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Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 December 2024) | Viewed by 19048

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Dr. Hung-Pei Tsai

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Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
Interests: biomarker; oncology; molecular biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue delves into the rapidly evolving field of glioma's molecular intricacies, with a specific focus on the role of signal pathways and their implications for novel therapeutic strategies. Gliomas, originating from the transformation of glial cells, are marked by a complex array of genetic, epigenetic, and signaling alterations. These include mutations in pivotal genes such as IDH1/2, TP53, and ATRX in lower-grade gliomas; PTEN, EGFR, and PDGFRA in primary glioblastomas; and DNA methylation and histone modifications. Crucially, this Special Issue highlights how disruptions in signal transduction pathways, such as the RTK/RAS/PI(3)K pathway, play a central role in glioma pathogenesis and offer potential targets for therapy.

A key focus of this Special Issue is on the innovative treatment strategies emerging in response to these challenges, particularly those targeting aberrant signaling in gliomas. Advances in immunotherapy, such as checkpoint inhibitors and CAR T-cell therapy, are being adapted to target the immunosuppressive tumor microenvironment and navigate the blood–brain barrier (BBB). Additionally, we explore gene therapy techniques using viral vectors for direct tumor targeting and the application of nanomedicine for enhanced drug delivery, both of which are critical in manipulating signaling pathways within the tumor.

The objective is to present a comprehensive overview of the current state of glioma treatment research, with a special emphasis on signal pathways. This includes illustrating the promising therapeutic avenues that are arising and acknowledging the considerable challenges that remain. We aim to foster a deeper understanding of these advancements and hurdles among researchers, clinicians, and stakeholders, with the ultimate goal of driving forward innovations that promise improved outcomes for glioma patients.

Dr. Hung-Pei Tsai
Guest Editor

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Keywords

glioma
molecular pathology
blood–brain barrier
immunotherapy
microenvironment
nanomedicine

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Published Papers (11 papers)

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Research

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24 pages, 19502 KiB

Open AccessArticle

by Zijiang Yang, Ting Zhang, Xuanlin Zhu and Xiaobiao Zhang

Biomedicines 2025, 13(1), 41; https://doi.org/10.3390/biomedicines13010041 - 27 Dec 2024

Viewed by 826

Abstract

Background/Objective: We aimed to elucidate the roles of ferroptosis-associated differentially expressed genes (DEGs) in glioblastoma and provide a comprehensive resource for researchers in the field of glioblastoma cell ferroptosis. Methods: We used RNA sequencing to identify the DEGs associated with erastin-induced ferroptosis in glioblastoma cells. We further unraveled the biological functions and clinical implications of cold-inducible RNA-binding protein (CIRBP) in the context of glioblastoma by using a multifaceted approach, encompassing gene expression profiling, survival analysis, and functional assays to elucidate its role in glioblastoma cell mortality and its potential influence on patient prognosis. Results: We identified and validated the gene encoding CIRBP, the expression of which is altered during glioblastoma ferroptosis. Our findings highlight the relationship between CIRBP expression and ferroptosis in glioblastoma cells. We demonstrated that CIRBP modulates key aspects of cell death, thereby altering the sensitivity of glioblastoma cells to erastin-induced ferroptosis. A prognostic model, constructed based on CIRBP expression levels, revealed an association between lower CIRBP levels and poorer prognosis in glioma patients; this finding was corroborated by our comprehensive in vitro and in vivo assays that highlighted the impact of modulating CIRBP expression on glioblastoma cell viability and ferroptotic response. Conclusion: Our research unravels the complex molecular dynamics of ferroptosis in glioblastoma and underscores CIRBP as a potential biomarker and therapeutic target. This improved understanding of the role of CIRBP in ferroptosis paves the way for more precise and efficacious treatments for glioblastoma, potentially improving patient outcomes. Full article

(This article belongs to the Special Issue Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies)

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29 pages, 5682 KiB

Open AccessArticle

Unveiling the Molecular Mechanisms of Glioblastoma through an Integrated Network-Based Approach

by Ali Kaynar, Woonghee Kim, Atakan Burak Ceyhan, Cheng Zhang, Mathias Uhlén, Hasan Turkez, Saeed Shoaie and Adil Mardinoglu

Biomedicines 2024, 12(10), 2237; https://doi.org/10.3390/biomedicines12102237 - 1 Oct 2024

Cited by 1 | Viewed by 2008

Abstract

Background/Objectives: Despite current treatments extending the lifespan of Glioblastoma (GBM) patients, the average survival time is around 15–18 months, underscoring the fatality of GBM. This study aims to investigate the impact of sample heterogeneity on gene expression in GBM, identify key metabolic pathways and gene modules, and explore potential therapeutic targets. Methods: In this study, we analysed GBM transcriptome data derived from The Cancer Genome Atlas (TCGA) using genome-scale metabolic models (GEMs) and co-expression networks. We examine transcriptome data incorporating tumour purity scores (TPSs), allowing us to assess the impact of sample heterogeneity on gene expression profiles. We analysed the metabolic profile of GBM by generating condition-specific GEMs based on the TPS group. Results: Our findings revealed that over 90% of genes showing brain and glioma specificity in RNA expression demonstrate a high positive correlation, underscoring their expression is dominated by glioma cells. Conversely, negatively correlated genes are strongly associated with immune responses, indicating a complex interaction between glioma and immune pathways and non-tumorigenic cell dominance on gene expression. TPS-based metabolic profile analysis was supported by reporter metabolite analysis, highlighting several metabolic pathways, including arachidonic acid, kynurenine and NAD pathway. Through co-expression network analysis, we identified modules that significantly overlap with TPS-correlated genes. Notably, SOX11 and GSX1 are upregulated in High TPS, show a high correlation with TPS, and emerged as promising therapeutic targets. Additionally, NCAM1 exhibits a high centrality score within the co-expression module, which shows a positive correlation with TPS. Moreover, LILRB4, an immune-related gene expressed in the brain, showed a negative correlation and upregulated in Low TPS, highlighting the importance of modulating immune responses in the GBM mechanism. Conclusions: Our study uncovers sample heterogeneity’s impact on gene expression and the molecular mechanisms driving GBM, and it identifies potential therapeutic targets for developing effective treatments for GBM patients. Full article

(This article belongs to the Special Issue Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies)

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18 pages, 2917 KiB

Open AccessArticle

Elevated Cellular Uptake of Succinimide- and Glucose-Modified Liposomes for Blood–Brain Barrier Transfer and Glioblastoma Therapy

by Larissa J. Lubitz, Moritz P. Haffner, Harden Rieger and Gero Leneweit

Biomedicines 2024, 12(9), 2135; https://doi.org/10.3390/biomedicines12092135 - 20 Sep 2024

Viewed by 1449

Abstract

The uptake of four liposomal formulations was tested with the murine endothelial cell line bEnd.3 and the human glioblastoma cell line U-87 MG. All formulations were composed of DPPC, cholesterol, 5 mol% of mPEG (2000 Da, conjugated to DSPE), and the dye DiD. Three of the formulations had an additional PEG chain (nominally 5000 Da, conjugated to DSPE) with either succinimide (NHS), glucose (PEG-bound at C-6), or 4-aminophenyl β-D-glucopyranoside (bound at C-1) as ligands at the distal end. Measuring the uptake kinetics at 1 h and 3 h for liposomal incubation concentrations of 100 µM, 500 µM, and 1000 µM, we calculated the liposomal uptake saturation S and the saturation half-time t_1/2. We show that only succinimide has an elevated uptake in bEnd.3 cells, which makes it a very promising and so far largely unexplored candidate for BBB transfer and brain cancer therapies. Half-times are uniform at low concentrations but diversify for high concentrations for bEnd.3 cells. Contrary, U-87 MG cells show almost identical saturations for all three ligands, making a uniform uptake mechanism likely. Only mPEG liposomes stay at 60% of the saturation for ligand-coated liposomes. Half-times are diverse at low concentrations but unify at high concentrations for U-87 MG cells. Full article

(This article belongs to the Special Issue Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies)

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17 pages, 9943 KiB

Open AccessArticle

Hyperbaric Oxygen Therapy as a Novel Approach to Modulating Macrophage Polarization for the Treatment of Glioblastoma

by Chun-Man Yuen, Hung-Pei Tsai, Tzu-Ting Tseng, Yu-Lung Tseng, Ann-Shung Lieu, Aij-Lie Kwan and Alice Y. W. Chang

Biomedicines 2024, 12(7), 1383; https://doi.org/10.3390/biomedicines12071383 - 21 Jun 2024

Cited by 1 | Viewed by 1579

Abstract

Glioblastoma multiforme (GBM) is a highly aggressive brain cancer with a poor prognosis despite current treatments. This is partially attributed to the immunosuppressive environment facilitated by tumor-associated macrophages, which predominantly underlie the tumor-promoting M2 phenotype. This study investigated the potential of hyperbaric oxygen (HBO) therapy, traditionally used to treat conditions such as decompression sickness, in modulating the macrophage phenotype toward the tumoricidal M1 state and disrupting the supportive tumor microenvironment. HBO has direct antiproliferative effects on tumor cells and reduces hypoxia, which may impair angiogenesis and tumor growth. This offers a novel approach to GBM treatment by targeting the role of the immune system within the tumor microenvironment. The effects of HBO on macrophage polarization and GBM cell viability and apoptosis were evaluated in this study. We detected that HBO promoted M1 macrophage cytokine expression while decreasing GBM cell viability and increasing apoptosis using GBM cell lines and THP-1-derived macrophage-conditioned media. These findings suggest that HBO therapy can shift macrophage polarization toward a tumoricidal M1 state. This can improve GBM cell survival and offers a potential therapeutic strategy. In conclusion, HBO can shift macrophages from a tumor-promoting M2 phenotype to a tumoricidal M1 phenotype in GBM. This can facilitate apoptosis and, in turn, improve treatment outcomes. Full article

(This article belongs to the Special Issue Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies)

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16 pages, 3859 KiB

Open AccessArticle

High PGC-1α Expression as a Poor Prognostic Indicator in Intracranial Glioma

by Yu-Wen Cheng, Jia-Hau Lee, Chih-Hui Chang, Tzu-Ting Tseng, Chee-Yin Chai, Ann-Shung Lieu and Aij-Lie Kwan

Biomedicines 2024, 12(5), 979; https://doi.org/10.3390/biomedicines12050979 - 29 Apr 2024

Viewed by 1507

Abstract

Gliomas are the most common primary brain tumors in adults. Despite multidisciplinary treatment approaches, the survival rates for patients with malignant glioma have only improved marginally, and few prognostic biomarkers have been identified. Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) is a crucial regulator of cancer metabolism, playing a vital role in cancer cell adaptation to fluctuating energy demands. In this study, the clinicopathological roles of PGC-1α in gliomas were evaluated. Employing immunohistochemistry, cell culture, siRNA transfection, cell viability assays, western blot analyses, and in vitro and in vivo invasion and migration assays, we explored the functions of PGC-1α in glioma progression. High PGC-1α expression was significantly associated with an advanced pathological stage in patients with glioma and with poorer overall survival. The downregulation of PGC-1α inhibited glioma cell proliferation, invasion, and migration and altered the expression of oncogenic markers. These results conclusively demonstrated that PGC-1α plays a critical role in maintaining the malignant phenotype of glioma cells and indicated that targeting PGC-1α could be an effective strategy to curb glioma progression and improve patient survival outcomes. Full article

(This article belongs to the Special Issue Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies)

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13 pages, 5942 KiB

Open AccessArticle

Antitumor Efficacy of Arylquin 1 through Dose-Dependent Cytotoxicity, Apoptosis Induction, and Synergy with Radiotherapy in Glioblastoma Models

by Ann-Shung Lieu, Yu-Chi Pan, Jia-Hau Lee, Yuan-Chin Hsieh, Chien-Ju Lin, Ya-Ling Hsu, Kung-Chao Chang, Shih-Hsun Kuo, Tzu-Ting Tseng and Hung-Pei Tsai

Biomedicines 2024, 12(4), 907; https://doi.org/10.3390/biomedicines12040907 - 19 Apr 2024

Viewed by 1443

Abstract

Glioblastoma (GBM), the most aggressive form of brain cancer, is characterized by rapid growth and resistance to conventional therapies. Current treatments offer limited effectiveness, leading to poor survival rates and the need for novel therapeutic strategies. Arylquin 1 has emerged as a potential therapeutic candidate because of its unique mechanism of inducing apoptosis in cancer cells without affecting normal cells. This study investigated the efficacy of Arylquin 1 against GBM using the GBM8401 and A172 cells by assessing its dose-dependent cytotoxicity, apoptosis induction, and synergy with radiotherapy. In vitro assays demonstrated a significant reduction in cell viability and increased apoptosis, particularly at high concentrations of Arylquin 1. Migration and invasion analyses revealed notable inhibition of cellular motility. In vivo experiments on NU/NU nude mice with intracranially implanted GBM cells revealed that Arylquin 1 substantially reduced tumor growth, an effect magnified by concurrent radiotherapy. These findings indicate that by promoting apoptosis and enhancing radiosensitivity, Arylquin 1 is a potent therapeutic option for GBM treatment. Full article

(This article belongs to the Special Issue Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies)

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21 pages, 12760 KiB

Open AccessArticle

Significant Genes Associated with Mortality and Disease Progression in Grade II and III Glioma

by Bo Mi Choi, Jin Hwan Cheong, Je Il Ryu, Yu Deok Won, Kyueng-Whan Min and Myung-Hoon Han

Biomedicines 2024, 12(4), 858; https://doi.org/10.3390/biomedicines12040858 - 12 Apr 2024

Viewed by 1832

Abstract

Background: The Wnt/β-catenin pathway plays a critical role in the tumorigenesis and maintenance of glioma stem cells. This study aimed to evaluate significant genes associated with the Wnt/β-catenin pathway involved in mortality and disease progression in patients with grade II and III glioma, using the Cancer Genome Atlas (TCGA) database. Methods: We obtained clinicopathological information and mRNA expression data from 515 patients with grade II and III gliomas from the TCGA database. We performed a multivariate Cox regression analysis to identify genes independently associated with glioma prognosis. Results: The analysis of 34 genes involved in Wnt/β-catenin signaling demonstrated that four genes (CER1, FRAT1, FSTL1, and RPSA) related to the Wnt/β-catenin pathway were significantly associated with mortality and disease progression in patients with grade II and III glioma. We also identified additional genes related to the four significant genes of the Wnt/β-catenin pathway mentioned above. The higher expression of BMP2, RPL18A, RPL19, and RPS12 is associated with better outcomes in patients with glioma. Conclusions: Using a large-scale open database, we identified significant genes related to the Wnt/β-catenin signaling pathway associated with mortality and disease progression in patients with grade II and III gliomas. Full article

(This article belongs to the Special Issue Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies)

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Review

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20 pages, 1501 KiB

Open AccessReview

GRP78 in Glioma Progression and Therapy: Implications for Targeted Approaches

by Yue Yang, Wen Li, Yu Zhao, Minxuan Sun, Feifei Xing, Jiao Yang and Yuanshuai Zhou

Biomedicines 2025, 13(2), 382; https://doi.org/10.3390/biomedicines13020382 - 6 Feb 2025

Viewed by 991

Abstract

Glioma is the most common primary malignant brain tumor, accounting for the majority of brain cancer-related deaths. Considering the limited efficacy of conventional therapies, novel molecular targeted therapies have been developed to improve outcomes and minimize toxicity. Glucose-regulated protein 78 (GRP78), a molecular chaperone primarily localized in the endoplasmic reticulum (ER), has received increasing attention for its role in glioma progression and resistance to conventional therapies. Overexpressed in gliomas, GRP78 supports tumor growth, survival, and therapeutic resistance by maintaining cellular homeostasis and regulating multiple signaling pathways. Its aberrant expression correlates with higher tumor grades and poorer patient prognosis. Beyond its intracellular functions, GRP78’s presence on the cell surface and its role in the tumor microenvironment underscore its potential as a therapeutic target. Recent studies have explored innovative strategies to target GRP78, including small molecule inhibitors, monoclonal antibodies, and chimeric antigen receptor (CAR) T cell therapy, showing significant potential in glioma treatment. This review explores the biological characteristics of GRP78, its role in glioma pathophysiology, and the potential of GRP78-targeted therapy as a novel strategy to overcome treatment resistance and improve clinical outcomes. GRP78-targeted therapy, either alone or in combination with conventional treatments, could be a novel and attractive strategy for future glioma treatment. Full article

(This article belongs to the Special Issue Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies)

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16 pages, 1722 KiB

Open AccessReview

Modulation of the Immune Environment in Glioblastoma by the Gut Microbiota

by George B. H. Green, Alexis N. Cox-Holmes, Anna Claire E. Potier, Gillian H. Marlow and Braden C. McFarland

Biomedicines 2024, 12(11), 2429; https://doi.org/10.3390/biomedicines12112429 - 23 Oct 2024

Cited by 3 | Viewed by 2176

Abstract

Studies increasingly support the role of the gut microbiota in glioma development and treatment, although the exact mechanisms remain unclear. Research indicates that the gut microbiota can influence glioma progression, response to therapies, and the effectiveness of treatments like immunotherapy, with certain microbial compositions being linked to better outcomes. Additionally, the gut microbiota impacts the tumor microenvironment, affecting both tumor growth and the response to treatment. This review will explore glioma, the gut microbiota, and how their interaction shapes glioma development and therapy responses. Additionally, this review examines the influence of gut microbiota metabolites, such as short-chain fatty acids (SCFAs) and tryptophan, on glioma development and treatment. It also explores gut microbiome signaling via pattern recognition receptors, and the role of molecular mimicry between microbial and tumor antigens in glioblastoma, and if these interactions affect glioma development and treatment. Full article

(This article belongs to the Special Issue Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies)

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18 pages, 1340 KiB

Open AccessReview

Deep Learning for MRI Segmentation and Molecular Subtyping in Glioblastoma: Critical Aspects from an Emerging Field

by Marta Bonada, Luca Francesco Rossi, Giovanni Carone, Flavio Panico, Fabio Cofano, Pietro Fiaschi, Diego Garbossa, Francesco Di Meco and Andrea Bianconi

Biomedicines 2024, 12(8), 1878; https://doi.org/10.3390/biomedicines12081878 - 16 Aug 2024

Cited by 11 | Viewed by 1548

Abstract

Deep learning (DL) has been applied to glioblastoma (GBM) magnetic resonance imaging (MRI) assessment for tumor segmentation and inference of molecular, diagnostic, and prognostic information. We comprehensively overviewed the currently available DL applications, critically examining the limitations that hinder their broader adoption in clinical practice and molecular research. Technical limitations to the routine application of DL include the qualitative heterogeneity of MRI, related to different machinery and protocols, and the absence of informative sequences, possibly compensated by artificial image synthesis. Moreover, taking advantage from the available benchmarks of MRI, algorithms should be trained on large amounts of data. Additionally, the segmentation of postoperative imaging should be further addressed to limit the inaccuracies previously observed for this task. Indeed, molecular information has been promisingly integrated in the most recent DL tools, providing useful prognostic and therapeutic information. Finally, ethical concerns should be carefully addressed and standardized to allow for data protection. DL has provided reliable results for GBM assessment concerning MRI analysis and segmentation, but the routine clinical application is still limited. The current limitations could be prospectively addressed, giving particular attention to data collection, introducing new technical advancements, and carefully regulating ethical issues. Full article

(This article belongs to the Special Issue Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies)

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15 pages, 1447 KiB

Open AccessReview

Microbubble-Enhanced Focused Ultrasound for Infiltrating Gliomas

by Alexandra A. Seas, Adarsha P. Malla, Nima Sharifai, Jeffrey A. Winkles, Graeme F. Woodworth and Pavlos Anastasiadis

Biomedicines 2024, 12(6), 1230; https://doi.org/10.3390/biomedicines12061230 - 1 Jun 2024

Cited by 4 | Viewed by 2103

Abstract

Infiltrating gliomas are challenging to treat, as the blood-brain barrier significantly impedes the success of therapeutic interventions. While some clinical trials for high-grade gliomas have shown promise, patient outcomes remain poor. Microbubble-enhanced focused ultrasound (MB-FUS) is a rapidly evolving technology with demonstrated safety and efficacy in opening the blood-brain barrier across various disease models, including infiltrating gliomas. Initially recognized for its role in augmenting drug delivery, the potential of MB-FUS to augment liquid biopsy and immunotherapy is gaining research momentum. In this review, we will highlight recent advancements in preclinical and clinical studies that utilize focused ultrasound to treat gliomas and discuss the potential future uses of image-guided precision therapy using focused ultrasound. Full article

(This article belongs to the Special Issue Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies)

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