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Frontiers in Immunology 2022Glioma is a brain tumor that arises in the central nervous system and is categorized according to histology and molecular genetic characteristics. Long non-coding RNAs... (Review)
Review
Glioma is a brain tumor that arises in the central nervous system and is categorized according to histology and molecular genetic characteristics. Long non-coding RNAs (lncRNAs) are RNAs longer than 200 nucleotides in length. They have been reported to influence significant events such as carcinogenesis, progression, and increased treatment resistance on glioma cells. Long non-coding RNAs promote cell proliferation, migration, epithelial-to-mesenchymal transition and invasion in glioma cells. Various significant advancements in transcriptomic profiling studies have enabled the identification of immune-related long non-coding RNAs as immune cell-specific gene expression regulators that mediates both stimulatory and suppressive immune responses, implying lncRNAs as potential candidates for improving immunotherapy efficacy against tumors and due to the lack of different diagnostic and treatments for glioma, lncRNAs are potential candidates to be used as future diagnostic, prognostic biomarker and treatment tools for glioma. This review's primary purpose is to concentrate on the role of long non-coding RNAs in early glioma identification, treatment, and immunotherapy.
Topics: Brain Neoplasms; Gene Expression Regulation, Neoplastic; Glioma; Humans; Immunologic Factors; Immunotherapy; RNA, Long Noncoding
PubMed: 35619711
DOI: 10.3389/fimmu.2022.897754 -
International Journal of Molecular... Jun 2021Glioma originates in the central nervous system and is classified based on both histological features and molecular genetic characteristics. Long non-coding RNAs... (Review)
Review
Glioma originates in the central nervous system and is classified based on both histological features and molecular genetic characteristics. Long non-coding RNAs (lncRNAs) are longer than 200 nucleotides and are known to regulate tumorigenesis and tumor progression, and even confer therapeutic resistance to glioma cells. Since oncogenic lncRNAs have been frequently upregulated to promote cell proliferation, migration, and invasion in glioma cells, while tumor-suppressive lncRNAs responsible for the inhibition of apoptosis and decrease in therapeutic sensitivity in glioma cells have been generally downregulated, the dysregulation of lncRNAs affects many features of glioma patients, and the expression profiles associated with these lncRNAs are needed to diagnose the disease stage and to determine suitable therapeutic strategies. Accumulating studies show that the orchestrations of oncogenic lncRNAs and tumor-suppressive lncRNAs in glioma cells result in signaling pathways that influence the pathogenesis and progression of glioma. Furthermore, several lncRNAs are related to the regulation of therapeutic sensitivity in existing anticancer therapies, including radiotherapy, chemotherapy and immunotherapy. Consequently, we undertook this review to improve the understanding of signaling pathways influenced by lncRNAs in glioma and how lncRNAs affect therapeutic resistance.
Topics: Animals; Biomarkers, Tumor; Carcinogenesis; Combined Modality Therapy; Disease Management; Disease Susceptibility; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Glioma; Humans; RNA Interference; RNA, Long Noncoding; Radiation Tolerance; Treatment Outcome
PubMed: 34202078
DOI: 10.3390/ijms22136834 -
JCI Insight Jan 2024Epilepsy has a profound impact on quality of life. Despite the development of new antiseizure medications (ASMs), approximately one-third of affected patients have... (Review)
Review
Epilepsy has a profound impact on quality of life. Despite the development of new antiseizure medications (ASMs), approximately one-third of affected patients have drug-refractory epilepsy and are nonresponsive to medical treatment. Nearly all currently approved ASMs target neuronal activity through ion channel modulation. Recent human and animal model studies have implicated new immunotherapeutic and metabolomic approaches that may benefit patients with epilepsy. In this Review, we detail the proinflammatory immune landscape of epilepsy and contrast this with the immunosuppressive microenvironment in patients with glioma-related epilepsy. In the tumor setting, excessive neuronal activity facilitates immunosuppression, thereby contributing to subsequent glioma progression. Metabolic modulation of the IDH1-mutant pathway provides a dual pathway for reversing immune suppression and dampening seizure activity. Elucidating the relationship between neurons and immunoreactivity is an area for the prioritization and development of the next era of ASMs.
Topics: Animals; Humans; Quality of Life; Epilepsy; Glioma; Drug Resistant Epilepsy; Immune System; Tumor Microenvironment
PubMed: 38193532
DOI: 10.1172/jci.insight.174753 -
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 -
Journal For Immunotherapy of Cancer Dec 2022Oncolytic viruses constitute a growing field of interest, both in human and veterinary oncology, given that they are particularly helpful for treating non-surgical...
BACKGROUND
Oncolytic viruses constitute a growing field of interest, both in human and veterinary oncology, given that they are particularly helpful for treating non-surgical tumors and disseminated cancer, such as high-grade gliomas. Companion dogs present malignant gliomas with biological, genetic, phenotypic, immunological, and clinical similarities to human gliomas. These features favor comparative approaches, leading to the treatment of canine oncological patients to achieve translational applications to the human clinic. The systemic administration of oncolytic viruses presents a challenge due to their limitations in effectively targeting tumors and metastases. Therefore, the aim of this study is to evaluate the safety and antitumor activity of a virotherapy used in spontaneous canine tumors.
METHODS
Ten dogs with high-grade rostrotentorial gliomas underwent weekly systemic endovenous cellular virotherapy with dCelyvir (canine mesenchymal stem cells infected with the canine oncolytic adenovirus ICOCAV17) for 8 weeks. Efficacy was determined in seven dogs according to the Response Assessment in Veterinary Neuro-Oncology criteria considering clinical status and MRI measurements. Medical history, physical and neurological examinations, and vaccination status were evaluated prior to and during follow-up. Safety was evaluated by physical examinations and hematological and biochemical changes in peripheral blood. Immune populations were analyzed by flow cytometry in peripheral blood and by gene expression and immunohistochemistry in the tumor microenvironment.
RESULTS
The treatment was well tolerated and major adverse effects were not observed. Two dogs had partial responses (76% and 86% reduction in tumor size), and 3/7 showed stable disease. ICOCAV17 was detected in peripheral blood in nine dogs, and a correlation between the ICOCAV17 particles and anti-canine adenovirus (CAV) antibodies was observed. ICOCAV17 was detected in 3/9 tumor tissues after necropsies. Regarding tumor-infiltrating lymphocytes, the dogs with disease stabilization and partial response tended to have reduced memory B-cell infiltration and increased monocyte/macrophage lineage cells.
CONCLUSIONS
These findings indicate that dCelyvir is safe and presents efficacy in canine rostrotentorial high-grade gliomas. These data are relevant to the ongoing phase Ib regulated human clinical trial that is administering this virotherapy to children, adolescents, and young adults with diffuse pontine glioma. Celyvir should be further explored as a treatment in veterinary and human neuro-oncology.
Topics: Animals; Dogs; Glioma; Medical Oncology; Oncolytic Virotherapy; Oncolytic Viruses; Tumor Microenvironment
PubMed: 36600663
DOI: 10.1136/jitc-2022-005669 -
Frontiers in Immunology 2021Exosomes, the small extracellular vesicles, are released by multiple cell types, including tumor cells, and represent a novel avenue for intercellular communication... (Review)
Review
Exosomes, the small extracellular vesicles, are released by multiple cell types, including tumor cells, and represent a novel avenue for intercellular communication transferring diverse biomolecules. Recently, microRNAs (miRNAs) were demonstrated to be enclosed in exosomes and therefore was protected from degradation. Such exosomal miRNAs can be transmitted to recipient cells where they could regulate multiple cancer-associated biological processes. Accumulative evidence suggests that exosomal miRNAs serve essential roles in modifying the glioma immune microenvironment and potentially affecting the malignant behaviors and therapeutic responses. As exosomal miRNAs are detectable in almost all kinds of biofluids and correlated with clinicopathological characteristics of glioma, they might be served as promising biomarkers for gliomas. We reviewed the novel findings regarding the biological functions of exosomal miRNAs during glioma pathogenesis and immune regulation. Furthermore, we elaborated on their potential clinical applications as biomarkers in glioma diagnosis, prognosis and treatment response prediction. Finally, we summarized the accessible databases that can be employed for exosome-associated miRNAs identification and functional exploration of cancers, including glioma.
Topics: Animals; Biomarkers, Tumor; Cell Communication; Cell Proliferation; Databases, Genetic; Disease Management; Disease Susceptibility; Exosomes; Glioma; Humans; Immunomodulation; MicroRNAs; Molecular Targeted Therapy; Neovascularization, Pathologic; RNA Transport; Signal Transduction
PubMed: 35095909
DOI: 10.3389/fimmu.2021.813747 -
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 -
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 -
Stem Cell Research & Therapy Apr 2023Recent studies have demonstrated that glioma-associated mesenchymal stem cells (GA-MSCs) are implicated in the regulation of glioma malignant progression. However, the...
Development and validation of a glioma-associated mesenchymal stem cell-related gene prognostic index for predicting prognosis and guiding individualized therapy in glioma.
BACKGROUND
Recent studies have demonstrated that glioma-associated mesenchymal stem cells (GA-MSCs) are implicated in the regulation of glioma malignant progression. However, the prognostic value of GA-MSCs has not been comprehensively explored in glioma.
METHODS
We extracted GA-MSCs from glioma tissues, established intracranial xenograft models in nude mice, and obtained GA-MSC-related genes (GA-MSCRGs) by using microarrays. The transcriptome data and clinical information of glioma patients were obtained from the CGGA and TCGA databases. We screened 8 prognostic GA-MSCRGs to construct a prognostic index by using the multivariate Cox regression method. The validity of the GA-MSCRGPI was verified in the training (CGGA693) and validation (TCGA and CGGA325) cohorts. The expression patterns of these 8 GA-MSCRGs were validated in 78 glioma tissue specimens by using a qRT‒PCR assay.
RESULTS
GA-MSCs were successfully isolated from glioma tissues. Based on intracranial xenograft models and transcriptome microarray screening, 8 genes (MCM7, CDK6, ORC1, CCL20, TNFRSF12A, POLA1, TRAF1 and TIAM1) were selected for the construction of a GA-MSC-related gene prognostic index (GA-MSCRGPI). In both the training and validation cohorts, high GA-MSCRGPI patients showed an inferior survival outcome compared with low GA-MSCRGPI patients. A nomogram was established based on independent prognostic indicators (age, WHO grade and GA-MSCRGPI) and exhibited a strong forecasting ability for overall survival (OS). Moreover, we found that the GA-MSCRGPI could evaluate the prognosis of glioma patients undergoing chemoradiotherapy. The high GA-MSCRGPI group exhibited higher immune, stromal and ESTIMATE scores; lower tumor purity; higher infiltration of Tregs and M2-type macrophages; fewer activated NK cells; and higher expression of immune checkpoints. Tumor Immune Dysfunction and Exclusion (TIDE) showed that the high GA-MSCRGPI group had more responders to ICI therapy. The results of the genetic mutation profile and tumor mutation burden (TMB) in different GA-MSCRGPI subgroups further supplement GA-MSCRGPI-related mechanisms. Finally, the expression patterns of 8 selected GA-MSCRGs in GA-MSCRGPI were correlated with glioma WHO grades to a certain extent.
CONCLUSION
The constructed GA-MSCRGPI could predict prognosis and guide individualized therapy in glioma patients.
Topics: Humans; Animals; Mice; Prognosis; Mice, Nude; Glioma; Biological Assay; Databases, Factual; Disease Models, Animal
PubMed: 37005685
DOI: 10.1186/s13287-023-03285-9 -
Nature Communications Oct 2022Glioma stem cells (GSC) exhibit plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely...
Glioma stem cells (GSC) exhibit plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely unknown. Here, we employ single-cell and whole transcriptomic analyses to uncover that radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide trophic support to promote proliferation of tumor cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular genes allowing for their increased expression post-treatment. Blocking P300 histone acetyltransferase activity reverses the epigenetic changes induced by radiation and inhibits the adaptive conversion of GSC into vascular-like cells and tumor growth. Our findings highlight a role for P300 in radiation-induced stress response, suggesting a therapeutic approach to prevent glioma recurrence.
Topics: Humans; Neoplasm Recurrence, Local; Glioma; Neoplastic Stem Cells; Chromatin; Histone Acetyltransferases
PubMed: 36261421
DOI: 10.1038/s41467-022-33943-0