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Biochimica Et Biophysica Acta. Reviews... Jan 2024Glioblastoma multiforme is a highly malignant brain tumor with significant intra- and intertumoral heterogeneity known for its aggressive nature and poor prognosis. The... (Review)
Review
Glioblastoma multiforme is a highly malignant brain tumor with significant intra- and intertumoral heterogeneity known for its aggressive nature and poor prognosis. The complex signaling cascade that regulates this heterogeneity makes targeted drug therapy ineffective. The development of an optimal preclinical model is crucial for the comprehension of molecular heterogeneity and enhancing therapeutic efficacy. The ideal model should establish a relationship between various oncogenes and their corresponding responses. This review presents an analysis of preclinical in vivo and in vitro models that have contributed to the advancement of knowledge in model development. The experimental designs utilized in vivo models consisting of both immunodeficient and immunocompetent mice induced with intracranial glioma. The transgenic model was generated using various techniques, like the viral vector delivery system, transposon system, Cre-LoxP model, and CRISPR-Cas9 approaches. The utilization of the patient-derived xenograft model in glioma research is valuable because it closely replicates the human glioma microenvironment, providing evidence of tumor heterogeneity. The utilization of in vitro techniques in the initial stages of research facilitated the comprehension of molecular interactions. However, these techniques are inadequate in reproducing the interactions between cells and extracellular matrix (ECM). As a result, bioengineered 3D-in vitro models, including spheroids, scaffolds, and brain organoids, were developed to cultivate glioma cells in a three-dimensional environment. These models have enabled researchers to understand the influence of ECM on the invasive nature of tumors. Collectively, these preclinical models effectively depict the molecular pathways and facilitate the evaluation of multiple molecules while tailoring drug therapy.
Topics: Humans; Animals; Mice; Glioblastoma; Brain; Brain Neoplasms; Oncogenes; Extracellular Matrix; Tumor Microenvironment
PubMed: 38109948
DOI: 10.1016/j.bbcan.2023.189059 -
Cells Sep 2023Optic pathway gliomas (OPGs) encompass two distinct categories: benign pediatric gliomas, which are characterized by favorable prognosis, and malignant adult gliomas,... (Review)
Review
Optic pathway gliomas (OPGs) encompass two distinct categories: benign pediatric gliomas, which are characterized by favorable prognosis, and malignant adult gliomas, which are aggressive cancers associated with a poor outcome. Our review aims to explore the established standards of care for both types of tumors, highlight the emerging therapeutic strategies for OPG treatment, and propose potential alternative therapies that, while originally studied in a broader glioma context, may hold promise for OPGs pending further investigation. These potential therapies encompass immunotherapy approaches, molecular-targeted therapy, modulation of the tumor microenvironment, nanotechnologies, magnetic hyperthermia therapy, cyberKnife, cannabinoids, and the ketogenic diet. Restoring visual function is a significant challenge in cases where optic nerve damage has occurred due to the tumor or its therapeutic interventions. Numerous approaches, particularly those involving stem cells, are currently being investigated as potential facilitators of visual recovery in these patients.
Topics: Adult; Humans; Child; Neurofibromatosis 1; Optic Nerve Glioma; Brain Neoplasms; Hyperthermia, Induced; Immunotherapy; Tumor Microenvironment
PubMed: 37830595
DOI: 10.3390/cells12192380 -
Journal of Translational Medicine Nov 2023Glioblastoma, the most common primary malignant tumor of the brain, is associated with poor prognosis. Glioblastoma cells exhibit high proliferative and invasive...
BACKGROUND
Glioblastoma, the most common primary malignant tumor of the brain, is associated with poor prognosis. Glioblastoma cells exhibit high proliferative and invasive properties, and glioblastoma stem cells (GSCs) have been shown to play a crucial role in the malignant behavior of glioblastoma cells. This study aims to investigate the molecular mechanisms involved in GSCs maintenance and malignant progression.
METHODS
Bioinformatics analysis was performed based on data from public databases to explore the expression profile of Mitotic arrest deficient 2 like 2 (MAD2L2) and its potential function in glioma. The impact of MAD2L2 on glioblastoma cell behaviors was assessed through cell viability assays (CCK8), colony formation assays, 5-Ethynyl-2'-deoxyuridine (EDU) incorporation assays, scratch assays, and transwell migration/invasion assays. The findings from in vitro experiments were further validated in vivo using xenograft tumor model. GSCs were isolated from the U87 and LN229 cell lines through flow cytometry and the stemness characteristics were verified by immunofluorescence staining. The sphere-forming ability of GSCs was examined using the stem cell sphere formation assay. Bioinformatics methods were conducted to identified the potential downstream target genes of MAD2L2, followed by in vitro experimental validation. Furthermore, potential upstream transcription factors that regulate MAD2L2 expression were confirmed through chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays.
RESULTS
The MAD2L2 exhibited high expression in glioblastoma samples and showed significant correlation with patient prognosis. In vitro and in vivo experiments confirmed that silencing of MAD2L2 led to decreased proliferation, invasion, and migration capabilities of glioblastoma cells, while decreasing stemness characteristics of glioblastoma stem cells. Conversely, overexpression of MAD2L2 enhanced these malignant behaviors. Further investigation revealed that MYC proto-oncogene (c-MYC) mediated the functional role of MAD2L2 in glioblastoma, which was further validated through a rescue experiment. Moreover, using dual-luciferase reporter gene assays and ChIP assays determined that the upstream transcription factor E2F-1 regulated the expression of MAD2L2.
CONCLUSION
Our study elucidated the role of MAD2L2 in maintaining glioblastoma stemness and promoting malignant behaviors through the regulation of c-MYC, suggesting its potential as a therapeutic target.
Topics: Animals; Humans; Glioblastoma; Brain Neoplasms; Cell Proliferation; Neoplastic Stem Cells; Glioma; Disease Models, Animal; Luciferases; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Mad2 Proteins
PubMed: 38017538
DOI: 10.1186/s12967-023-04740-0 -
Continuum (Minneapolis, Minn.) Dec 2023This article highlights key aspects of the diagnosis and management of adult-type diffuse gliomas, including glioblastomas and IDH-mutant gliomas relevant to the daily...
OBJECTIVE
This article highlights key aspects of the diagnosis and management of adult-type diffuse gliomas, including glioblastomas and IDH-mutant gliomas relevant to the daily practice of the general neurologist.
LATEST DEVELOPMENTS
The advances in molecular characterization of gliomas have translated into more accurate prognostication and tumor classification. Gliomas previously categorized by histological appearance solely as astrocytomas or oligodendrogliomas are now also defined by molecular features. Furthermore, ongoing clinical trials have incorporated these advances to tailor more effective treatments for specific glioma subtypes.
ESSENTIAL POINTS
Despite recent insights into the molecular aspects of gliomas, these tumors remain incurable. Care for patients with these complex tumors requires a multidisciplinary team in which the general neurologist has an important role. Efforts focus on translating the latest data into more effective therapies that can prolong survival.
Topics: Adult; Humans; Brain Neoplasms; Glioma; Oligodendroglioma; Astrocytoma; Prognosis; Mutation; Isocitrate Dehydrogenase
PubMed: 38085893
DOI: 10.1212/CON.0000000000001352 -
Pharmacological Reports : PR Apr 2024Glioblastoma (GBM) is the most prevalent primary malignant tumor of the nervous system. While the treatment of other neoplasms is increasingly more efficacious the... (Review)
Review
Glioblastoma (GBM) is the most prevalent primary malignant tumor of the nervous system. While the treatment of other neoplasms is increasingly more efficacious the median survival rate of GBM patients remains low and equals about 14 months. Due to this fact, there are intensive efforts to find drugs that would help combat GBM. Nowadays cannabinoids are becoming more and more important in the field of cancer and not only because of their properties of antiemetic drugs during chemotherapy. These compounds may have a direct cytotoxic effect on cancer cells. Studies indicate GBM has disturbances in the endocannabinoid system-changes in cannabinoid metabolism as well as in the cannabinoid receptor expression. The GBM cells show expression of cannabinoid receptors 1 and 2 (CB1R and CB2R), which mediate various actions of cannabinoids. Through these receptors, cannabinoids inhibit the proliferation and invasion of GBM cells, along with changing their morphology. Cannabinoids also induce an intrinsic pathway of apoptosis in the tumor. Hence the use of cannabinoids in the treatment of GBM may be beneficial to the patients. So far, studies focusing on using cannabinoids in GBM therapy are mainly preclinical and involve cell lines and mice. The results are promising and show cannabinoids inhibit GBM growth. Several clinical studies are also being carried out. The preliminary results show good tolerance of cannabinoids and prolonged survival after administration of these drugs. In this review, we describe the impact of cannabinoids on GBM and glioma cells in vitro and in animal studies. We also provide overview of clinical trials on using cannabinoids in the treatment of GBM.
Topics: Humans; Mice; Animals; Cannabinoids; Glioblastoma; Glioma; Endocannabinoids; Antineoplastic Agents; Brain Neoplasms
PubMed: 38457018
DOI: 10.1007/s43440-024-00580-x -
Cell Biology and Toxicology Dec 2023Human malignant gliomas are the most common and aggressive primary malignant tumors of the human central nervous system. Vasculogenic mimicry (VM), which refers to the...
Human malignant gliomas are the most common and aggressive primary malignant tumors of the human central nervous system. Vasculogenic mimicry (VM), which refers to the formation of a tumor blood supply system independently of endothelial cells, contributes to the malignant progression of glioma. Therefore, VM is considered a potential target for glioma therapy. Accumulated evidence indicates that alterations in SUMOylation, a reversible post-translational modification, are involved in tumorigenesis and progression. In the present study, we found that UBA2 and RALY were upregulated in glioma tissues and cell lines. Downregulation of UBA2 and RALY inhibited the migration, invasion, and VM of glioma cells. RALY can be SUMOylated by conjugation with SUMO1, which is facilitated by the overexpression of UBA2. The SUMOylation of RALY increases its stability, which in turn increases its expression as well as its promoting effect on FOXD1 mRNA. The overexpression of FOXD1 promotes DKK1 transcription by activating its promoter, thereby promoting glioma cell migration, invasion, and VM. Remarkably, the combined knockdown of UBA2, RALY, and FOXD1 resulted in the smallest tumor volumes and the longest survivals of nude mice in vivo. UBA2/RALY/FOXD1/DKK1 axis may play crucial roles in regulating VM in glioma, which may contribute to the development of potential strategies for the treatment of gliomas.
Topics: Mice; Animals; Humans; Brain Neoplasms; Sumoylation; Mice, Nude; Endothelial Cells; Neovascularization, Pathologic; Glioma; Cell Line, Tumor; Heterogeneous-Nuclear Ribonucleoprotein Group C; Ubiquitin-Activating Enzymes; Intercellular Signaling Peptides and Proteins; Forkhead Transcription Factors
PubMed: 37906341
DOI: 10.1007/s10565-023-09836-3 -
Cell Death & Disease Nov 2023Glioma, the most common primary malignant tumor of the central nervous system, lacks effective targeted therapies. This study investigates the role of SOAT1, a key gene...
Glioma, the most common primary malignant tumor of the central nervous system, lacks effective targeted therapies. This study investigates the role of SOAT1, a key gene involved in cholesterol esterification, in glioma prognosis and its association with ferroptosis. Although the impact of SOAT1 on glioma prognosis has been recognized, its precise mechanism remains unclear. In this study, we demonstrate that inhibiting SOAT1 increases the sensitivity of glioma cells to ferroptosis, both in vitro and in vivo. Mechanistically, SOAT1 positively modulates the expression of SLC40A1, an iron transporter, resulting in enhanced intracellular iron outflow, reduced intracellular iron levels, and subsequent disruption of ferroptosis. Importantly, we find that SOAT1 regulates ferroptosis independently of SREBPs, which are known to be involved in ferroptosis regulation. Furthermore, we identify the involvement of the PI3K-AKT-mTOR signaling pathway in mediating the regulatory effects of SOAT1 on SLC40A1 expression and ferroptosis sensitivity. These findings highlight the contribution of intracellular signaling cascades in the modulation of ferroptosis by SOAT1. We show that inhibiting SOAT1 enhances the efficacy of radiotherapy in gliomas, both in vitro and in vivo, by promoting sensitivity to ferroptosis. This suggests that targeting SOAT1 could potentially improve therapeutic outcomes for glioma patients. In summary, this study uncovers the pivotal role of SOAT1 as a link between cholesterol esterification and ferroptosis in glioma. Our findings underscore the potential of SOAT1 as a promising clinical therapeutic target, providing new avenues for the development of effective treatments for glioma. Further research is warranted to unravel the complete regulatory mechanisms of SOAT1 and explore its clinical applications.
Topics: Humans; Ferroptosis; Phosphatidylinositol 3-Kinases; Glioma; Cholesterol; Iron
PubMed: 37980334
DOI: 10.1038/s41419-023-06282-1 -
Frontiers in Immunology 2023Gliomas account for the majority of brain malignant tumors. As the most malignant subtype of glioma, glioblastoma (GBM) is barely effectively treated by traditional... (Review)
Review
Gliomas account for the majority of brain malignant tumors. As the most malignant subtype of glioma, glioblastoma (GBM) is barely effectively treated by traditional therapies (surgery combined with radiochemotherapy), resulting in poor prognosis. Meanwhile, due to its "cold tumor" phenotype, GBM fails to respond to multiple immunotherapies. As its capacity to prime T cell response, dendritic cells (DCs) are essential to anti-tumor immunity. In recent years, as a therapeutic method, dendritic cell vaccine (DCV) has been immensely developed. However, there have long been obstacles that limit the use of DCV yet to be tackled. As is shown in the following review, the role of DCs in anti-tumor immunity and the inhibitory effects of tumor microenvironment (TME) on DCs are described, the previous clinical trials of DCV in the treatment of GBM are summarized, and the challenges and possible development directions of DCV are analyzed.
Topics: Humans; Glioma; Glioblastoma; Brain Neoplasms; Dendritic Cells; Cancer Vaccines; Tumor Microenvironment
PubMed: 37781367
DOI: 10.3389/fimmu.2023.1259562 -
Cancer Letters Oct 2023Preoperative MRI is an essential diagnostic and therapeutic reference for gliomas. This study aims to evaluate the prognostic aspect of a radiomics biomarker for glioma...
Preoperative MRI is an essential diagnostic and therapeutic reference for gliomas. This study aims to evaluate the prognostic aspect of a radiomics biomarker for glioma and further investigate its relationship with tumor microenvironment and macrophage infiltration. We covered preoperative MRI of 664 glioma patients from three independent datasets: Jiangsu Province Hospital (JSPH, n = 338), The Cancer Genome Atlas dataset (TCGA, n = 252), and Repository of Molecular Brain Neoplasia Data (REMBRANDT, n = 74). Incorporating a multistep post-processing workflow, 20 radiomics features (Rads) were selected and a radiomics survival biomarker (RadSurv) was developed, proving highly efficient in risk stratification of gliomas (cut-off = 1.06), as well as lower-grade gliomas (cut-off = 0.64) and glioblastomas (cut-off = 1.80) through three fixed cut-off values. Through immune infiltration analysis, we found a positive correlation between RadSurv and macrophage infiltration (R = 0.297, p < 0.001; R = 0.241, p < 0.001), further confirmed by immunohistochemical-staining (glioblastomas, n = 32) and single-cell sequencing (multifocal glioblastomas, n = 2). In conclusion, RadSurv acts as a strong prognostic biomarker for gliomas, exhibiting a non-negligible positive correlation with macrophage infiltration, especially with M2 macrophage, which strongly suggests the promise of radiomics-based models as a preoperative alternative to conventional genomics for predicting tumor macrophage infiltration and provides clinical guidance for immunotherapy.
Topics: Humans; Glioblastoma; Glioma; Brain Neoplasms; Genomics; Macrophages; Tumor Microenvironment
PubMed: 37660885
DOI: 10.1016/j.canlet.2023.216380 -
Annals of Medicine Dec 2023Low-grade glioma (LGG), which is the second most frequent adult brain malignancy, severely threatens patients' health and has a high recurrence rate. Histone H3/H4...
AIM
Low-grade glioma (LGG), which is the second most frequent adult brain malignancy, severely threatens patients' health and has a high recurrence rate. Histone H3/H4 chaperone anti-silencing function 1 B () has a tight association with the initiation and development of tumours. The expression and regulation mechanism of in LGG were discussed.
METHODS
expression in LGG patients as well as the association of with overall survival and disease-free survival of LGG patients were predicted by GEPIA database. The independent prognostic value of ASF1B in LGG patients was investigated by TCGA database. RT-qPCR, together with western blot was applied for the assessment of ASF1B in LGG cell lines. After expression was inhibited, CCK8 and colony formation assays judged cell proliferation. Flow cytometry analysis and TUNEL assay appraised cell cycle as well as apoptosis. Cell migratory and invasive capacities were measured by wound healing as well as Transwell assays. Western blot tested the expression of proliferation-, cycle-, apoptosis-, and metastasis-associated proteins. STRING and GeneMANIA database predicted the relationship between and tousled-like kinase 1 (. ChIP assay testified the affinity of with Subsequently, was overexpressed and expression interfered, and the functional assays were executed.
RESULTS
was discovered to be increased in LGG tissues and cells and indicates an unfavourable prognosis for LGG patients. was not an independent prognostic factor for LGG. deficiency obstructed the proliferation, cell cycle as well as metastasis of LGG cells, and induced cell death, which might be realized through the interaction with .
CONCLUSION
The interaction between and promoted the malignant progression of LGG.Key messagesTLK1 interacts with ASF1B.Interference with ASF1B inhibits the proliferative, invasive and migratory capabilities and induces the cycle arrest, along with the apoptosis of LGG cells.The interaction between ASF1B and TLK1 promotes the malignant progression of LGG.
Topics: Adult; Humans; Cell Cycle Proteins; Histones; Cell Proliferation; Glioma; Brain Neoplasms; Protein Serine-Threonine Kinases
PubMed: 36947060
DOI: 10.1080/07853890.2023.2169751