification, as well as the current understanding of the major genetic alterations in glioma and the potential use of these alterations as diagnostic criteria.
Topics: Glioma; Humans; Mutation; World Health Organization
PubMed: 25744348
DOI: 10.2176/nmc.ra.2014-0229 -
Cancer Biology & Medicine Nov 2022
Topics: Humans; Tumor Microenvironment; Glioma; Isocitrate Dehydrogenase
PubMed: 36350003
DOI: 10.20892/j.issn.2095-3941.2022.0363 -
Scientific Reports Apr 2023This study aimed to find any ambiguous genetic outlier for "oligodendroglioma, IDH-mutant and 1p/19q-codeleted (O_IDH_mut)" and "astrocytoma, IDH-mutant (A_IDH_mut)"...
This study aimed to find any ambiguous genetic outlier for "oligodendroglioma, IDH-mutant and 1p/19q-codeleted (O_IDH_mut)" and "astrocytoma, IDH-mutant (A_IDH_mut)" and to redefine the genetic landscape and prognostic factors of IDH-mutant gliomas. Next-generation sequencing (NGS) using a brain tumor-targeted gene panel, methylation profiles, and clinicopathological features were analyzed for O_IDH_mut (n = 74) in 70 patients and for A_IDH_mut (n = 95) in 90 patients. 97.3% of O_IDH_mut and 98.9% of A_IDH_mut displayed a classic genomic landscape. Combined CIC (75.7%) and/or FUBP1 (45.9%) mutations were detected in 93.2% and MGMTp methylation in 95.9% of O_IDH_mut patients. In A_IDH_mut, TP53 mutations were found in 86.3% and combined ATRX (82.1%) and TERTp (6.3%) mutations in 88.4%. Although there were 3 confusing cases, NOS (not otherwise specified) category, based on genetic profiles, but they were clearly classified by combining histopathology and DKFZ methylation classifier algorithms. The patients with MYCN amplification and/or CDKN2A/2B homozygous deletion in the A_IDH_mut category had a worse prognosis than those without these gene alterations and MYCN-amplified A_IDH_mut showed the worst prognosis. However, there was no prognostic genetic marker in O_IDH_mut. In histopathologically or genetically ambiguous cases, methylation profiles can be used as an objective tool to avoid a diagnosis of NOS or NEC (not elsewhere classified), as well as for tumor classification. The authors have not encountered a case of true mixed oligoastrocytoma using an integrated diagnosis of histopathological, genetic and methylation profiles. MYCN amplification, in addition to CDKN2A/2B homozygous deletion, should be included in the genetic criteria for CNS WHO grade 4 A_IDH_mut.
Topics: Humans; Astrocytoma; Brain Neoplasms; DNA-Binding Proteins; Genetic Profile; Glioma; Homozygote; Isocitrate Dehydrogenase; Mutation; N-Myc Proto-Oncogene Protein; Prognosis; RNA-Binding Proteins; Sequence Deletion
PubMed: 37185778
DOI: 10.1038/s41598-023-32153-y -
Frontiers in Immunology 2022Gliomas are one of the most frequent types of nervous system tumours and have significant morbidity and mortality rates. As a result, it is critical to fully comprehend...
Gliomas are one of the most frequent types of nervous system tumours and have significant morbidity and mortality rates. As a result, it is critical to fully comprehend the molecular mechanism of glioma to predict prognosis and target gene therapy. The goal of this research was to discover the hub genes of glioma and investigate their prognostic and diagnostic usefulness. In this study, we collected mRNA expression profiles and clinical information from glioma patients in the TCGA, GTEx, GSE68848, and GSE4920 databases. WGCNA and differential expression analysis identified 170 DEGs in the collected datasets. GO and KEGG pathway analyses revealed that DEGs were mainly enriched in gliogenesis and extracellular matrix. LASSO was performed to construct prognostic signatures in the TCGA cohort, and 17 genes were used to build risk models and were validated in the CGGA database. The ROC curve confirmed the accuracy of the prognostic signature. Univariate and multivariate Cox regression analyses showed that all independent risk factors for glioma except gender. Next, we performed ssGSEA to demonstrate a high correlation between risk score and immunity. Subsequently, 7 hub genes were identified by the PPI network and found to have great drug targeting potential. Finally, RPL39, as one of the hub genes, was found to be closely related to the prognosis of glioma patients. Knockdown of RPL39 significantly inhibited the proliferation and migration of glioma cells, whereas overexpression of RPL39 had the opposite effect. And we found that knockdown of RPL39 inhibited the polarization and infiltration of M2 phenotype macrophages. In conclusion, our new prognosis-related model provides more potential therapeutic strategies for glioma patients.
Topics: Cohort Studies; Glioma; Humans; Prognosis; RNA, Messenger
PubMed: 36248799
DOI: 10.3389/fimmu.2022.1000396