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16 pages, 2930 KiB

Open AccessArticle

Morphological and Molecular Biological Characteristics of Experimental Rat Glioblastoma Tissue Strains Induced by Different Carcinogenic Chemicals

by Alexandra Sentyabreva, Ekaterina Miroshnichenko, Daria Artemova, Anna Alekseeva and Anna Kosyreva

Biomedicines 2024, 12(4), 713; https://doi.org/10.3390/biomedicines12040713 - 22 Mar 2024

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Abstract

Glioblastoma (GBM) is a highly aggressive human neoplasm with poor prognosis due to its malignancy and therapy resistance. To evaluate the efficacy of antitumor therapy, cell models are used most widely, but they are not as relevant to human GBMs as tissue models [...] Read more.

Glioblastoma (GBM) is a highly aggressive human neoplasm with poor prognosis due to its malignancy and therapy resistance. To evaluate the efficacy of antitumor therapy, cell models are used most widely, but they are not as relevant to human GBMs as tissue models of gliomas, closely corresponding to human GBMs in cell heterogeneity. In this work, we compared three different tissue strains of rat GBM 101.8 (induced by DMBA), GBM 11-9-2, and GBM 14-4-5 (induced by ENU). Materials and methods: We estimated different gene expressions by qPCR-RT and conducted Western blotting and histological and morphometric analysis of three different tissue strains of rat GBM. Results: GBM 101.8 was characterized by the shortest period of tumor growth and the greatest number of necroses and mitoses; overexpression of Abcb1, Sox2, Cdkn2a, Cyclin D, and Trp53; and downregulated expression of Vegfa, Pdgfra, and Pten; as well as a high level of HIF-1α protein content. GBM 11-9-2 and GBM 14-4-5 were relevant to low-grade gliomas and characterized by downregulated Mgmt expression; furthermore, a low content of CD133 protein was found in GBM 11-9-2. Conclusions: GBM 101.8 is a reliable model for further investigation due to its similarity to high-grade human GBMs, while GBM 11-9-2 and GBM 14-4-5 correspond to Grade 2–3 gliomas. Full article

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

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20 pages, 7227 KiB

Open AccessArticle

SRPK1 Promotes Glioma Proliferation, Migration, and Invasion through Activation of Wnt/β-Catenin and JAK-2/STAT-3 Signaling Pathways

by Mengna Shi, Dan Sun, Lu Deng, Jing Liu and Min-Jie Zhang

Biomedicines 2024, 12(2), 378; https://doi.org/10.3390/biomedicines12020378 - 06 Feb 2024

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Abstract

Currently, the treatment of gliomas still relies primarily on surgery and radiochemotherapy. Although there are various drugs available, including temozolomide, the overall therapeutic effect is unsatisfactory, and the prognosis remains poor. Therefore, the in-depth study of the mechanism of glioma development and a [...] Read more.

Currently, the treatment of gliomas still relies primarily on surgery and radiochemotherapy. Although there are various drugs available, including temozolomide, the overall therapeutic effect is unsatisfactory, and the prognosis remains poor. Therefore, the in-depth study of the mechanism of glioma development and a search for new therapeutic targets are the keys to improving the therapeutic treatment of gliomas and improving the prognosis of patients. Immunohistochemistry is used to detect the expression of relevant molecules in tissues, qPCR and Western blot are used to detect the mRNA and protein expression of relevant molecules, CCK-8 (Cell Counting Kit-8) is used to assess cell viability and proliferation capacity, Transwell is used to evaluate cell migration and invasion ability, and RNA transcriptome sequencing is used to identify the most influential pathways. SRPK1 (SRSF protein kinase 1) is highly expressed in gliomas but is not expressed in normal tissues. Its expression is positively correlated with the grades of gliomas and negatively correlated with prognosis. SRPK1 significantly promotes the occurrence and development of gliomas. Knocking down SRPK1 leads to a significant decrease in the proliferation, migration, and invasion abilities of gliomas. Loss of SRPK1 expression induces G2/M phase arrest and mitotic catastrophe, leading to apoptosis in cells. Overexpression of SRPK1 activates the Wnt/β-catenin (wingless-int1/β-catenin) and JAK-2/STAT-3 (Janus kinase 2/signal transducer and activator of transcription 3) signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Overexpression of SRPK1 rescues the reduced cell proliferation, migration, and invasion abilities caused by the silencing of β-catenin or JAK-2. A stable shRNA-LN229 cell line was constructed, and using a nude mouse model, it was found that stable knockout of SRPK1 significantly reduced the tumorigenic ability of glioma cells, as evidenced by a significant decrease in the subcutaneous tumor volume and weight in nude mice. We have demonstrated that SRPK1 is highly expressed in gliomas. Overexpression of SRPK1 activates the Wnt/β-catenin and JAK-2/STAT-3 signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Silencing SRPK1-related signaling pathways may provide potential therapeutic options for glioma patients. Full article

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

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21 pages, 2814 KiB

Open AccessArticle

Transforming Growth Factor Beta 2 (TGFB2) and Interferon Gamma Receptor 2 (IFNGR2) mRNA Levels in the Brainstem Tumor Microenvironment (TME) Significantly Impact Overall Survival in Pediatric DMG Patients

by Sanjive Qazi, Zahra Talebi and Vuong Trieu

Biomedicines 2024, 12(1), 191; https://doi.org/10.3390/biomedicines12010191 - 15 Jan 2024

Cited by 1 | Viewed by 1459

Abstract

This hypothesis-generating study characterized the mRNA expression profiles and prognostic impacts of antigen-presenting cell (APC) markers (CD14, CD163, CD86, and ITGAX/CD11c) in pediatric brainstem diffuse midline glioma (pbDMG) tumors. We also assessed the mRNA levels of two therapeutic targets, transforming growth factor beta [...] Read more.

This hypothesis-generating study characterized the mRNA expression profiles and prognostic impacts of antigen-presenting cell (APC) markers (CD14, CD163, CD86, and ITGAX/CD11c) in pediatric brainstem diffuse midline glioma (pbDMG) tumors. We also assessed the mRNA levels of two therapeutic targets, transforming growth factor beta 2 (TGFB2) and interferon gamma receptor 2 (IFNGR2), for their biomarker potentials in these highly aggressive pbDMG tumors. The expressions of CD14, CD163, and ITGAX/CD11c mRNAs exhibited significant decreases of 1.64-fold (p = 0.037), 1.75-fold (p = 0.019), and 3.33-fold (p < 0.0001), respectively, in pbDMG tumors relative to those in normal brainstem/pons samples. The pbDMG samples with high levels of TGFB2 in combination with low levels of APC markers, reflecting the cold immune state of pbDMG tumors, exhibited significantly worse overall survival outcomes at low expression levels of CD14, CD163, and CD86. The expression levels of IFNGR2 and TGFB2 (1.51-fold increase (p = 0.002) and 1.58-fold increase (p = 5.5 × 10⁻⁴), respectively) were significantly upregulated in pbDMG tumors compared with normal brainstem/pons samples. We performed multivariate Cox proportional hazards modelling that showed TGFB2 was a prognostic indicator (HR for patients in the TGFB2^high group of pbDMG patients = 2.88 (1.12–7.39); p = 0.028) for poor overall survival (OS) and was independent of IFNGR2 levels, the age of the patient, and the significant interaction effect observed between IFNGR2 and TGFB2 (p = 0.015). Worse survival outcomes in pbDMG patients when comparing high versus low TGFB2 levels in the context of low IFNGR2 levels suggest that the abrogation of the TGFB2 mRNA expression in the immunologically cold tumor microenvironment can be used to treat pbDMG patients. Furthermore, pbDMG patients with low levels of JAK1 or STAT1 mRNA expression in combination with high levels of TGFB2 also exhibited poor OS outcomes, suggesting that the inclusion of (interferon-gamma) IFN-γ to stimulate and activate JAK1 and STAT1 in anti-tumor APC cells present the brainstem TME can enhance the effect of the TGFB2 blockade. Full article

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

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17 pages, 3989 KiB

Open AccessArticle

Fibronectin Type III Domain Containing 3B as a Potential Prognostic and Therapeutic Biomarker for Glioblastoma

by Hyukjun Kwon, Minji Yun, Taek-Hyun Kwon, Minji Bang, Jungsul Lee, Yeo Song Lee, Hae Young Ko and Kyuha Chong

Biomedicines 2023, 11(12), 3168; https://doi.org/10.3390/biomedicines11123168 - 28 Nov 2023

Cited by 1 | Viewed by 906

Abstract

Glioblastoma (GBM) is a representative malignant brain tumor characterized by a dismal prognosis, with survival rates of less than 2 years and high recurrence rates. Despite surgical resection and several alternative treatments, GBM remains a refractory disease due to its aggressive invasiveness and [...] Read more.

Glioblastoma (GBM) is a representative malignant brain tumor characterized by a dismal prognosis, with survival rates of less than 2 years and high recurrence rates. Despite surgical resection and several alternative treatments, GBM remains a refractory disease due to its aggressive invasiveness and resistance to anticancer therapy. In this report, we explore the role of fibronectin type III domain containing 3B (FNDC3B) and its potential as a prognostic and therapeutic biomarker in GBM. GBM exhibited a significantly higher cancer-to-normal ratio compared to other organs, and patients with high FNDC3B expression had a poor prognosis (p < 0.01). In vitro studies revealed that silencing FNDC3B significantly reduced the expression of Survivin, an apoptosis inhibitor, and also reduced cell migration, invasion, extracellular matrix adhesion ability, and stem cell properties in GBM cells. Furthermore, we identified that FNDC3B regulates PTEN/PI3K/Akt signaling in GBM cells using MetaCore integrated pathway bioinformatics analysis and a proteome profiler phospho-kinase array with sequential western blot analysis. Collectively, our findings suggest FNDC3B as a potential biomarker for predicting GBM patient survival and for the development of treatment strategies for GBM. Full article

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

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12 pages, 1464 KiB

Open AccessArticle

From Pediatric to Adult Brain Cancer: Exploring Histone H3 Mutations in Australian Brain Cancer Patients

by Benedicte Grebstad Tune, Heena Sareen, Branka Powter, Smadar Kahana-Edwin, Adam Cooper, Eng-Siew Koh, Cheok S. Lee, Joseph W. Po, Geoff McCowage, Mark Dexter, Lucy Cain, Geraldine O’Neill, Victoria Prior, Jonathan Karpelowsky, Maria Tsoli, Lars O. Baumbusch, David Ziegler, Tara L. Roberts, Paul DeSouza, Therese M. Becker and Yafeng Ma Show full author list Hide full author list

Biomedicines 2023, 11(11), 2907; https://doi.org/10.3390/biomedicines11112907 - 27 Oct 2023

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Abstract

Genetic histone variants have been implicated in cancer development and progression. Mutations affecting the histone 3 (H3) family, H3.1 (encoded by HIST1H3B and HIST1H3C) and H3.3 (encoded by H3F3A), are mainly associated with pediatric brain cancers. While considered poor prognostic brain [...] Read more.

Genetic histone variants have been implicated in cancer development and progression. Mutations affecting the histone 3 (H3) family, H3.1 (encoded by HIST1H3B and HIST1H3C) and H3.3 (encoded by H3F3A), are mainly associated with pediatric brain cancers. While considered poor prognostic brain cancer biomarkers in children, more recent studies have reported H3 alterations in adult brain cancer as well. Here, we established reliable droplet digital PCR based assays to detect three histone mutations (H3.3-K27M, H3.3-G34R, and H3.1-K27M) primarily linked to childhood brain cancer. We demonstrate the utility of our assays for sensitively detecting these mutations in cell-free DNA released from cultured diffuse intrinsic pontine glioma (DIPG) cells and in the cerebral spinal fluid of a pediatric patient with DIPG. We further screened tumor tissue DNA from 89 adult patients with glioma and 1 with diffuse hemispheric glioma from Southwestern Sydney, Australia, an ethnically diverse region, for these three mutations. No histone mutations were detected in adult glioma tissue, while H3.3-G34R presence was confirmed in the diffuse hemispheric glioma patient. Full article

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

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18 pages, 3812 KiB

Open AccessArticle

Pharmacological Akt and JNK Kinase Inhibitors 10-DEBC and SP600125 Potentiate Anti-Glioblastoma Effect of Menadione and Ascorbic Acid Combination in Human U251 Glioblastoma Cells

by Ana Despotović, Kristina Janjetović, Nevena Zogović and Gordana Tovilović-Kovačević

Biomedicines 2023, 11(10), 2652; https://doi.org/10.3390/biomedicines11102652 - 27 Sep 2023

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Abstract

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults, characterized by a highly invasive nature and therapy resistance. Combination of menadione and ascorbic acid (AA+MD) exerts strong ROS-mediated anti-GBM activity in vitro. The objective of this study was to improve [...] Read more.

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults, characterized by a highly invasive nature and therapy resistance. Combination of menadione and ascorbic acid (AA+MD) exerts strong ROS-mediated anti-GBM activity in vitro. The objective of this study was to improve AA+MD anti-GBM potential by modulating the activity of Akt and c-Jun N-terminal kinase (JNK), molecules with an important role in GBM development. The effects of Akt and JNK modulation on AA+MD toxicity in U251 human glioblastoma cells were assessed by cell viability assays, flow cytometry, RNA interference and plasmid overexpression, and immunoblot analysis. The AA+MD induced severe oxidative stress, an early increase in Akt phosphorylation followed by its strong inhibition, persistent JNK activation, and U251 cell death. Small molecule Akt kinase inhibitor 10-DEBC enhanced, while pharmacological and genetic Akt activation decreased, AA+MD-induced toxicity. The U251 cell death potentiation by 10-DEBC correlated with an increase in the combination-induced autophagic flux and was abolished by genetic autophagy silencing. Additionally, pharmacological JNK inhibitor SP600125 augmented combination toxicity toward U251 cells, an effect linked with increased ROS accumulation. These results indicate that small Akt and JNK kinase inhibitors significantly enhance AA+MD anti-GBM effects by autophagy potentiation and amplifying deleterious ROS levels. Full article

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

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18 pages, 15138 KiB

Open AccessArticle

Post-Surgical Depositions of Blood Products Are No Major Confounder for the Diagnostic and Prognostic Performance of CEST MRI in Patients with Glioma

by Nikolaus von Knebel Doeberitz, Florian Kroh, Laila König, Philip S. Boyd, Svenja Graß, Cora Bauspieß, Moritz Scherer, Andreas Unterberg, Martin Bendszus, Wolfgang Wick, Peter Bachert, Jürgen Debus, Mark E. Ladd, Heinz-Peter Schlemmer, Steffen Goerke, Andreas Korzowski and Daniel Paech

Biomedicines 2023, 11(9), 2348; https://doi.org/10.3390/biomedicines11092348 - 23 Aug 2023

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Abstract

Amide proton transfer (APT) and semi-solid magnetization transfer (ssMT) imaging can predict clinical outcomes in patients with glioma. However, the treatment of brain tumors is accompanied by the deposition of blood products within the tumor area in most cases. For this reason, the [...] Read more.

Amide proton transfer (APT) and semi-solid magnetization transfer (ssMT) imaging can predict clinical outcomes in patients with glioma. However, the treatment of brain tumors is accompanied by the deposition of blood products within the tumor area in most cases. For this reason, the objective was to assess whether the diagnostic interpretation of the APT and ssMT is affected by methemoglobin (mHb) and hemosiderin (Hs) depositions at the first follow-up MRI 4 to 6 weeks after the completion of radiotherapy. A total of 34 participants underwent APT and ssMT imaging by applying reconstruction methods described by Zhou et al. (APTw_asym), Goerke et al. (MTR_RexAPT and MTR_RexMT) and Mehrabian et al. (MT_const). Contrast-enhancing tumor (CE), whole tumor (WT), mHb and Hs were segmented on contrast-enhanced T₁w_CE, T₂w-FLAIR, T₁w and T₂*w images. ROC-analysis, Kaplan–Meier analysis and the log rank test were used to test for the association of mean contrast values with therapy response and overall survival (OS) before (WT and CE) and after correcting tumor volumes for mHb and Hs (CE_C and WT_C). CE_C showed higher associations of the MTR_RexMT with therapy response (CE: AUC = 0.677, p = 0.081; CE_C: AUC = 0.705, p = 0.044) and of the APTw_asym with OS (CE: HR = 2.634, p = 0.040; CE_C: HR = 2.240, p = 0.095). In contrast, WT_C showed a lower association of the APTw_asym with survival (WT: HR = 2.304, p = 0.0849; WT_C: HR = 2.990, p = 0.020). Overall, a sophisticated correction for blood products did not substantially influence the clinical performance of APT and ssMT imaging in patients with glioma early after radiotherapy. Full article

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

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17 pages, 4006 KiB

Open AccessArticle

Profile Characterization of Biogenic Amines in Glioblastoma Patients Undergoing Standard-of-Care Treatment

by Orwa Aboud, Yin Liu, Lina Dahabiyeh, Ahmad Abuaisheh, Fangzhou Li, John Paul Aboubechara, Jonathan Riess, Orin Bloch, Rawad Hodeify, Ilias Tagkopoulos and Oliver Fiehn

Biomedicines 2023, 11(8), 2261; https://doi.org/10.3390/biomedicines11082261 - 13 Aug 2023

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Abstract

Introduction: Biogenic amines play important roles throughout cellular metabolism. This study explores a role of biogenic amines in glioblastoma pathogenesis. Here, we characterize the plasma levels of biogenic amines in glioblastoma patients undergoing standard-of-care treatment. Methods: We examined 138 plasma samples from 36 [...] Read more.

Introduction: Biogenic amines play important roles throughout cellular metabolism. This study explores a role of biogenic amines in glioblastoma pathogenesis. Here, we characterize the plasma levels of biogenic amines in glioblastoma patients undergoing standard-of-care treatment. Methods: We examined 138 plasma samples from 36 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma at multiple stages of treatment. Untargeted gas chromatography–time of flight mass spectrometry (GC-TOF MS) was used to measure metabolite levels. Machine learning approaches were then used to develop a predictive tool based on these datasets. Results: Surgery was associated with increased levels of 12 metabolites and decreased levels of 11 metabolites. Chemoradiation was associated with increased levels of three metabolites and decreased levels of three other metabolites. Ensemble learning models, specifically random forest (RF) and AdaBoost (AB), accurately classified treatment phases with high accuracy (RF: 0.81 ± 0.04, AB: 0.78 ± 0.05). The metabolites sorbitol and N-methylisoleucine were identified as important predictive features and confirmed via SHAP. Conclusion: To our knowledge, this is the first study to describe plasma biogenic amine signatures throughout the treatment of patients with glioblastoma. A larger study is needed to confirm these results with hopes of developing a diagnostic algorithm. Full article

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

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23 pages, 3830 KiB

Open AccessArticle

Metabolic Profiles Point Out Metabolic Pathways Pivotal in Two Glioblastoma (GBM) Cell Lines, U251 and U-87MG

by Filipa Martins, David van der Kellen, Luís G. Gonçalves and Jacinta Serpa

Biomedicines 2023, 11(7), 2041; https://doi.org/10.3390/biomedicines11072041 - 20 Jul 2023

Cited by 1 | Viewed by 1335

Abstract

Glioblastoma (GBM) is the most lethal central nervous system (CNS) tumor, mainly due to its high heterogeneity, invasiveness, and proliferation rate. These tumors remain a therapeutic challenge, and there are still some gaps in the GBM biology literature. Despite the significant amount of [...] Read more.

Glioblastoma (GBM) is the most lethal central nervous system (CNS) tumor, mainly due to its high heterogeneity, invasiveness, and proliferation rate. These tumors remain a therapeutic challenge, and there are still some gaps in the GBM biology literature. Despite the significant amount of knowledge produced by research on cancer metabolism, its implementation in cancer treatment has been limited. In this study, we explored transcriptomics data from the TCGA database to provide new insights for future definition of metabolism-related patterns useful for clinical applications. Moreover, we investigated the impact of key metabolites (glucose, lactate, glutamine, and glutamate) in the gene expression and metabolic profile of two GBM cell lines, U251 and U-87MG, together with the impact of these organic compounds on malignancy cell features. GBM cell lines were able to adapt to the exposure to each tested organic compound. Both cell lines fulfilled glycolysis in the presence of glucose and were able to produce and consume lactate. Glutamine dependency was also highlighted, and glutamine and glutamate availability favored biosynthesis observed by the increase in the expression of genes involved in fatty acid (FA) synthesis. These findings are relevant and point out metabolic pathways to be targeted in GBM and also reinforce that patients’ metabolic profiling can be useful in terms of personalized medicine. Full article

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

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8 pages, 1147 KiB

Open AccessCommunication

PSMA Expression Correlates with Improved Overall Survival and VEGF Expression in Glioblastoma

by Alexander Yuile, Adrian Lee, Elizabeth A. Moon, Amanda Hudson, Marina Kastelan, Samuel Miller, David Chan, Joe Wei, Michael F. Back and Helen R. Wheeler

Biomedicines 2023, 11(4), 1148; https://doi.org/10.3390/biomedicines11041148 - 11 Apr 2023

Cited by 1 | Viewed by 1454

Abstract

Background: Glioblastomas are the most common and fatal primary brain malignancy in adults. There is a growing interest in identifying the molecular mechanisms of these tumors to develop novel treatments. Glioblastoma neo-angiogenesis is driven by VEGF, and another potential molecule linked to angiogenesis [...] Read more.

Background: Glioblastomas are the most common and fatal primary brain malignancy in adults. There is a growing interest in identifying the molecular mechanisms of these tumors to develop novel treatments. Glioblastoma neo-angiogenesis is driven by VEGF, and another potential molecule linked to angiogenesis is PSMA. Our study suggests the potential for an association between PSMA and VEGF expression in glioblastoma neo-vasculature. Methods: Archived IDH1/2 wild-type glioblastomas were accessed; demographic and clinical outcomes were recorded. PSMA and VEGF expression by IHC were examined. Patients were dichotomized into PSMA expression high (3+) and low (0–2+) groups. The association between PSMA and VEGF expression was evaluated using Chi² analysis. OS in PSMA high and low expression groups were compared using multi-linear regression. Results: In total, 247 patients with IDH1/2 wild-type glioblastoma with archival tumor samples (between 2009–2014) were examined. PSMA expression correlated positively with VEGF expression (p = 0.01). We detected a significant difference in median OS between PSMA vascular endothelial expression high and low groups—16.1 and 10.8 months, respectively (p = 0.02). Conclusion: We found a potential positive correlation between PSMA and VEGF expression. Secondly, we showed a potential positive correlation between PSMA expression and overall survival. Full article

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

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12 pages, 3247 KiB

Open AccessArticle

Characterization of Inflammatory Signals in BV-2 Microglia in Response to Wnt3a

by Cheng Li, Ying Wu, Ming-Yue Huang and Xue-Jun Song

Biomedicines 2023, 11(4), 1121; https://doi.org/10.3390/biomedicines11041121 - 07 Apr 2023

Cited by 1 | Viewed by 1569

Abstract

Activation of microglia is one of the pathological bases of neuroinflammation, which involves various diseases of the central nervous system. Inhibiting the inflammatory activation of microglia is a therapeutic approach to neuroinflammation. In this study, we report that activation of the Wnt/β-catenin signaling [...] Read more.

Activation of microglia is one of the pathological bases of neuroinflammation, which involves various diseases of the central nervous system. Inhibiting the inflammatory activation of microglia is a therapeutic approach to neuroinflammation. In this study, we report that activation of the Wnt/β-catenin signaling pathway in a model of neuroinflammation in Lipopolysaccharide (LPS)/IFN-γ-stimulated BV-2 cells can result in inhibition of production of nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Activation of the Wnt/β-catenin signaling pathway also results in inhibition of the phosphorylation of nuclear factor-κB (NF-κB) and extracellular signal-regulated kinase (ERK) in the LPS/IFN-γ-stimulated BV-2 cells. These findings indicate that activation of the Wnt/β-catenin signaling pathway can inhibit neuroinflammation through downregulating the pro-inflammatory cytokines including iNOS, TNF-α, and IL-6, and suppress NF-κB/ERK-related signaling pathways. In conclusion, this study indicates that the Wnt/β-catenin signaling activation may play an important role in neuroprotection in certain neuroinflammatory diseases. Full article

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

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17 pages, 8626 KiB

Open AccessArticle

Integrative Analysis of the Predictive Value of Perilipin Family on Clinical Significance, Prognosis and Immunotherapy of Glioma

by Xuanxuan Li, Kuo Kang, Lin Shen, Liangfang Shen and Yangying Zhou

Biomedicines 2023, 11(4), 1009; https://doi.org/10.3390/biomedicines11041009 - 24 Mar 2023

Cited by 1 | Viewed by 1315

Abstract

Gliomas are common tumors of the central nervous system. The PLINs family is widely involved in the regulation of lipid metabolism and has been associated with the development and invasive metastasis of various malignancies. However, the biological role of the PLINs family in [...] Read more.

Gliomas are common tumors of the central nervous system. The PLINs family is widely involved in the regulation of lipid metabolism and has been associated with the development and invasive metastasis of various malignancies. However, the biological role of the PLINs family in gliomas is still unclear. TIMER and UALCAN were used to assess PLINs mRNA expression in gliomas. “Survminer” and “Survival” were used to evaluate the connection between PLINs expression and glioma patients’ survival. cBioPortal was applied to assess PLINs’ genetic alterations in glioblastoma multiforme (GBM) and low-grade glioma (LGG). The correlation of PLINs expression with tumor immune cells was analyzed by TIMER. The expressions of PLIN1, PLIN4, and PLIN5 were decreased in GBM compared to normal tissues. However, PLIN2 and PLIN3 were significantly increased in GBM. Prognostic analysis showed that LGG patients with high PLIN1 expression had better overall survival (OS), and high expression of PLIN2/3/4/5 was associated with unfavorable OS. We further determined that the expression of PLINs members in gliomas was strongly related to tumor immune cells and immune checkpoint-associated genes. PLINS may be potential biomarkers for regulating the tumor microenvironment and predicting the efficacy of immunotherapy. In addition, we determined that PLIN1 may affect glioma patients’ therapeutic sensitivity to temozolomide. Our results demonstrated the biological significance and clinical values of PLINs in gliomas and provide a basis for future in-depth exploration of the specific mechanisms of each member of PLINs in gliomas. Full article

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

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11 pages, 529 KiB

Open AccessArticle

The Current State of Adult Glial Tumor Patients’ Care in Kazakhstan: Challenges in Diagnosis and Patterns in Survival Outcomes

by Aisha Babi, Karashash Menlibayeva, Torekhan Bex, Shynar Kuandykova and Serik Akshulakov

Biomedicines 2023, 11(3), 886; https://doi.org/10.3390/biomedicines11030886 - 13 Mar 2023

Cited by 2 | Viewed by 1182

Abstract

Background: The study aimed to analyze the 5-year survival of adult patients with glial tumors and to define characteristics that are associated with the disease outcomes in Kazakhstan. Methods: Medical records of patients that were surgically treated at the National Center for Neurosurgery [...] Read more.

Background: The study aimed to analyze the 5-year survival of adult patients with glial tumors and to define characteristics that are associated with the disease outcomes in Kazakhstan. Methods: Medical records of patients that were surgically treated at the National Center for Neurosurgery during the 5-year period from 2016 to 2020 were collected retrospectively. Patients with a histologically confirmed diagnosis of diffuse astrocytic or oligodendroglial tumor type were included and their survival was assessed with life tables, Kaplan–Meier plot, and Cox regression using STATA 16 statistical software. Results: Almost half of the patients had glioblastoma. The 5-year survival rate of the whole sample was 45.93%. Among Grade 4 patients, 15.6% survived the 5-year mark. Differences in survival between grades 1–3 were not significant. Grade 1 patients demonstrated worse survival rates compared to Grade 2 patients (69% vs. 74%). Worse survival rates were observed among patients of Russian ethnicity and in rural residents. Conclusions: The study described the unusual patterns in survival rates of glial tumor patients in Kazakhstan, pointing to the need for reassessment of diagnostic accuracy and resulting treatment of glial patients in Kazakhstan, and the need to introduce molecular and genetic parameters in tumor type classification. Moreover, the observed difference in survival of different ethnic groups and residents of rural and urban areas should be further investigated and addressed by healthcare professionals. Full article

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

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21 pages, 6506 KiB

Open AccessArticle

Effect of Polyunsaturated Fatty Acids on Temozolomide Drug-Sensitive and Drug-Resistant Glioblastoma Cells

by Janaína Alessandra Silva and Alison Colquhoun

Biomedicines 2023, 11(3), 779; https://doi.org/10.3390/biomedicines11030779 - 04 Mar 2023

Cited by 2 | Viewed by 1804

Abstract

Glioblastomas (GBMs) are notoriously difficult to treat, and the development of multiple drug resistance (MDR) is common during the course of the disease. The polyunsaturated fatty acids (PUFAs) gamma-linolenic acid (GLA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have been reported to improve [...] Read more.

Glioblastomas (GBMs) are notoriously difficult to treat, and the development of multiple drug resistance (MDR) is common during the course of the disease. The polyunsaturated fatty acids (PUFAs) gamma-linolenic acid (GLA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have been reported to improve MDR in several tumors including breast, bladder, and leukaemia. However, the effects of PUFAs on GBM cell MDR are poorly understood. The present study investigated the effects of PUFAs on cellular responses to temozolomide (TMZ) in U87MG cells and the TMZ-resistant (TMZR) cells derived from U87MG. Cells were treated with PUFAs in the absence or presence of TMZ and dose–response, viable cell counting, gene expression, Western blotting, flow cytometry, gas chromatography-mass spectrometry (GCMS), and drug efflux studies were performed. The development of TMZ resistance caused an increase in ABC transporter ABCB1 and ABCC1 expression. GLA-, EPA-, and DHA-treated cells had altered fatty acid composition and accumulated lipid droplets in the cytoplasm. The most significant reduction in cell growth was seen for the U87MG and TMZR cells in the presence of EPA. GLA and EPA caused more significant effects on ABC transporter expression than DHA. GLA and EPA in combination with TMZ caused significant reductions in rhodamine 123 efflux from U87MG cells but not from TMZR cells. Overall, these findings support the notion that PUFAs can modulate ABC transporters in GBM cells. Full article

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

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Review

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25 pages, 1803 KiB

Open AccessReview

CRISPR/Cas9-Mediated Gene Therapy for Glioblastoma: A Scoping Review

by Emir Begagić, Hakija Bečulić, Nermin Đuzić, Amina Džidić-Krivić, Ragib Pugonja, Asja Muharemović, Belma Jaganjac, Naida Salković, Haso Sefo and Mirza Pojskić

Biomedicines 2024, 12(1), 238; https://doi.org/10.3390/biomedicines12010238 - 21 Jan 2024

Cited by 1 | Viewed by 1721

Abstract

This scoping review examines the use of CRISPR/Cas9 gene editing in glioblastoma (GBM), a predominant and aggressive brain tumor. Categorizing gene targets into distinct groups, this review explores their roles in cell cycle regulation, microenvironmental dynamics, interphase processes, and therapy resistance reduction. The [...] Read more.

This scoping review examines the use of CRISPR/Cas9 gene editing in glioblastoma (GBM), a predominant and aggressive brain tumor. Categorizing gene targets into distinct groups, this review explores their roles in cell cycle regulation, microenvironmental dynamics, interphase processes, and therapy resistance reduction. The complexity of CRISPR-Cas9 applications in GBM research is highlighted, providing unique insights into apoptosis, cell proliferation, and immune responses within the tumor microenvironment. The studies challenge conventional perspectives on specific genes, emphasizing the potential therapeutic implications of manipulating key molecular players in cell cycle dynamics. Exploring CRISPR/Cas9 gene therapy in GBMs yields significant insights into the regulation of cellular processes, spanning cell interphase, renewal, and migration. Researchers, by precisely targeting specific genes, uncover the molecular orchestration governing cell proliferation, growth, and differentiation during critical phases of the cell cycle. The findings underscore the potential of CRISPR/Cas9 technology in unraveling the complex dynamics of the GBM microenvironment, offering promising avenues for targeted therapies to curb GBM growth. This review also outlines studies addressing therapy resistance in GBM, employing CRISPR/Cas9 to target genes associated with chemotherapy resistance, showcasing its transformative potential in effective GBM treatments. Full article

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

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33 pages, 1717 KiB

Open AccessReview

Cellular Components of the Tumor Environment in Gliomas—What Do We Know Today?

by Reinhold Nafe and Elke Hattingen

Biomedicines 2024, 12(1), 14; https://doi.org/10.3390/biomedicines12010014 - 20 Dec 2023

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Abstract

A generation ago, the molecular properties of tumor cells were the focus of scientific interest in oncology research. Since then, it has become increasingly apparent that the tumor environment (TEM), whose major components are non-neoplastic cell types, is also of utmost importance for [...] Read more.

A generation ago, the molecular properties of tumor cells were the focus of scientific interest in oncology research. Since then, it has become increasingly apparent that the tumor environment (TEM), whose major components are non-neoplastic cell types, is also of utmost importance for our understanding of tumor growth, maintenance and resistance. In this review, we present the current knowledge concerning all cellular components within the TEM in gliomas, focusing on their molecular properties, expression patterns and influence on the biological behavior of gliomas. Insight into the TEM of gliomas has expanded considerably in recent years, including many aspects that previously received only marginal attention, such as the phenomenon of phagocytosis of glioma cells by macrophages and the role of the thyroid-stimulating hormone on glioma growth. We also discuss other topics such as the migration of lymphocytes into the tumor, phenotypic similarities between chemoresistant glioma cells and stem cells, and new clinical approaches with immunotherapies involving the cells of TEM. Full article

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

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16 pages, 1829 KiB

Open AccessReview

Peritumoral Edema in Gliomas: A Review of Mechanisms and Management

by Kazufumi Ohmura, Hiroyuki Tomita and Akira Hara

Biomedicines 2023, 11(10), 2731; https://doi.org/10.3390/biomedicines11102731 - 09 Oct 2023

Cited by 5 | Viewed by 2687

Abstract

Treating malignant glioma is challenging owing to its highly invasive potential in healthy brain tissue and the formation of intense surrounding edema. Peritumoral edema in gliomas can lead to severe symptoms including neurological dysfunction and brain herniation. For the past 50 years, the [...] Read more.

Treating malignant glioma is challenging owing to its highly invasive potential in healthy brain tissue and the formation of intense surrounding edema. Peritumoral edema in gliomas can lead to severe symptoms including neurological dysfunction and brain herniation. For the past 50 years, the standard treatment for peritumoral edema has been steroid therapy. However, the discovery of cerebral lymphatic vessels a decade ago prompted a re-evaluation of the mechanisms involved in brain fluid regulation and the formation of cerebral edema. This review aimed to describe the clinical features of peritumoral edema in gliomas. The mechanisms currently known to cause glioma-related edema are summarized, the limitations in current cerebral edema therapies are discussed, and the prospects for future cerebral edema therapies are presented. Further research concerning edema surrounding gliomas is needed to enhance patient prognosis and improve treatment efficacy. Full article

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

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27 pages, 1304 KiB

Open AccessReview

The Spectrum of Molecular Pathways in Gliomas—An Up-to-Date Review

by Reinhold Nafe and Elke Hattingen

Biomedicines 2023, 11(8), 2281; https://doi.org/10.3390/biomedicines11082281 - 16 Aug 2023

Cited by 2 | Viewed by 1137

Abstract

During the last 20 years, molecular alterations have gained increasing significance in the diagnosis and biological assessment of tumors. Gliomas represent the largest group of tumors of the central nervous system, and the main aim of this review is to present the current [...] Read more.

During the last 20 years, molecular alterations have gained increasing significance in the diagnosis and biological assessment of tumors. Gliomas represent the largest group of tumors of the central nervous system, and the main aim of this review is to present the current knowledge on molecular pathways and their alterations in gliomas. A wide range of new insights has been gained, including evidence for the involvement of the WNT pathway or the hippo pathway in the pathobiology of gliomas, indicating a broad involvement of different pathways formerly not considered to play a central role in gliomas. Even new aspects of angiogenic, apoptotic, and metabolic pathways are presented, as well as the rapidly growing field of epigenetic processes, including non-coding RNAs. The two major conclusions drawn from the present review are the distinct interconnectivity of the whole spectrum of molecular pathways and the prominent role of non-coding RNAs, especially circular RNAs, in the regulation of specific targets. All these new insights are discussed, even considering the topic of the resistance to therapy of gliomas, along with aspects that are still incompletely understood, like the role of hydroxymethylation, or even ferroptosis, in the pathobiology of gliomas. Full article

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

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28 pages, 2774 KiB

Open AccessReview

H3G34-Mutant Gliomas—A Review of Molecular Pathogenesis and Therapeutic Options

by Anthony V. Nguyen, Jose M. Soto, Sarah-Marie Gonzalez, Jennifer Murillo, Eric R. Trumble, Frank Y. Shan and Jason H. Huang

Biomedicines 2023, 11(7), 2002; https://doi.org/10.3390/biomedicines11072002 - 15 Jul 2023

Cited by 2 | Viewed by 1659

Abstract

The 2021 World Health Organization Classification of Tumors of the Central Nervous System reflected advances in understanding of the roles of oncohistones in gliomagenesis with the introduction of the H3.3-G34R/V mutant glioma to the already recognized H3-K27M altered glioma, which represent the diagnoses [...] Read more.

The 2021 World Health Organization Classification of Tumors of the Central Nervous System reflected advances in understanding of the roles of oncohistones in gliomagenesis with the introduction of the H3.3-G34R/V mutant glioma to the already recognized H3-K27M altered glioma, which represent the diagnoses of pediatric-type diffuse hemispheric glioma and diffuse midline glioma, respectively. Despite advances in research regarding these disease entities, the prognosis remains poor. While many studies and clinical trials focus on H3-K27M-altered-glioma patients, those with H3.3-G34R/V mutant gliomas represent a particularly understudied population. Thus, we sought to review the current knowledge regarding the molecular mechanisms underpinning the gliomagenesis of H3.3-G34R/V mutant gliomas and the diagnosis, treatment, long-term outcomes, and possible future therapeutics. Full article

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

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19 pages, 1137 KiB

Open AccessReview

MDM2 Inhibition in the Treatment of Glioblastoma: From Concept to Clinical Investigation

by Karolina I. Pellot Ortiz, Julian S. Rechberger, Leo F. Nonnenbroich, David J. Daniels and Jann N. Sarkaria

Biomedicines 2023, 11(7), 1879; https://doi.org/10.3390/biomedicines11071879 - 02 Jul 2023

Cited by 4 | Viewed by 7576

Abstract

Inhibition of the interaction between MDM2 and p53 has emerged as a promising strategy for combating cancer, including the treatment of glioblastoma (GBM). Numerous MDM2 inhibitors have been developed and are currently undergoing rigorous testing for their potential in GBM therapy. Encouraging results [...] Read more.

Inhibition of the interaction between MDM2 and p53 has emerged as a promising strategy for combating cancer, including the treatment of glioblastoma (GBM). Numerous MDM2 inhibitors have been developed and are currently undergoing rigorous testing for their potential in GBM therapy. Encouraging results from studies conducted in cell culture and animal models suggest that MDM2 inhibitors could effectively treat a specific subset of GBM patients with wild-type TP53 or functional p53. Combination therapy with clinically established treatment modalities such as radiation and chemotherapy offers the potential to achieve a more profound therapeutic response. Furthermore, an increasing array of other molecularly targeted therapies are being explored in combination with MDM2 inhibitors to increase the effects of individual treatments. While some MDM2 inhibitors have progressed to early phase clinical trials in GBM, their efficacy, alone and in combination, is yet to be confirmed. In this article, we present an overview of MDM2 inhibitors currently under preclinical and clinical investigation, with a specific focus on the drugs being assessed in ongoing clinical trials for GBM patients. Full article

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

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19 pages, 1739 KiB

Open AccessReview

Temozolomide Resistance in Glioblastoma by NRF2: Protecting the Evil

by Karoline Almeida Lima, Isabeli Yumi Araújo Osawa, Maria Carolina Clares Ramalho, Izadora de Souza, Camila Banca Guedes, Cláudio Henrique Dahne de Souza Filho, Linda Karolynne Seregni Monteiro, Marcela Teatin Latancia and Clarissa Ribeiro Reily Rocha

Biomedicines 2023, 11(4), 1081; https://doi.org/10.3390/biomedicines11041081 - 03 Apr 2023

Cited by 4 | Viewed by 3029

Abstract

The transcription factor NRF2 is constitutively active in glioblastoma, a highly aggressive brain tumor subtype with poor prognosis. Temozolomide (TMZ) is the primary chemotherapeutic agent for this type of tumor treatment, but resistance to this drug is often observed. This review highlights the [...] Read more.

The transcription factor NRF2 is constitutively active in glioblastoma, a highly aggressive brain tumor subtype with poor prognosis. Temozolomide (TMZ) is the primary chemotherapeutic agent for this type of tumor treatment, but resistance to this drug is often observed. This review highlights the research that is demonstrating how NRF2 hyperactivation creates an environment that favors the survival of malignant cells and protects against oxidative stress and TMZ. Mechanistically, NRF2 increases drug detoxification, autophagy, DNA repair, and decreases drug accumulation and apoptotic signaling. Our review also presents potential strategies for targeting NRF2 as an adjuvant therapy to overcome TMZ chemoresistance in glioblastoma. Specific molecular pathways, including MAPKs, GSK3β, βTRCP, PI3K, AKT, and GBP, that modulate NRF2 expression leading to TMZ resistance are discussed, along with the importance of identifying NRF2 modulators to reverse TMZ resistance and develop new therapeutic targets. Despite the significant progress in understanding the role of NRF2 in GBM, there are still unanswered questions regarding its regulation and downstream effects. Future research should focus on elucidating the precise mechanisms by which NRF2 mediates resistance to TMZ, and identifying potential novel targets for therapeutic intervention. Full article

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

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