Search Results (106)

Glioblastoma (GBM) is a highly aggressive and heterogeneous brain tumor. Glioma stem-like cells (GSCs) play a central role in tumor progression, therapeutic resistance, and recurrence. Although immune cells are known to shape the GBM microenvironment, the impact of antigen-presenting-cell (APC) signature genes on tumor-intrinsic phenotypes remains underexplored. We analyzed both bulk- and single-cell RNA sequencing datasets of GBM to investigate the association between APC gene expression and tumor-cell states, including stemness and metabolic reprogramming. Signature scores were computed using curated gene sets related to APC activity, KEGG metabolic pathways, and cancer hallmark pathways. Protein–protein interaction (PPI) networks were constructed to examine the links between immune regulators and metabolic programs. The high expression of APC-related genes, such as HLA-DRA, CD74, CD80, CD86, and CIITA, was associated with lower stemness signatures and enhanced inflammatory signaling. These APC-high states (mean difference = –0.43, adjusted p < 0.001) also showed a shift in metabolic activity, with decreased oxidative phosphorylation and increased lipid and steroid metabolism. This pattern suggests coordinated changes in immune activity and metabolic status. Furthermore, TNF-α and other inflammatory markers were more highly expressed in the less stem-like tumor cells, indicating a possible role of inflammation in promoting differentiation. Our findings revealed that elevated APC gene signatures are associated with more differentiated and metabolically specialized GBM cell states. These transcriptional features may also reflect greater immunogenicity and inflammation sensitivity. The APC metabolic signature may serve as a useful biomarker to identify GBM subpopulations with reduced stemness and increased immune engagement, offering potential therapeutic implications. Full article

Background: Glioblastoma (GBM) is the most malignant brain tumor, with a cellular hierarchy dominated by glioma stem cells (GSCs). Understanding global communications among GSCs and other cells helps us identify potential new therapeutic targets. In this study, multi-transcriptomic analysis was utilized to explore the communication pattern of GSCs in GBM. Methods: CellChat was used to quantitatively infer and analyze intercellular communication networks from GBM single-cell RNA-sequencing (scRNA-seq) data. Gene set enrichment analysis (GSEA) was conducted to identify specific biological pathways (epithelial–mesenchymal transition, EMT) involved in the communication pattern of GSCs. Spatial transcriptomic database was used to support the relationship between EMT and GSC proliferation. Single-sample GSEA (ssGSEA) was employed to assess which GSC state exhibited the strongest association with the EMT signature. Results: The cell communication pattern of GSCs is mostly related to EMT. Multiple EMT-related genes are highly expressed in GBM, particularly in GSCs, which are associated with poor prognosis. In addition, EMT-related genes are most enriched in mesenchymal-like (MES-like) GSCs. Tumor patients with MES-like GSC-enriched signatures demonstrate the most unfavorable prognosis compared to those harboring proneural-like (PN-like) or classical-like (CL-like) GSCs. Conclusions: This study suggests that GSCs facilitate GBM progression through intercellular communication in the pattern of EMT. EMT-associated genes may drive the differentiation of GSCs toward a MES-like phenotype, thereby leading to poorer clinical outcomes. Consequently, targeting EMT-related pathways could represent a novel therapeutic strategy for GBM treatment. Full article

Glioblastoma is a fatal and aggressive cancer with no cure. It is becoming increasingly clear that glioblastoma initiation is a result of adult neural stem cell (NSC) transformation—most likely those within the subventricular zone (SVZ). Indeed, transcriptomic analysis indicates that glioblastomas are reminiscent of a neurodevelopmental hierarchy, in which neural stem and progenitor markers are widely expressed by tumour stem-like cells. However, NSC fates and the cues that drive them are poorly understood. Studying the crosstalk within NSC niches may better inform our understanding of glioblastoma initiation and development. Insulin-like growth factor binding protein 2 (IGFBP-2) has a well-established prognostic role in glioblastoma, and cell-based mechanistic studies show the independent activation of downstream oncogenic pathways. However, IGFBP-2 is more commonly recognised as a modulator of insulin-like growth factors (IGFs) for receptor tyrosine kinase signal propagation or attenuation. In the adult human brain, both IGFBP-2 and IGF-II expression are retained in the choroid plexus (ChP) and secreted into the cerebral spinal fluid (CSF). Moreover, secretion by closely associated cells and NSCs themselves position IGFBP-2 and IGF-II as interesting factors within the NSC niche. In this review, we will highlight the experimental findings that show IGFBP-2 and IGF-II influence NSC behaviour. Moreover, we will link this to glioblastoma biology and demonstrate the requirement for further analysis of these factors in glioma stem cells (GSCs). Full article

Attempts to activate an anti-tumor immune response in glioblastoma (GBM) have been met with many challenges due to its inherently immunosuppressive tumor microenvironment. The degree and mechanisms by which molecularly and phenotypically diverse tumor-propagating glioma stem cells (GSCs) contribute to this state are poorly defined. In this study, our multifaceted approach combining bioinformatics analyses of clinical and experimental datasets, single-cell sequencing, and the molecular and pharmacologic manipulation of patient-derived cells identified GSCs expressing immunosuppressive effectors mimicking regulatory T cells (Tregs). We showed that this immunosuppressive Treg-like (ITL) GSC state is specific to the mesenchymal GSC subset and is associated with and driven specifically by TGFβ type II receptor (TGFBR2) in contrast to TGFBR1. Transgenic TGFBR2 expression in patient-derived GBM neurospheres promoted a mesenchymal transition and induced a six-gene ITL signature consisting of CD274 (PD-L1), NT5E (CD73), ENTPD1 (CD39), LGALS1 (galectin-1), PDCD1LG2 (PD-L2), and TGFB1. This TGFBR2-driven ITL signature was identified in clinical GBM specimens, patient-derived GSCs, and systemic mesenchymal malignancies. TGFBR2^high GSCs inhibited CD4+ and CD8+ T cell viability and their capacity to kill GBM cells, effects reversed by pharmacologic and shRNA-based TGFBR2 inhibition. Collectively, our data identify an immunosuppressive GSC state that is TGFBR2-dependent and susceptible to TGFBR2-targeted therapeutics. Full article

Malignant glioma is a highly aggressive, therapeutically non-responsive, and deadly disease with a unique tumor microenvironment (TME). Of the 14 currently recognized and described cancer hallmarks, five are especially implicated in malignant glioma and targetable with repurposed drugs: cancer stem-like cells, in general, and glioma stem-like cells in particular (GSCs), vascularization and hypoxia, metabolic reprogramming, tumor-promoting inflammation and sustained proliferative signaling. Each hallmark drives malignant glioma development, both individually and through interactions with other hallmarks, in which the TME plays a critical role. To combat the aggressive malignant glioma spatio-temporal heterogeneity driven by TME interactions, and to overcome its therapeutic challenges, a combined treatment strategy including anticancer therapies, repurposed drugs and multimodal immunotherapy should be the aim for future treatment approaches. Full article

Background/Objectives: Late epilepsy occurring in the late stage after glioblastoma (GBM) resection is suggested to be caused by increased extracellular glutamate (Glu). To elucidate the mechanism underlying postoperative late epilepsy, the present study aimed to investigate the expressions and relations of molecules related to Glu metabolism in tumor tissues from GBM patients and cultured glioma stem-like cells (GSCs). Methods: Expressions of CD44, xCT and excitatory amino acid transporter (EAAT) 2 and extracellular Glu concentration in GBM patients with and without epilepsy were examined and their relationships were analyzed. For the study using GSCs, expressions and relationships of the same molecules were analyzed and the effects of CD44 knock-down on xCT, EAAT2, and Glu were investigated. In addition, the effects of hypoxia on the expressions of these molecules were investigated. Results: Tumor tissues highly expressed CD44 and xCT in the periphery of GBM with epilepsy, whereas no significant difference in EAAT2 expression was seen between groups with and without epilepsy. Extracellular Glu concentration was higher in patients with epilepsy than those without epilepsy. GSCs displayed reciprocal expressions of CD44 and xCT. Concentrations of extracellular Glu coincided with the degree of xCT expression, and CD44 knock-down elevated xCT expression and extracellular Glu concentrations. Hypoxia of 1% O₂ elevated expression of CD44, while 5% O₂ increased xCT and extracellular Glu concentration. Conclusions: Late epilepsy after GBM resection was related to extracellular Glu concentrations that were regulated by reciprocal expression of CD44 and xCT, which were stimulated by differential hypoxia for each molecule. Full article

Glioblastoma (GBM) is the most common and lethal intracranial tumor in adults. Despite advances in the understanding of the molecular events responsible for disease development and progression, survival rates and mortality statistics for GBM patients have been virtually unchanged for decades and chemotherapeutic drugs used to treat GBM are limited. Arsenic derivatives, known as highly effective anticancer agents for leukemia therapy, has been demonstrated to exhibit cytocidal effects toward GBM cells by inducing cell death, cell cycle arrest, inhibition of migration/invasion, and angiogenesis. Differentiation induction of glioma stem-like cells (GSCs) and inhibition of neurosphere formation have also been attributed to the cytotoxicity of arsenic derivatives. Intriguingly, similar cytotoxic effects against GBM cells and GSCs have also been observed in natural agents such as anthocyanidins, tetrandrine, and bufadienolides. In the current review, we highlight the available data on the molecular mechanisms underlying the multifaceted anticancer activity of arsenic compounds and natural agents against cancer cells, especially focusing on GBM cells and GCSs. We also outline possible strategies for developing anticancer therapy by combining natural agents and arsenic compounds, as well as temozolomide, an alkylating agent used to treat GBM, in terms of improvement of chemotherapy sensitivity and minimization of side effects. Full article

Background: Targeted therapies have been largely ineffective against glioblastoma (GBM) owing to the tumor’s heterogeneity and intrinsic and adaptive treatment resistance. Targeting multiple pro-survival pathways simultaneously may overcome these limitations and yield effective treatments. Heat shock protein 90 (HSP90), an essential component of the epichaperome complex, is critical for the proper folding and activation of several pro-survival oncogenic proteins that drive GBM biology. Methods: Using a panel of biochemical and biological assays, we assessed the expression of HSP90 and its downstream targets and the effects of PU-H71, a highly specific and potent HSP90 inhibitor, on target modulation, downstream biochemical alterations, cell cycle progression, proliferation, migration, and apoptosis in patient-derived glioma stem-like cells (GSCs) with molecular profiles characteristic of GBM, as well as commercial glioma cell lines and normal human astrocytes (NHAs). Results: HSP90 inhibition by PU-H71 in GSCs significantly reduced cell proliferation, colony formation, wound healing, migration, and angiogenesis. In glioma cells, but not NHAs, potent PU-H71-mediated HSP90 inhibition resulted in the downregulation of pro-survival client proteins such as EGFR, MAPK, AKT, and S6. This reduction in pro-survival signals increased glioma cells’ sensitivity to temozolomide, a monofunctional alkylator, and the combination of PU-H71 and temozolomide had greater anticancer efficacy than either agent alone. Conclusions: These results confirm that HSP90 is a strong pro-survival factor in molecularly heterogeneous gliomas and suggest that epichaperome inhibition with HSP90 inhibitors warrants further investigation for the treatment of gliomas. Full article

Glioblastoma multiforme (GBM) is among the most aggressive brain cancers, and it contains glioma stem cells (GSCs) that drive tumor initiation, progression, and recurrence. These cells resist conventional therapies, contributing to high recurrence rates in GBM patients. Developing in vitro models that mimic the tumor microenvironment (TME), particularly the GSC niche, is crucial for understanding GBM growth and therapeutic resistance. Three-dimensional (3D) spheroid models provide a more physiologically relevant approach than traditional two-dimensional (2D) cultures, recapitulating key tumor features like hypoxia, cell heterogeneity, and drug resistance. This review examines scaffold-free and scaffold-based methods for generating 3D GBM spheroids, focusing on their applications in studying the cancer stem cell niche. The discussion encompasses methods such as the hanging drop, low-adhesion plates, and magnetic levitation, alongside advancements in embedding spheroids within extracellular matrix-based hydrogels and employing 3D bioprinting to fabricate more intricate tumor models. These 3D culture systems offer substantial potential for enhancing our understanding of GBM biology and devising more effective targeted therapies. Full article

Glioblastoma (GBM) is the most aggressive type of brain tumor, characterized by poor outcome and limited therapeutic options. During tumor progression, GBM may undergo the process of vasculogenic mimicry (VM), consisting of the formation of vascular-like structures which further promote tumor aggressiveness and malignancy. The resulting resistance to anti-angiogenetic therapies urges the identification of new compounds targeting VM. Extracts of natural plants may represent potential therapeutic tools. Among these, components of Ruta graveolens water extract (RGWE) display a wide range of biological activities. To test the effect of RGWE on human GBM and rat glioma cell line VM, tube formation on a gelled matrix was monitored. Quantitative assessment of VM formation shows the clear-cut inhibitory activity of RGWE. Unlike rutin, one of the most abundant extract components, the whole RGWE strongly reduced the migration and invasion of GBM tumor cells. Moreover, RGWE induced cell death of GBM patient-derived cancer stem cells and impaired VM at sub-lethal doses. Overall, our data reveal a marked RGWE-dependent inhibition of GBM cell survival, migration, invasion, and VM formation. Thus, the clear-cut ability of RGWE to counteract GBM malignancy deserves attention, holding the promise to bring natural products to clinical use, thus uncovering new therapeutic opportunities. Full article

Cancer-associated fibroblast (CAF) composition within the same organ varies across different cancer subtypes. Distinct CAF subtypes exhibit unique features due to interactions with immune cells and the tumor microenvironment. However, data on CAF subtypes in individuals with vestibular schwannoma (VS) are lacking. Therefore, we aimed to distinguish CAF subtypes at the single-cell level, investigate how stem-like CAF characteristics influence the tumor immune microenvironment, and identify CAF subtype-specific metabolic reprogramming pathways that contribute to tumor development. Data were analyzed from three patients with VS, encompassing 33,081 single cells, one bulk transcriptome cohort, and The Cancer Genome Atlas Pan-Cancer database (RNA sequencing and clinical data). Our findings revealed that antigen-presenting CAFs are linked to substantially heightened immune activity, supported by metabolic reprogramming, which differs from tumorigenesis. High expression of the stem-like CAF gene signature correlated with poor prognosis in low-grade gliomas within the pan-cancer database. This is the first study to classify CAF subtypes in VS patients and identify a therapeutic vulnerability biomarker by developing a stem-like CAF gene signature. Personalized treatments tailored to individual patients show promise in advancing precision medicine. Full article

Gliomas’ aggressive nature and resistance to therapy make them a major problem in oncology. Gliomas continue to have dismal prognoses despite significant advancements in medical science, and traditional treatments like surgery, radiation (RT), and chemotherapy (CT) frequently prove to be ineffective. After glioma stem cells (GSCs) were discovered, the traditional view of gliomas as homogeneous masses changed. GSCs are essential for tumor growth, treatment resistance, and recurrence. These cells’ distinct capacities for differentiation and self-renewal are changing our knowledge of the biology of gliomas. This systematic literature review aims to uncover the molecular mechanisms driving glioma progression associated with GSCs. The systematic review adhered to PRISMA guidelines, with a thorough literature search conducted on PubMed, Ovid MED-LINE, and Ovid EMBASE. The first literature search was performed on 1 March 2024, and the search was updated on 15 May 2024. Employing MeSH terms and Boolean operators, the search focused on molecular mechanisms associated with GCSs-mediated glioma progression. Inclusion criteria encompassed English language studies, preclinical studies, and clinical trials. A number of 957 papers were initially identified, of which 65 studies spanning from 2005 to 2024 were finally included in the review. The main GSC model distribution is arranged in decreasing order of frequency: U87: 20 studies (32.0%); U251: 13 studies (20.0%); A172: 4 studies (6.2%); and T98G: 2 studies (3.17%). From most to least frequent, the distribution of the primary GSC pathway is as follows: Notch: 8 studies (12.3%); STAT3: 6 studies (9.2%); Wnt/β-catenin: 6 studies (9.2%); HIF: 5 studies (7.7%); and PI3K/AKT: 4 studies (6.2%). The distribution of molecular effects, from most to least common, is as follows: inhibition of differentiation: 22 studies (33.8%); increased proliferation: 18 studies (27.7%); enhanced invasive ability: 15 studies (23.1%); increased self-renewal: 5 studies (7.7%); and inhibition of apoptosis: 3 studies (4.6%). This work highlights GSC heterogeneity and the dynamic interplay within the glioblastoma microenvironment, underscoring the need for a tailored approach. A few key pathways influencing GSC behavior are JAK/STAT3, PI3K/AKT, Wnt/β-catenin, and Notch. Therapy may target these pathways. This research urges more study to fill in knowledge gaps in the biology of GSCs and translate findings into useful treatment approaches that could improve GBM patient outcomes. Full article

Glioblastoma (GBM), as the most common primary brain tumor, usually results in an extremely poor prognosis, in which glioma stem cells (GSCs) and their immunosuppressive microenvironment prominently intervene in the resistance to radiotherapy and chemotherapy that directly leads to tumor recurrence and shortened survival time. The specific mechanism through which exosomes generated from GSCs support the creation of an immunosuppressive microenvironment remains unknown, while it is acknowledged to be engaged in intercellular communication and the regulation of the glioma immunosuppressive microenvironment. The elevated expression of LncRNA-NEAT1 was found in glioma cells after radiotherapy, chemotherapy, and DNA damage stimulation, and NEAT1 could promote the malignant biological activities of GSCs. Emerging evidence suggests that lncRNAs may reply to external stimuli or DNA damage by playing a role in modulating different aspects of tumor biology. Our study demonstrated a promotive role of the carried NEAT1 by GSC-derived exosomes in the polarization of M2-like macrophages. Further experiments demonstrated the mediative role of miR-125a and its target gene STAT3 in NEAT1-induced polarization of M2-like macrophages that promote glioma progression. Our findings elucidate the mechanism by which GSCs influence the polarization of M2-like macrophages through exosomes, which may contribute to the formation of immunosuppressive microenvironments. Taken together, our study reveals the miR-125a-STAT3 pathway through which exosomal NEAT1 from treatment-resistant GSCs contributes to M2-like macrophage polarization, indicating the potential of exosomal NEAT1 for treating glioma. Full article

Cancer treatments are advancing to harness the body’s immune system against tumours, aiming for lasting effects. This progress involves combining potent chemotherapy drugs with immunogens to kill cancer cells and trigger lasting immunity. Developing new prodrugs that integrate both chemotherapy and immune-boosting elements could significantly improve anticancer outcomes by activating multiple mechanisms to kill cancer cells. While bacterial polysaccharides are typically not used in therapy due to their immune-stimulating properties, we propose a safe application of an extremophilic bacterial polysaccharide, Mauran (MR), modified with the anticancer drug 5-fluorouracil (5FU) to create a novel prodrug. This obtained prodrug, chloracetyl-MR-5FU, is specifically targeted using gold nanocages to CD133+ glioma cells. Test results have shown a high encapsulation efficiency of the drug during the polysaccharide modification process; its anticancer activity was demonstrated in vitro and the release of the prodrug was demonstrated in ex vivo studies. Full article

On a molecular level, glioma is very diverse and presents a whole spectrum of specific genetic and epigenetic alterations. The tumors are unfortunately resistant to available therapies and the survival rate is low. The explanation of significant intra- and inter-tumor heterogeneity and the infiltrative capability of gliomas, as well as its resistance to therapy, recurrence and aggressive behavior, lies in a small subset of tumor-initiating cells that behave like stem cells and are known as glioma cancer stem cells (GCSCs). They are responsible for tumor plasticity and are influenced by genetic drivers. Additionally, GCSCs also display greater migratory abilities. A great effort is under way in order to find ways to eliminate or neutralize GCSCs. Many different treatment strategies are currently being explored, including modulation of the tumor microenvironment, posttranscriptional regulation, epigenetic modulation and immunotherapy. Full article