RESUMEN
Diffuse midline gliomas (DMGs) are aggressive and fatal pediatric tumors of the central nervous system that are highly resistant to treatments. Lysine to methionine substitution of residue 27 on histone H3 (H3-K27M) is a driver mutation in DMGs, reshaping the epigenetic landscape of these cells to promote tumorigenesis. H3-K27M gliomas are characterized by deregulation of histone acetylation and methylation pathways, as well as the oncogenic MYC pathway. In search of effective treatment, we examined the therapeutic potential of dual targeting of histone deacetylases (HDACs) and MYC in these tumors. Treatment of H3-K27M patient-derived cells with Sulfopin, an inhibitor shown to block MYC-driven tumors in vivo, in combination with the HDAC inhibitor Vorinostat, resulted in substantial decrease in cell viability. Moreover, transcriptome and epigenome profiling revealed synergistic effect of this drug combination in downregulation of prominent oncogenic pathways such as mTOR. Finally, in vivo studies of patient-derived orthotopic xenograft models showed significant tumor growth reduction in mice treated with the drug combination. These results highlight the combined treatment with PIN1 and HDAC inhibitors as a promising therapeutic approach for these aggressive tumors.
Diffuse midline gliomas (DMGs) are among the most aggressive and fatal brain cancers in children. They are often associated with changes in histones, the proteins that control gene activity and give chromosomes their structure. Most children with DMGs, for example, share the same anomaly in their histone H3 protein (referred to as the H3-K27M mutation). This change affects how small chemical tags called methyl and acetyl groups can be added onto histone 3, which in turn alters the way the protein can switch genes on and off. As a result, tumours start to develop. One potential therapeutic strategy against DMGs is to use histone deacetylase inhibitors (HDACi), a promising type of drugs which inhibits the enzymes that remove acetyl groups from histones. Patients can develop resistance to HDACi, however, highlighting the need to explore other approaches. One possibility is to treat patients with several types of drugs, each usually targeting a distinct biological process that contributes to the emergence of cancer. This combined approach can have multiple benefits; the drugs potentially amplify each other's effect, for example, and it is also less likely for cells to become resistant to more than one compound at the time. In addition, each drug in the combination can be used in a lower dose to reduce side effects and benefit patients. DMG tumour cells often feature higher activity levels of a protein known as MYC, which can contribute to the growth of the tumour. Algranati, Oren et al. therefore set out to test whether combining an HDACi known as Vorinostat with a drug that blocks MYC activity (Sulfopin) can act as an effective treatment for this cancer. Tumour samples from eight DMG patients were treated with either Sulfopin alone, or Sulfopin in association with Vorinostat. Cells exposed to both drugs were less likely to survive, and additional genetic experiments showed that the combined treatment had resulted in pathways that promote tumour development being blocked. When both Sulfopin and Vorinostat were administered to mice made to grow human DMG tumors, the animals showed a greater reduction in tumor growth. Treatment options for DMG are usually limited, with chemotherapy often being ineffective and surgery impossible. The work by Algranati, Oren et al. suggests that combining HDACi and drugs targeting the MYC pathway is a strategy that should be examined further to determine whether clinical applications are possible.
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Glioma , Inhibidores de Histona Desacetilasas , Histona Desacetilasas , Histonas , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/patología , Humanos , Animales , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Histonas/metabolismo , Histonas/genética , Inhibidores de Histona Desacetilasas/farmacología , Ratones , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Vorinostat/farmacología , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Línea Celular Tumoral , Niño , Modelos Animales de Enfermedad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: New targeted drugs about angiogenesis could develop the treatment of glioma. We aimed to explore the role of phosducin like 3 (PDCL3) in angiogenesis of glioma. MATERIALS AND METHODS: RNA sequencing data and matched clinical data were downloaded from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. To screen for the reliable genes with the filtering analyses, survival, multivariate Cox, receiver operating characteristic (ROC) curve filtration, and clinical correlation analyses were performed. The PDCL3 gene was validated by immunohistochemistry as a reliable gene for further analysis. Then we used the combined data of TCGA and Genotype-Tissue Expression from UCSC to detect the differential gene expression of PDCL3. Related signal pathways in glioma were explored by the gene set enrichment analysis and co-expression analysis. Lastly, we performed in vitro experiments to verify the gene functions and related mechanisms. RESULTS: The three filtering analyses and immunostaining indicated that the expression of PDCL3 in glioma tissues was higher than the normal tissues. Gene function analysis showed that PDCL3 activated the vascular endothelial growth factor (VEGF) signal pathway, and its mechanism was related to pathways in cancer, like NOD like receptor signaling pathway, the RIG-I like receptor signaling pathway and the P53 signaling pathway by MAPK/AKT in gliomas. This suggested that the proliferation, migration and invasion of glioma cells might be inhibited by the downregulation of PDCL3 in vitro, which may be related to the activation of VEGF signaling pathway. CONCLUSION: We demonstrated that PDCL3 could function as an independent adverse prognostic marker in glioma. Its pro-oncogenic mechanism may be related to the VEGF signaling pathway.
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Biomarcadores de Tumor , Regulación Neoplásica de la Expresión Génica , Glioma , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular , Humanos , Glioma/genética , Glioma/metabolismo , Glioma/patología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Pronóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Femenino , Masculino , Movimiento Celular/genética , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Persona de Mediana Edad , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: In this study, we present a novel method for reference-based cell deconvolution using data from DNA methylation arrays. Different from existing methods like IDOL-Ext, which operate on probe-level data, our approach represents features in the principal component analysis (PCA) space for cell type deconvolution. RESULTS: Our method's accuracy in estimating cell compositions is validated across various public datasets, including blood samples from glioma patients. It demonstrates precision comparable to IDOL-Ext, with R2 values ranging from 0.73 to 0.99 for most cell types, while offering improved discrimination between similar cell types, particularly T cell subtypes in glioma patient samples (R2 0.42-0.75 vs. 0.36-0.66 for IDOL-Ext). However, both methods showed lower accuracy for certain cell types, such as memory CD8 T cells in glioma patients (R2 0.42 vs. 0.36 for IDOL-Ext), highlighting the challenges in distinguishing closely related cell populations. We have made this method available as an R package "BloodCellDecon" on GitHub. CONCLUSIONS: Our study confirms the efficacy of cell type deconvolution in PCA space. The results indicate wide-ranging applicability and potential for adaptation to other forms of genomic data.
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Metilación de ADN , Glioma , Análisis de Componente Principal , Humanos , Glioma/genética , Glioma/patologíaRESUMEN
Glioma represents the most common central nervous system neoplasm in adults. Current classification scheme utilizes molecular alterations, particularly IDH1.R132H, to stratify lesions into distinct prognostic groups. Identification of the single nucleotide variant through traditional tissue biopsy assessment poses procedural risks and does not fully reflect the heterogeneous and evolving tumor landscape. Here, we introduce a liquid biopsy assay, mt-IDH1dx. The blood-based test allows minimally invasive detection of tumor-derived extracellular vesicle RNA using only 2 ml plasma volume. We perform rigorous, blinded validation testing across the study population (n = 133), comprising of IDH1.R132H patients (n = 80), IDH1 wild-type gliomas (n = 44), and age matched healthy controls (n = 9). Results from our plasma testing demonstrate an overall sensitivity of 75.0% (95% CI: 64.1%-84.0%), specificity 88.7% (95% CI: 77.0%-95.7%), positive predictive value 90.9%, and negative predictive value 70.1% compared to the tissue gold standard. In addition to fundamental diagnostic applications, the study also highlights the utility of mt-IDH1dx platform for blood-based monitoring and surveillance, offering valuable prognostic information. Finally, the optimized workflow enables rapid and efficient completion of both tumor tissue and plasma testing in under 4 hours from the time of sampling.
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Neoplasias Encefálicas , Glioma , Isocitrato Deshidrogenasa , Mutación , Humanos , Isocitrato Deshidrogenasa/genética , Glioma/genética , Glioma/sangre , Glioma/diagnóstico , Glioma/patología , Femenino , Masculino , Persona de Mediana Edad , Adulto , Biopsia Líquida/métodos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/sangre , Neoplasias Encefálicas/diagnóstico , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Sensibilidad y Especificidad , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Estudios de Casos y ControlesRESUMEN
Although gliomatosis cerebri (GC) has been removed as an independent tumor type from the WHO classification, its extensive infiltrative pattern may harbor a unique biological behavior. However, the clinical implication of GC in the context of the 2021 WHO classification is yet to be unveiled. This study investigated the incidence, clinicopathologic and imaging correlations, and prognostic implications of GC in adult-type diffuse glioma patients. Retrospective chart and imaging review of 1,211 adult-type diffuse glioma patients from a single institution between 2005 and 2021 was performed. Among 1,211 adult-type diffuse glioma patients, there were 99 (8.2%) patients with GC. The proportion of molecular types significantly differed between patients with and without GC (P = 0.017); IDH-wildtype glioblastoma was more common (77.8% vs. 66.5%), while IDH-mutant astrocytoma (16.2% vs. 16.9%) and oligodendroglioma (6.1% vs. 16.5%) were less common in patients with GC than in those without GC. The presence of contrast enhancement, necrosis, cystic change, hemorrhage, and GC type 2 were independent risk factors for predicting IDH mutation status in GC patients. GC remained as an independent prognostic factor (HR = 1.25, P = 0.031) in IDH-wildtype glioblastoma patients on multivariable analysis, along with clinical, molecular, and surgical factors. Overall, our data suggests that although no longer included as a distinct pathological entity in the WHO classification, recognition of GC may be crucial considering its clinical significance. There is a relatively high incidence of GC in adult-type diffuse gliomas, with different proportion according to molecular types between patients with and without GC. Imaging may preoperatively predict the molecular type in GC patients and may assist clinical decision-making. The prognostic role of GC promotes its recognition in clinical settings.
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Neoplasias Encefálicas , Glioma , Isocitrato Deshidrogenasa , Neoplasias Neuroepiteliales , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Neuroepiteliales/genética , Neoplasias Neuroepiteliales/patología , Neoplasias Neuroepiteliales/diagnóstico por imagen , Glioma/genética , Glioma/patología , Glioma/diagnóstico por imagen , Estudios Retrospectivos , Anciano , Isocitrato Deshidrogenasa/genética , Mutación , Adulto Joven , Imagen por Resonancia Magnética , GenómicaRESUMEN
INTRODUCTION: Glioma is one of the most commonly tumours which occurs in the central nervous system and accounts for nearly 80% of brain tumours, with a significantly high mortality and morbidity. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are used as EGFR targeted therapy in various types of solid tumours; however, effective treatment for glioma is still limited. Osimertinib is an irreversible, oral third-generation TKI that targets the mutation at T790M, which causes cancer cells to acquire resistance to drugs. Osimertinib could be effective in the treatment of EGFR mutations with minimal effects on the activity of wild-type EGFR. Absent in melanoma 2 (AIM2) is highly expressed in glioma cells, promoting the maturation of pro-cancer cytokines and contributing to progression of glioma. However, the secretion of pro-cancer cytokines of tumour cells has been regarded as the resistance mechanism to EGFR-TKIs, including osimertinib. A high level of these cytokines also indicates a shorter progression-free survival (PFS). As AIM2 regulates the secretion of pro-cancer cytokines, we thought inhibition of AIM2 may contribute to the therapeutic effect of EGFR-TKIs. MATERIAL AND METHODS: We first established AIM2 inhibition and overexpression in cells. Then, the viability rate of cells was calculated by cell counting kit-8 (CCK-8) method, and apoptotic ratio of cells were measured by flow cytometry. The expression of inflammatory-related genes was detected using quantitative polymerase chain reaction (qPCR), concentrations of inflammatory-related factors were measured using enzyme-linked immunosorbent assay (ELISA). The expression of Wnt/b-catenin and EGFR/Ras/Mitogen-activated protein kinase kinase 1 (MEK) signalling pathway components was detected using western blotting. RESULTS: We found that inhibition of AIM2 enlarged the effect of osimertinib on the upregulation of inflammatory gene expression and secretion of these genes, increasing apoptosis. In addition, we also found that AIM2 could enhance the effect of osimertinib on reducing the expression of the Wnt/b-catenin and EGFR/Ras/MEK signalling pathways, resulting in the inhibition of cellular proliferation, and exerting an anti-tumour effect. These effects were also observed using in vivo experiments. CONCLUSIONS: AIM2 presents a potential therapeutic target in treatment of glioma.
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Acrilamidas , Compuestos de Anilina , Neoplasias Encefálicas , Glioma , Acrilamidas/farmacología , Acrilamidas/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/genética , Humanos , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Animales , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores ErbB/genética , Ratones Desnudos , Indoles , PirimidinasRESUMEN
Glioma is the most common brain tumor, accounting for a large majority of cancer-related deaths. ß-galactoside α2, 6 sialyltranferase 1 (ST6Gal1), the primary enzyme responsible for the conjugation of α2, 6 sialic acids to protein and lipid targets, is strongly associated with the occurrence and development of several brain tumor types. Still, the expression, targets, and functions of ST6Gal1 in glioma patients remain undetermined. As sialylation of the Ig-like cell adhesion family molecules have prominent roles in the latter's regulation in other biological contexts, we screened for members that have potential to be regulated by ST6Gal1 in silico and examined co-expressed protein modules using data derived from the Cancer Genome Atlas (TCGA) database, and we identified neural cell adhesion molecule (NCAM1) as a major ST6Gal1-interacting target. Bioinformatic binding analysis confirmed the interaction of ST6Gal1 and NCAM1. Immunohistochemistry was then used to evaluate post-operative samples from 156 patients with gliomas. ST6Gal1 and NCAM1 were co-expressed in gliomas, and their expression correlated significantly (p = 0.002) by univariate analysis. Our study also found that the expression levels of both ST6Gal1 and NCAM1 corresponded negatively with glioma grade, isocitrate dehydrogenase (IDH) mutation, and proliferation index (Ki67). Consistently, Kaplan-Meier survival curves showed that lower ST6Gal1 and NCAM1 protein levels are linked to unfavorable outcomes in glioma patients (p = 0.018 and p < 0.001, respectively). Our data indicate that ST6Gal1 may participate in the inhibition of oncogenesis and malignant progression via interacting with and targeting NCAM1 in glioma, thus presenting a novel strategy for intervention.
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Neoplasias Encefálicas , Glioma , Sialiltransferasas , Humanos , Glioma/patología , Glioma/genética , Glioma/metabolismo , Sialiltransferasas/genética , Sialiltransferasas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Masculino , Femenino , Adulto , Persona de Mediana Edad , Antígenos CD/metabolismo , Antígeno CD56/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , beta-D-Galactósido alfa 2-6-SialiltransferasaRESUMEN
Venous thromboembolism (VTE) is a prevalent complication among patients with cancer, contributing significantly to morbidity and mortality. However, the relationship between VTE-related genes (VRGs) and their potential impact on prognosis, immune response, and therapeutic targets in various cancer types remains unclear. Based on the coagulation and complement pathways, we identified hub VRGs that play a role in regulating the immune response in cancer. Specifically, coagulation factor III (F3), plasminogen activator (PLAT) and complement C1s (C1S) were identified as genes that exhibit high expression levels, positively correlating with tumor stemness and copy number variations, while inversely correlating with methylation levels, in particular cancer types. Pan-cancer survival analysis revealed detrimental effects of these VRGs in several cancer types, notably in glioblastoma and lower grade glioma (GMBLGG). Further analysis using receiver operating characteristic (ROC) curves demonstrated a high accuracy of F3, PLAT and C1S in predicting outcomes in GBMLGG, with area under the curve (AUC) values ranging from 0.78 to 0.9. Validation of the prognostic value of these three genes in GMBLGG was conducted using an independent Gene Expression Omnibus (GEO) dataset. Additionally, gene-drug association analysis identified ciclosporin, ouabain and 6- mercaptopurine, which all exhibit immunosuppressive properties, as potential therapeutic options for tumor patients exhibiting high F3, PLAT or C1S expression, respectively. In summary, our findings provide a bioinformatics perspective on VRGs in pan-cancer, highlighting the pivotal roles of F3, PLAT and C1S, which could potentially be therapeutically exploited and targeted in several cancers, especially in GBMLGG.
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Biomarcadores de Tumor , Regulación Neoplásica de la Expresión Génica , Glioblastoma , Glioma , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/genética , Tromboembolia Venosa/etiología , Glioblastoma/genética , Biomarcadores de Tumor/genética , Pronóstico , Glioma/genética , Neoplasias Encefálicas/genética , Curva ROC , Variaciones en el Número de Copia de ADN , Perfilación de la Expresión Génica , Clasificación del Tumor , Biología Computacional , Antitrombina IIIRESUMEN
Background: Spinal cord glioma (SCG), a rare subset of central nervous system (CNS) glioma, represents a complex challenge in neuro-oncology. There has been research showing that Retinol Dehydrogenase 10 (RDH10) may be a tumor promoting factor in brain glioma, but the biological effects of RDH10 remain undefined in SCG. Methods: We performed gene set enrichment analysis (GSEA) and unsupervised clustering analysis to investigate the roles of EMT (epithelial-mesenchymal transition) in glioma. DEG (differently expressed gene) screening and correlation analysis were conducted to filter the candidate genes which were closely associated with EMT process in SCG. Enrichment analysis and GSVA (Gene Set Variation Analysis) were conducted to investigate the potential mechanism of RDH10 for SCG. Trans-well and healing assay were performed to explore the role of RDH10 in the invasion of SCG. Western blotting was performed to evaluate the levels of markers in PI3K-AKT and EMT pathway. In vivo tests were conducted to verify the role of RDH10 in EMT process. Results: Bioinformatic analysis demonstrated the EMT pathway was associated with dismal prognosis of glioma. Further analysis demonstrated that RDH10 showed the strongest correlation with the EMT process. Retinol Dehydrogenase 10 expression was significantly increased in SCG tissues, correlating with advanced tumor grade and unfavorable prognosis. Functional analysis indicated that decreasing RDH10 levels impeded the invasive and migratory abilities of SCG cells, whereas increasing RDH10 levels augmented them. Enrichment analysis and western blot revealed that RDH10 regulated EMT process of SCG by PI3K-AKT pathway. We observed that the enhanced invasion ability and increased EMT-related protein induced by RDH10 overexpression can be suppressed by PI3K-AKT pathway inhibitor (LY294002). Conclusion: Our research found that RDH10 was an effective biomarker associated with tumor grade and prognosis of SCG. RDH10 could regulate EMT process of SCG through PI3K-AKT pathway.
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Oxidorreductasas de Alcohol , Transición Epitelial-Mesenquimal , Glioma , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Proteínas Proto-Oncogénicas c-akt/metabolismo , Oxidorreductasas de Alcohol/genética , Oxidorreductasas de Alcohol/metabolismo , Humanos , Glioma/patología , Glioma/genética , Glioma/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Línea Celular Tumoral , Animales , Neoplasias de la Médula Espinal/patología , Neoplasias de la Médula Espinal/genética , Neoplasias de la Médula Espinal/metabolismo , Movimiento Celular , Ratones Desnudos , Regulación Neoplásica de la Expresión Génica , Masculino , RatonesRESUMEN
Immunologic treatment options are uncommon in low-grade gliomas, although such therapies might be beneficial for inoperable and aggressive cases. Knowledge of the immune and stromal cells in low-grade gliomas is highly relevant for such approaches but still needs to be improved. Published gene-expression data from 400 low-grade gliomas and 193 high-grade gliomas were gathered to quantify 10 microenvironment cell populations with a deconvolution method designed explicitly for brain tumors. First, we investigated general differences in the microenvironment of low- and high-grade gliomas. Lower-grade and high-grade tumors cluster together, respectively, and show a general similarity within and distinct differences between these groups, the main difference being a higher infiltration of fibroblasts and T cells in high-grade gliomas. Among the analyzed entities, gangliogliomas and pleomorphic xanthoastrocytomas presented the highest overall immune cell infiltration. Further analyses of the low-grade gliomas presented three distinct microenvironmental signatures of immune cell infiltration, which can be divided into T-cell/dendritic/natural killer cell-, neutrophilic/B lineage/natural killer cell-, and monocytic/vascular/stromal-cell-dominated immune clusters. These clusters correlated with tumor location, age, and histological diagnosis but not with sex or progression-free survival. A survival analysis showed that the prognosis can be predicted from gene expression, clinical data, and a combination of both with a support vector machine and revealed the negative prognostic relevance of vascular markers. Overall, our work shows that low- and high-grade gliomas can be characterized and differentiated by their immune cell infiltration. Low-grade gliomas cluster into three distinct immunologic tumor microenvironments, which may be of further interest for upcoming immunotherapeutic research.
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Neoplasias Encefálicas , Glioma , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Glioma/genética , Glioma/inmunología , Glioma/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/inmunología , Niño , Femenino , Masculino , Clasificación del Tumor , Perfilación de la Expresión Génica , Transcriptoma , Preescolar , Adolescente , Células del Estroma/patología , Células del Estroma/metabolismo , Células del Estroma/inmunologíaRESUMEN
The use of targeted agents in the treatment of pediatric low-grade gliomas (pLGGs) relies on the determination of molecular status. It has been shown that genetic alterations in pLGG can be identified non-invasively using MRI-based radiomic features or convolutional neural networks (CNNs). We aimed to build and assess a combined radiomics and CNN non-invasive pLGG molecular status identification model. This retrospective study used the tumor regions, manually segmented from T2-FLAIR MR images, of 336 patients treated for pLGG between 1999 and 2018. We designed a CNN and Random Forest radiomics model, along with a model relying on a combination of CNN and radiomic features, to predict the genetic status of pLGG. Additionally, we investigated whether CNNs could predict radiomic feature values from MR images. The combined model (mean AUC: 0.824) outperformed the radiomics model (0.802) and CNN (0.764). The differences in model performance were statistically significant (p-values < 0.05). The CNN was able to learn predictive radiomic features such as surface-to-volume ratio (average correlation: 0.864), and difference matrix dependence non-uniformity normalized (0.924) well but was unable to learn others such as run-length matrix variance (- 0.017) and non-uniformity normalized (- 0.042). Our results show that a model relying on both CNN and radiomic-based features performs better than either approach separately in differentiating the genetic status of pLGGs, and that CNNs are unable to express all handcrafted features.
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Neoplasias Encefálicas , Glioma , Imagen por Resonancia Magnética , Redes Neurales de la Computación , Humanos , Glioma/genética , Glioma/diagnóstico por imagen , Glioma/patología , Niño , Femenino , Estudios Retrospectivos , Masculino , Imagen por Resonancia Magnética/métodos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Adolescente , Preescolar , Clasificación del Tumor , LactanteRESUMEN
Gliomas are among the most common cancers in the central nervous system, arising through various signaling pathways. One significant pathway is Wnt signaling, a tightly regulated process that plays a crucial role in gliomagenesis and development. The current study aims to explore the relationship between circular RNAs (circRNAs) and the Wnt/ß-catenin signaling pathway in gliomas, considering the growing recognition of circRNAs in disease pathogenesis. A comprehensive review of recent research was conducted to investigate the roles of circRNAs in gliomas, focusing on their expression patterns and interactions with the Wnt signaling pathway. The analysis included studies examining circRNAs' function as microRNA sponges and their impact on glioma biology. The findings reveal that circRNAs are differentially expressed in gliomas and significantly influence the occurrence, growth, and metastasis of these tumors. Specifically, circRNAs interact with the Wnt signaling pathway, affecting glioma development and progression. This interaction highlights the importance of circRNAs in glioma pathophysiology. Understanding the regulatory network involving circRNAs and Wnt signaling offers valuable insights into glioma pathophysiology. CircRNAs hold promise as diagnostic and prognostic biomarkers and may serve as targets for novel therapeutic strategies in glioma treatment.
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Neoplasias Encefálicas , Glioma , ARN Circular , Vía de Señalización Wnt , Humanos , Glioma/genética , Glioma/patología , Glioma/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , Vía de Señalización Wnt/genética , Vía de Señalización Wnt/fisiología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
BACKGROUND: Treatment of gliomas, the most prevalent primary malignant neoplasm of the central nervous system, is challenging. Arachidonate 5-lipoxygenase activating protein (ALOX5AP) is crucial for converting arachidonic acid into leukotrienes and is associated with poor prognosis in multiple cancers. Nevertheless, its relationship with the prognosis and the immune microenvironment of gliomas remains incompletely understood. METHODS: The differential expression of ALOX5AP was evaluated based on public Databases. Kaplan-Meier, multivariate Cox proportional hazards regression analysis, time-dependent receiver operating characteristic, and nomogram were used to estimate the prognostic value of ALOX5AP. The relationship between ALOX5AP and immune infiltration was calculated using ESTIMATE and CIBERSORT algorithms. Relationships between ALOX5AP and human leukocyte antigen molecules, immune checkpoints, tumor mutation burden, TIDE score, and immunophenoscore were calculated to evaluate glioma immunotherapy response. Single gene GSEA and co-expression network-based GO and KEGG enrichment analysis were performed to explore the potential function of ALOX5AP. ALOX5AP expression was verified using multiplex immunofluorescence staining and its prognostic effects were confirmed using a glioma tissue microarray. RESULT: ALOX5AP was highly expressed in gliomas, and the expression level was related to World Health Organization (WHO) grade, age, sex, IDH mutation status, 1p19q co-deletion status, MGMTp methylation status, and poor prognosis. Single-cell RNA sequencing showed that ALOX5AP was expressed in macrophages, monocytes, and T cells but not in tumor cells. ALOX5AP expression positively correlated with M2 macrophage infiltration and poor immunotherapy response. Immunofluorescence staining demonstrated that ALOX5AP was upregulated in WHO higher-grade gliomas, localizing to M2 macrophages. Glioma tissue microarray confirmed the adverse effect of ALOX5AP in the prognosis of glioma. CONCLUSION: ALOX5AP is highly expressed in M2 macrophages and may act as a potential biomarker for predicting prognosis and immunotherapy response in patients with glioma.
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Proteínas Activadoras de la 5-Lipooxigenasa , Biología Computacional , Glioma , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Glioma/genética , Glioma/inmunología , Glioma/patología , Proteínas Activadoras de la 5-Lipooxigenasa/genética , Pronóstico , Masculino , Femenino , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Persona de Mediana Edad , Regulación Neoplásica de la Expresión GénicaRESUMEN
Glioma, especially glioblastoma patients, present highly heterogeneous and immunosuppressive microenvironment, leading to their poor response to treatment and survival. Targeting the tumor microenvironment is considered a promising therapeutic strategy. M2 macrophages are highly infiltrated in glioma tissue, even up to 50% of the total number of bulk tissue cells. Here, we identified GPR65 as the hub gene of the M2 macrophage-related module in glioma through WGCNA analysis. The expression and prognosis analysis suggested that GPR65 was positively correlated with the malignancy and poor prognosis of glioma, and the heterogeneity analysis found that GPR65 was highly expressed in the vascular proliferation area of glioma, which matched the spatial expression characteristics of M2 macrophages. We further verified that GPR65 was highly expressed in macrophages but not tumor cells in the glioma microenvironment by single-cell data analysis and immunofluorescence. Most importantly, we found that inhibition of GPR65 was sufficient to reduce macrophages' polarization response to glioma cell and break the malignant cooperation with glioma cells. Our study reports the expression characteristics and malignant behavior of GPR65 in the glioma microenvironment, which provides a new alternative target of treatment to glioma microenvironment.
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Neoplasias Encefálicas , Glioma , Receptores Acoplados a Proteínas G , Microambiente Tumoral , Humanos , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Glioma/patología , Glioma/genética , Macrófagos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Tumor-associated macrophages (TAMs) residing in the tumor microenvironment (TME) are characterized by their pivotal roles in tumor progression, antitumor immunity, and TME remodeling. However, a thorough comparative characterization of tumor-TAM crosstalk across IDH-defined categories of glioma remains elusive, likely contributing to mixed outcomes in clinical trials. We delineated the phenotypic heterogeneity of TAMs across IDH-stratified gliomas. Notably, two TAM subsets with a mesenchymal phenotype were enriched in IDH-WT glioblastoma (GBM) and correlated with poorer patient survival and reduced response to anti-PD-1 immune checkpoint inhibitor (ICI). We proposed SLAMF9 receptor as a potential therapeutic target. Inference of gene regulatory networks identified PPARG, ELK1, and MXI1 as master transcription factors of mesenchymal BMD-TAMs. Our analyses of reciprocal tumor-TAM interactions revealed distinct crosstalk in IDH-WT tumors, including ANXA1-FPR1/3, FN1-ITGAVB1, VEGFA-NRP1, and TNFSF12-TNFRSF12A with known contribution to immunosuppression, tumor proliferation, invasion and TAM recruitment. Spatially resolved transcriptomics further elucidated the architectural organization of highlighted communications. Furthermore, we demonstrated significant upregulation of ANXA1, FN1, NRP1, and TNFRSF12A genes in IDH-WT tumors using bulk RNA-seq and RT-qPCR. Longitudinal expression analysis of candidate genes revealed no difference between primary and recurrent tumors indicating that the interactive network of malignant states with TAMs does not drastically change upon recurrence. Collectively, our study offers insights into the unique cellular composition and communication of TAMs in glioma TME, revealing novel vulnerabilities for therapeutic interventions in IDH-WT GBM.
Asunto(s)
Neoplasias Encefálicas , Glioma , Isocitrato Deshidrogenasa , Transcriptoma , Microambiente Tumoral , Macrófagos Asociados a Tumores , Humanos , Microambiente Tumoral/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Isocitrato Deshidrogenasa/genética , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/patología , Glioma/genética , Glioma/patología , Glioma/metabolismo , Análisis de la Célula IndividualRESUMEN
Glioblastoma (GBM) is one of the most malignant primary brain tumors in adults. The NPC2 gene (Niemann-Pick type C intracellular cholesterol transporter 2) is a protein-coding gene with a lipid recognition domain. The NPC2 gene was found to be significantly increased in gliomas (LGG and GBM), and it is now thought to be a risk factor. COX analysis demonstrated that NPC2 was a significant risk factor for glioma. Functional enrichment analysis of genes that were differentially expressed between high and low expression groups revealed that genes were primarily enriched in the regulation of trans-synaptic signaling, Retrograde endocannabinoid signaling and other pathways. According to the findings of the immunoinfiltration investigation, the NPC2 gene and macrophage, DC, etc. have a strong positive association. In addition, patients with high NPC2 expression had higher levels of immune cell expression. Medication sensitivity research revealed that NPC2's differential expression had some bearing on patients' medication sensitivity. There was a strong correlation between the prognosis of glioma patients and the gene sets NUDT19 and NUME. In brief, the NPC2 gene was identified to be a possible biomarker of glioma, and preliminary analysis was done on the role of the NPC2 gene in immunological microenvironment of glioma.
Asunto(s)
Biología Computacional , Glioma , Humanos , Biología Computacional/métodos , Glioma/genética , Glioma/patología , Regulación Neoplásica de la Expresión Génica , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Pronóstico , Glicoproteínas/genética , Glicoproteínas/metabolismo , Proteínas de Transporte Vesicular/genética , Biomarcadores de Tumor/genética , Microambiente Tumoral/genética , FemeninoRESUMEN
CD58 has been implicated in immune suppression and is associated with stemness in various types of cancer. Nonetheless, efficient biomarkers for assessing cancer patient response to immunotherapy are lacking. The present work focused on assessing the immune predictive significance of CD58 for patients with glioma. The expression of CD58 correlates with the clinicopathologic characteristics of patients with glioma, suggesting CD58high cells to signify glioma with tumorigenic potential. The CD58high cells displayed accelerated tumor formation compared to CD58low cells in vivo. Taken together, CD58 could potentially serve as a marker for glioma. CD58high glioma induces macrophage polarization through CXCL5 secretion, where M2 macrophages regulate PD-L1 expression within CD58high glioma via IL-6 production in vitro. Moreover, it was found that combination treatment with CD58 significantly increased the volume of tumors in the xenograft specimens. Evaluating CD58 expression represents a promising approach for identifying patients who can benefit from immunotherapy.
Asunto(s)
Antígenos CD58 , Glioma , Macrófagos , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Animales , Ratones , Macrófagos/inmunología , Macrófagos/metabolismo , Glioma/inmunología , Glioma/patología , Glioma/metabolismo , Glioma/genética , Antígenos CD58/metabolismo , Antígenos CD58/genética , Femenino , Línea Celular Tumoral , Masculino , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genéticaRESUMEN
Gliomas are the most prevalent malignancies of the central nervous system (CNS). Downregulation of microRNA124 (miR124) has been identified in glioma; however, its biological functions in glioma are not yet fully understood. Specificity protein 1 (SP1) is a type of transcription factor that is involved in cancer progression. In this study, we examined the targeting of Sp1 mRNA by miR-124-3p in a rat glioma model. After confirming and selecting the binding of Sp1 to miR-124 with the help of bioinformatics methods, adult male Wistar rats were used to induce glioma by microinjection of 1 × 106 C6 cells into the striatum area of brain. The rats were divided into 3 groups; intact, sham and glioma groups. The presence of glioma was confirmed 21 days after implantation through histological analysis. The expression levels of miR-124 and SP1 genes in the experimental groups were examined using quantitative real-time polymerase chain reaction (qRT-PCR). Our data showed that the expression of miR-124 was significantly downregulated in glioma group compared to the sham and intact group, while the expression of SP1 was significantly upregulated. We found that the expression levels of miR-124 and Sp1 were decreased and increased in C6 cell line compared to the normal brain tissue cell line, respectively. The results indicated that Sp1 was identified as a direct target of miR124 through luciferase reporter assays. In summary, this study demonstrated for the first time that miR-124 expression is downregulated and Sp1 expression is upregulated in an animal model of glioma, which, in turn, may be involved in the development of glioma brain cancer.
Asunto(s)
Neoplasias Encefálicas , Regulación Neoplásica de la Expresión Génica , Glioma , MicroARNs , Ratas Wistar , Factor de Transcripción Sp1 , Animales , MicroARNs/genética , MicroARNs/metabolismo , Glioma/genética , Glioma/patología , Glioma/metabolismo , Factor de Transcripción Sp1/metabolismo , Factor de Transcripción Sp1/genética , Masculino , Ratas , Línea Celular Tumoral , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Progresión de la Enfermedad , Regulación hacia AbajoRESUMEN
It is well known how the precise localization of glioblastoma multiforme (GBM) predicts the direction of tumor spread in the surrounding neuronal structures. The aim of the present review is to reveal the lateralization of GBM by evaluating the anatomical regions where it is frequently located as well as the main molecular alterations observed in different brain regions. According to the literature, the precise or most frequent lateralization of GBM has yet to be determined. However, it can be said that GBM is more frequently observed in the frontal lobe. Tractus and fascicles involved in GBM appear to be focused on the corticospinal tract, superior longitudinal I, II and III fascicles, arcuate fascicle long segment, frontal strait tract, and inferior frontooccipital fasciculus. Considering the anatomical features of GBM and its brain involvement, it is logical that the main brain regions involved are the frontaltemporalparietaloccipital lobes, respectively. Although tumor volumes are higher in the right hemisphere, it has been determined that the prognosis of patients diagnosed with cancer in the left hemisphere is worse, probably reflecting the anatomical distribution of some detrimental alterations such as TP53 mutations, PTEN loss, EGFR amplification, and MGMT promoter methylation. There are theories stating that the right hemisphere is less exposed to external influences in its development as it is responsible for the functions necessary for survival while tumors in the left hemisphere may be more aggressive. To shed light on specific anatomical and molecular features of GBM in different brain regions, the present review article is aimed at describing the main lateralization pathways as well as gene mutations or epigenetic modifications associated with the development of brain tumors.