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Targeting EZH2 regulates the biological characteristics of glioma stem cells via the Notch1 pathway.Experimental Brain Research Oct 2023Glioma is the most common malignant brain tumor, and its behavior is closely related to the presence of glioma stem cells (GSCs). We found that the enhancer of zeste...
Glioma is the most common malignant brain tumor, and its behavior is closely related to the presence of glioma stem cells (GSCs). We found that the enhancer of zeste homolog 2 (EZH2) is highly expressed in glioma and that its expression is correlated with the prognosis of glioblastoma multiforme (GBM) in two databases: The Cancer Genome Atlas and the Chinese Glioma Genome Atlas. Additionally, EZH2 is known to regulate the stemness-associated gene expression, proliferation, and invasion ability of GSCs, which may be achieved through the activation of the STAT3 and Notch1 pathways. Furthermore, we demonstrated the effect of the EZH2-specific inhibitor GSK126 on GSCs; these results not only corroborate our hypothesis, but also provide a potential novel treatment approach for glioma.
Topics: Humans; Antineoplastic Agents; Asian People; Brain Neoplasms; Enhancer of Zeste Homolog 2 Protein; Glioma; Neoplastic Stem Cells
PubMed: 37644332
DOI: 10.1007/s00221-023-06693-8 -
Clinical Cancer Research : An Official... Dec 2023Treatment of IDH-mutated non-enhancing grade 2 and 3 diffuse gliomas with ivosidenib leads to reduction of tumor size when assessed via volumetric MRI. Isocitrate...
Treatment of IDH-mutated non-enhancing grade 2 and 3 diffuse gliomas with ivosidenib leads to reduction of tumor size when assessed via volumetric MRI. Isocitrate dehydrogenase inhibition has a therapeutic benefit in patients with these tumors. See related article by Kamson et al., p. 4863.
Topics: Humans; Brain Neoplasms; Mutation; Glioma; Magnetic Resonance Imaging; Isocitrate Dehydrogenase
PubMed: 37738033
DOI: 10.1158/1078-0432.CCR-23-2164 -
International Journal of Molecular... Aug 2023Gliomas are aggressive, primary central nervous system tumours arising from glial cells. Glioblastomas are the most malignant. They are known for their poor prognosis or... (Review)
Review
Gliomas are aggressive, primary central nervous system tumours arising from glial cells. Glioblastomas are the most malignant. They are known for their poor prognosis or median overall survival. The current standard of care is overwhelmed by the heterogeneous, immunosuppressive tumour microenvironment promoting immune evasion and tumour proliferation. The advent of immunotherapy with its various modalities-immune checkpoint inhibitors, cancer vaccines, oncolytic viruses and chimeric antigen receptor T cells and NK cells-has shown promise. Clinical trials incorporating combination immunotherapies have overcome the microenvironment resistance and yielded promising survival and prognostic benefits. Rolling these new therapies out in the real-world scenario in a low-cost, high-throughput manner is the unmet need of the hour. These will have practice-changing implications to the glioma treatment landscape. Here, we review the immunobiological hallmarks of the TME of gliomas, how the TME evades immunotherapies and the work that is being conducted to overcome this interplay.
Topics: Humans; Tumor Microenvironment; Glioma; Immunotherapy; Glioblastoma; Neuroglia
PubMed: 37686020
DOI: 10.3390/ijms241713215 -
Cell Communication and Signaling : CCS May 2024In the tumor immune microenvironment (TIME), triggering receptor expressed on myeloid cells 2 (trem2) is widely considered to be a crucial molecule on tumor-associated...
BACKGROUND
In the tumor immune microenvironment (TIME), triggering receptor expressed on myeloid cells 2 (trem2) is widely considered to be a crucial molecule on tumor-associated macrophages(TAMs). Multiple studies have shown that trem2 may function as an immune checkpoint in various malignant tumors, mediating tumor immune evasion. However, its specific molecular mechanisms, especially in glioma, remain elusive.
METHODS
Lentivirus was transfected to establish cells with stable knockdown of trem2. A Transwell system was used for segregated coculture of glioma cells and microglia. Western blotting, quantitative real-time polymerase chain reaction (qRT‒PCR), and immunofluorescence (IF) were used to measure the expression levels of target proteins. The proliferation, invasion, and migration of cells were detected by colony formation, cell counting kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU) and transwell assays. The cell cycle, apoptosis rate and reactive oxygen species (ROS) level of cells were assessed using flow cytometry assays. The comet assay and tube formation assay were used to detect DNA damage in glioma cells and angiogenesis activity, respectively. Gl261 cell lines and C57BL/6 mice were used to construct the glioma orthotopic transplantation tumor model.
RESULTS
Trem2 was highly overexpressed in glioma TAMs. Knocking down trem2 in microglia suppressed the growth and angiogenesis activity of glioma cells in vivo and in vitro. Mechanistically, knockdown of trem2 in microglia promoted proinflammatory microglia and inhibited anti-inflammatory microglia by activating jak2/stat1 and inhibiting the NF-κB p50 signaling pathway. The proinflammatory microglia produced high concentrations of nitric oxide (NO) and high levels of the proinflammatory cytokines TNF-α, IL-6, and IL-1β, and caused further DNA damage and promoted the apoptosis rate of tumor cells.
CONCLUSIONS
Our findings revealed that trem2 in microglia plays a significant role in the TIME of gliomas. Knockdown of trem2 in microglia might help to improve the efficiency of inhibiting glioma growth and delaying tumor progression and provide new ideas for further treatment of glioma.
Topics: Glioma; Janus Kinase 2; Microglia; Animals; Receptors, Immunologic; Membrane Glycoproteins; NF-kappa B; Mice; STAT3 Transcription Factor; Signal Transduction; Cell Line, Tumor; Mice, Inbred C57BL; Gene Knockdown Techniques; Cell Proliferation; Humans; Inflammation; Apoptosis; Disease Progression; Cell Movement
PubMed: 38750472
DOI: 10.1186/s12964-024-01642-6 -
Scientific Reports Dec 2023Glioma is the most common primary malignant brain tumor in adults and remains an incurable disease at present. Thus, there is an urgent need for progress in finding...
Glioma is the most common primary malignant brain tumor in adults and remains an incurable disease at present. Thus, there is an urgent need for progress in finding novel molecular mechanisms that control the progression of glioma which could be used as therapeutic targets for glioma patients. The RNA binding protein cytoplasmic polyadenylate element-binding protein 2 (CPEB2) is involved in the pathogenesis of several tumors. However, the role of CPEB2 in glioma progression is unknown. In this study, the functional characterization of the role and molecular mechanism of CPEB2 in glioma were examined using a series of biological and cellular approaches in vitro and in vivo. Our work shows CPEB2 is significantly downregulated in various glioma patient cohorts. Functional characterization of CPEB2 by overexpression and knockdown revealed that it inhibits glioma cell proliferation and promotes apoptosis. CPEB2 exerts an anti-tumor effect by increasing p21 mRNA stability and inducing G1 cell cycle arrest in glioma. Overall, this work stands as the first report of CPEB2 downregulation and involvement in glioma pathogenesis, and identifies CPEB2 as an important tumor suppressor gene through targeting p21 in glioma, which revealed that CPEB2 may become a promising predictive biomarker for prognosis in glioma patients.
Topics: RNA-Binding Proteins; Cell Proliferation; Oncogene Protein p21(ras); RNA Stability; Glioma; Gene Knockdown Techniques; Apoptosis; Gene Expression Regulation, Neoplastic; Cell Cycle Checkpoints; Biomarkers, Tumor; Down-Regulation; Cell Line, Tumor; Mice, Inbred BALB C; HEK293 Cells; Humans; Female; Animals; Mice
PubMed: 38158431
DOI: 10.1038/s41598-023-50848-0 -
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 -
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 -
Molecular Therapy : the Journal of the... Oct 2023Gliomas are the most prevalent and devastating primary malignant brain tumors in adults. Despite substantial advances in understanding glioma biology, there have been no... (Review)
Review
Gliomas are the most prevalent and devastating primary malignant brain tumors in adults. Despite substantial advances in understanding glioma biology, there have been no regulatory drug approvals in the US since bevacizumab in 2009 and tumor treating fields in 2011. Recent phase III clinical trials have failed to meet their prespecified therapeutic primary endpoints, highlighting the need for novel therapies. The poor prognosis of glioma patients, resistance to chemo-radiotherapy, and the immunosuppressive tumor microenvironment underscore the need for the development of novel therapies. Gene therapy-based immunotherapeutic strategies that couple the ability of the host immune system to specifically kill glioma cells and develop immunological memory have shown remarkable progress. Two adenoviral vectors expressing Ad-HSV1-TK/GCV and Ad-Flt3L have shown promising preclinical data, leading to FDA approval of a non-randomized, phase I open-label, first in human trial to test safety, cytotoxicity, and immune-stimulatory efficiency in high-grade glioma patients (NCT01811992). This review provides a thorough overview of immune-stimulatory gene therapy highlighting recent advancements, potential drawbacks, future directions, and recommendations for future implementation of clinical trials.
Topics: Animals; Humans; Brain Neoplasms; Rodentia; Adenoviridae; Glioma; Genetic Therapy; Thymidine Kinase; Genetic Vectors; Tumor Microenvironment
PubMed: 37574780
DOI: 10.1016/j.ymthe.2023.08.009 -
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 -
Journal of Cancer Research and Clinical... Nov 2023Glioma is the prevailing malignant tumor affecting the brain and central nervous system, constituting over 80% of all malignant brain tumors. HOXD9 has been implicated...
BACKGROUND
Glioma is the prevailing malignant tumor affecting the brain and central nervous system, constituting over 80% of all malignant brain tumors. HOXD9 has been implicated in the development of glioma, but the specific mechanism of its influence on glioma pathogenesis remains incompletely understood. The purpose of this study was to investigate the role of HOXD9 in glioma and examine the changes in HOXD9 expression during the progression of glioma, thus contributing new insights into the pathogenesis of glioma.
METHODS
Glioma samples from the Cancer Gene Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets were included in this study. Variations in HOXD9 expression in gliomas between different subgroups of multiple clinical characteristics were explored, and the expression was validated in glioma samples using qRT-PCR and western blotting. Next, the impact of HOXD9 on the prognosis of gliomas was explored by survival analysis, receiver operating characteristic curve, and nomogram plots. Subsequently, the association between HOXD9 and the tumor immune microenvironment was explored using the ssGSEA algorithm and the ESTIMATE algorithm. Then, immune-related pathways associated with HOXD9 were determined by differential express analysis and GSEA. Finally, HOXD9-related genomic alterations were identified.
RESULTS
HOXD9 expression is upregulated and correlated with malignant properties in glioma. Similarly, our validation results showed significantly upregulated protein and mRNA levels of HOXD9 in glioma brain tissues. In addition, high HOXD9 expression was indicative of a poor prognosis for glioma patients. Additionally, elevated HOXD9 levels were associated with reduced tumor purity and higher levels of immune invasion. Finally, HOXD9 was significantly associated with genomic alterations.
CONCLUSION
Overall, this study has unveiled a significant association between HOXD9 and the prognosis and survival of glioma patients. Our findings highlight the potential of HOXD9 as a prognostic biomarker, implicating its role in influencing the glioma immune microenvironment.
Topics: Humans; Prognosis; Glioma; Brain Neoplasms; Oncogenes; Biomarkers; Tumor Microenvironment; Neoplasm Proteins; Homeodomain Proteins
PubMed: 37603105
DOI: 10.1007/s00432-023-05275-z