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Editorial

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4 pages, 242 KiB

Open AccessEditorial

Glioblastoma Biology, Genetics and Possible Therapies

by Javier S. Castresana and Bárbara Meléndez

Cells 2023, 12(16), 2063; https://doi.org/10.3390/cells12162063 - 14 Aug 2023

Viewed by 951

Abstract

Glioblastoma is the most aggressive intracranial tumor [...] Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma II)

Research

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20 pages, 3675 KiB

Open AccessArticle

Flavonoids Regulate Redox-Responsive Transcription Factors in Glioblastoma and Microglia

by Natali Joma, Issan Zhang, Germanna L. Righetto, Laura McKay, Evan Rizzel Gran, Ashok Kakkar and Dusica Maysinger

Cells 2023, 12(24), 2821; https://doi.org/10.3390/cells12242821 - 12 Dec 2023

Viewed by 1257

Abstract

The tumor microenvironment (TME) has emerged as a valuable therapeutic target in glioblastoma (GBM), as it promotes tumorigenesis via an increased production of reactive oxygen species (ROS). Immune cells such as microglia accumulate near the tumor and its hypoxic core, fostering tumor proliferation [...] Read more.

The tumor microenvironment (TME) has emerged as a valuable therapeutic target in glioblastoma (GBM), as it promotes tumorigenesis via an increased production of reactive oxygen species (ROS). Immune cells such as microglia accumulate near the tumor and its hypoxic core, fostering tumor proliferation and angiogenesis. In this study, we explored the therapeutic potential of natural polyphenols with antioxidant and anti-inflammatory properties. Notably, flavonoids, including fisetin and quercetin, can protect non-cancerous cells while eliminating transformed cells (2D cultures and 3D tumoroids). We tested the hypothesis that fisetin and quercetin are modulators of redox-responsive transcription factors, for which subcellular location plays a critical role. To investigate the sites of interaction between natural compounds and stress-responsive transcription factors, we combined molecular docking with experimental methods employing proximity ligation assays. Our findings reveal that fisetin decreased cytosolic acetylated high mobility group box 1 (acHMGB1) and increased transcription factor EB (TFEB) abundance in microglia but not in GBM. Moreover, our results suggest that the most powerful modulator of the Nrf2-KEAP1 complex is fisetin. This finding is in line with molecular modeling and calculated binding properties between fisetin and Nrf2-KEAP1, which indicated more sites of interactions and stronger binding affinities than quercetin. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma II)

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22 pages, 4110 KiB

Open AccessArticle

Insights into Gene Regulation under Temozolomide-Promoted Cellular Dormancy and Its Connection to Stemness in Human Glioblastoma

by Carolin Kubelt, Dana Hellmold, Daniela Esser, Hajrullah Ahmeti, Michael Synowitz and Janka Held-Feindt

Cells 2023, 12(11), 1491; https://doi.org/10.3390/cells12111491 - 27 May 2023

Cited by 1 | Viewed by 1273

Abstract

The aggressive features of glioblastoma (GBM) are associated with dormancy. Our previous transcriptome analysis revealed that several genes were regulated during temozolomide (TMZ)-promoted dormancy in GBM. Focusing on genes involved in cancer progression, Chemokine (C-C motif) Receptor-Like (CCRL)1, Schlafen (SLFN)13, Sloan-Kettering Institute (SKI), [...] Read more.

The aggressive features of glioblastoma (GBM) are associated with dormancy. Our previous transcriptome analysis revealed that several genes were regulated during temozolomide (TMZ)-promoted dormancy in GBM. Focusing on genes involved in cancer progression, Chemokine (C-C motif) Receptor-Like (CCRL)1, Schlafen (SLFN)13, Sloan-Kettering Institute (SKI), Cdk5 and Abl Enzyme Substrate (Cables)1, and Dachsous Cadherin-Related (DCHS)1 were selected for further validation. All showed clear expression and individual regulatory patterns under TMZ-promoted dormancy in human GBM cell lines, patient-derived primary cultures, glioma stem-like cells (GSCs), and human GBM ex vivo samples. All genes exhibited complex co-staining patterns with different stemness markers and with each other, as examined by immunofluorescence staining and underscored by correlation analyses. Neurosphere formation assays revealed higher numbers of spheres during TMZ treatment, and gene set enrichment analysis of transcriptome data revealed significant regulation of several GO terms, including stemness-associated ones, indicating an association between stemness and dormancy with the involvement of SKI. Consistently, inhibition of SKI during TMZ treatment resulted in higher cytotoxicity, proliferation inhibition, and lower neurosphere formation capacity compared to TMZ alone. Overall, our study suggests the involvement of CCRL1, SLFN13, SKI, Cables1, and DCHS1 in TMZ-promoted dormancy and demonstrates their link to stemness, with SKI being particularly important. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma II)

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20 pages, 20395 KiB

Open AccessArticle

Glycation Leads to Increased Invasion of Glioblastoma Cells

by Paola Schildhauer, Philipp Selke, Christian Scheller, Christian Strauss, Rüdiger Horstkorte, Sandra Leisz and Maximilian Scheer

Cells 2023, 12(9), 1219; https://doi.org/10.3390/cells12091219 - 23 Apr 2023

Cited by 3 | Viewed by 1749

Abstract

Glioblastoma (GBM) is a highly aggressive and invasive brain tumor with a poor prognosis despite extensive treatment. The switch to aerobic glycolysis, known as the Warburg effect, in cancer cells leads to an increased production of methylglyoxal (MGO), a potent glycation agent with [...] Read more.

Glioblastoma (GBM) is a highly aggressive and invasive brain tumor with a poor prognosis despite extensive treatment. The switch to aerobic glycolysis, known as the Warburg effect, in cancer cells leads to an increased production of methylglyoxal (MGO), a potent glycation agent with pro-tumorigenic characteristics. MGO non-enzymatically reacts with proteins, DNA, and lipids, leading to alterations in the signaling pathways, genomic instability, and cellular dysfunction. In this study, we investigated the impact of MGO on the LN229 and U251 (WHO grade IV, GBM) cell lines and the U343 (WHO grade III) glioma cell line, along with primary human astrocytes (hA). The results showed that increasing concentrations of MGO led to glycation, the accumulation of advanced glycation end-products, and decreasing cell viability in all cell lines. The invasiveness of the GBM cell lines increased under the influence of physiological MGO concentrations (0.3 mmol/L), resulting in a more aggressive phenotype, whereas glycation decreased the invasion potential of hA. In addition, glycation had differential effects on the ECM components that are involved in the invasion progress, upregulating TGFβ, brevican, and tenascin C in the GBM cell lines LN229 and U251. These findings highlight the importance of further studies on the prevention of glycation through MGO scavengers or glyoxalase 1 activators as a potential therapeutic strategy against glioma and GBM. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma II)

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21 pages, 5704 KiB

Open AccessArticle

Elucidating the Anti-Tumorigenic Efficacy of Oltipraz, a Dithiolethione, in Glioblastoma

by Upasana Kapoor-Narula and Nibedita Lenka

Cells 2022, 11(19), 3057; https://doi.org/10.3390/cells11193057 - 29 Sep 2022

Cited by 2 | Viewed by 1700

Abstract

Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, displays a highly infiltrative growth pattern and remains refractory to chemotherapy. Phytochemicals carrying specificity and low cytotoxicity may serve as potent and safer alternatives to conventional chemotherapy for treating GBM. We have evaluated the [...] Read more.

Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, displays a highly infiltrative growth pattern and remains refractory to chemotherapy. Phytochemicals carrying specificity and low cytotoxicity may serve as potent and safer alternatives to conventional chemotherapy for treating GBM. We have evaluated the anticancer effects of Oltipraz (Olt), a synthetic dithiolethione found in many vegetables, including crucifers. While Olt exposure was non-toxic to the HEK-293 cell line, it impaired the cell growth in three GBM cell lines (LN18, LN229, and U-87 MG), arresting those at the G2/M phase. Olt-exposed GBM cells induced the generation of reactive oxygen species (ROS), mitochondrial depolarization, caspase 3/7-mediated apoptosis, nuclear condensation, and DNA fragmentation, and decreased glutathione, a natural ROS scavenger, as well as vimentin and β-catenin, the EMT-associated markers. Its effect on a subpopulation of GBM cells exhibiting glioblastoma stem cell (GSCs)-like characteristics revealed a reduced expression of Oct4, Sox2, CD133, CD44, and a decrease in ALDH⁺, Nestin⁺ and CD44⁺ cells. In contrast, there was an increase in the expression of GFAP and GFAP⁺ cells. The Olt also significantly suppressed the oncosphere-forming ability of cells. Its efficacy was further validated in vivo, wherein oral administration of Olt could suppress the ectopically established GBM tumor growth in SCID mice. However, there was no alteration in body weight, organ ratio, and biochemical parameters, reflecting the absence of any toxicity otherwise. Together, our findings could demonstrate the promising chemotherapeutic efficacy of Olt with potential implications in treating GBM. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma II)

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14 pages, 2763 KiB

Open AccessArticle

The Glycoprotein M6a Is Associated with Invasiveness and Radioresistance of Glioblastoma Stem Cells

by Marie Geraldine Lacore, Caroline Delmas, Yvan Nicaise, Aline Kowalski-Chauvel, Elizabeth Cohen-Jonathan-Moyal and Catherine Seva

Cells 2022, 11(14), 2128; https://doi.org/10.3390/cells11142128 - 06 Jul 2022

Cited by 6 | Viewed by 1875

Abstract

Systematic recurrence of glioblastoma (GB) despite surgery and chemo-radiotherapy is due to GB stem cells (GBSC), which are particularly invasive and radioresistant. Therefore, there is a need to identify new factors that might be targeted to decrease GBSC invasive capabilities as well as [...] Read more.

Systematic recurrence of glioblastoma (GB) despite surgery and chemo-radiotherapy is due to GB stem cells (GBSC), which are particularly invasive and radioresistant. Therefore, there is a need to identify new factors that might be targeted to decrease GBSC invasive capabilities as well as radioresistance. Patient-derived GBSC were used in this study to demonstrate a higher expression of the glycoprotein M6a (GPM6A) in invasive GBSC compared to non-invasive cells. In 3D invasion assays performed on primary neurospheres of GBSC, we showed that blocking GPM6A expression by siRNA significantly reduced cell invasion. We also demonstrated a high correlation of GPM6A with the oncogenic protein tyrosine phosphatase, PTPRZ1, which regulates GPM6A expression and cell invasion. The results of our study also show that GPM6A and PTPRZ1 are crucial for GBSC sphere formation. Finally, we demonstrated that targeting GPM6A or PTPRZ1 in GBSC increases the radiosensitivity of GBSC. Our results suggest that blocking GPM6A or PTPRZ1 could represent an interesting approach in the treatment of glioblastoma since it would simultaneously target proliferation, invasion, and radioresistance. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma II)

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14 pages, 11159 KiB

Open AccessArticle

XRN2 Is Required for Cell Motility and Invasion in Glioblastomas

by Tuyen T. Dang, Megan Lerner, Debra Saunders, Nataliya Smith, Rafal Gulej, Michelle Zalles, Rheal A. Towner and Julio C. Morales

Cells 2022, 11(9), 1481; https://doi.org/10.3390/cells11091481 - 28 Apr 2022

Cited by 3 | Viewed by 1847

Abstract

One of the major obstacles in treating brain cancers, particularly glioblastoma multiforme, is the occurrence of secondary tumor lesions that arise in areas of the brain and are inoperable while obtaining resistance to current therapeutic agents. Thus, gaining a better understanding of the [...] Read more.

One of the major obstacles in treating brain cancers, particularly glioblastoma multiforme, is the occurrence of secondary tumor lesions that arise in areas of the brain and are inoperable while obtaining resistance to current therapeutic agents. Thus, gaining a better understanding of the cellular factors that regulate glioblastoma multiforme cellular movement is imperative. In our study, we demonstrate that the 5′-3′ exoribonuclease XRN2 is important to the invasive nature of glioblastoma. A loss of XRN2 decreases cellular speed, displacement, and movement through a matrix of established glioblastoma multiforme cell lines. Additionally, a loss of XRN2 abolishes tumor formation in orthotopic mouse xenograft implanted with G55 glioblastoma multiforme cells. One reason for these observations is that loss of XRN2 disrupts the expression profile of several cellular factors that are important for tumor invasion in glioblastoma multiforme cells. Importantly, XRN2 mRNA and protein levels are elevated in glioblastoma multiforme patient samples. Elevation in XRN2 mRNA also correlates with poor overall patient survival. These data demonstrate that XRN2 is an important cellular factor regulating one of the major obstacles in treating glioblastomas and is a potential molecular target that can greatly enhance patient survival. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma II)

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15 pages, 2687 KiB

Open AccessArticle

Transcriptomic Profiling of DNA Damage Response in Patient-Derived Glioblastoma Cells before and after Radiation and Temozolomide Treatment

by Mathew Lozinski, Nikola A. Bowden, Moira C. Graves, Michael Fay, Bryan W. Day, Brett W. Stringer and Paul A. Tooney

Cells 2022, 11(7), 1215; https://doi.org/10.3390/cells11071215 - 04 Apr 2022

Cited by 6 | Viewed by 2652

Abstract

Glioblastoma is a highly aggressive, invasive and treatment-resistant tumour. The DNA damage response (DDR) provides tumour cells with enhanced ability to activate cell cycle arrest and repair treatment-induced DNA damage. We studied the expression of DDR, its relationship with standard treatment response and [...] Read more.

Glioblastoma is a highly aggressive, invasive and treatment-resistant tumour. The DNA damage response (DDR) provides tumour cells with enhanced ability to activate cell cycle arrest and repair treatment-induced DNA damage. We studied the expression of DDR, its relationship with standard treatment response and patient survival, and its activation after treatment. The transcriptomic profile of DDR pathways was characterised within a cohort of isocitrate dehydrogenase (IDH) wild-type glioblastoma from The Cancer Genome Atlas (TCGA) and 12 patient-derived glioblastoma cell lines. The relationship between DDR expression and patient survival and cell line response to temozolomide (TMZ) or radiation therapy (RT) was assessed. Finally, the expression of 84 DDR genes was examined in glioblastoma cells treated with TMZ and/or RT. Although distinct DDR cluster groups were apparent in the TCGA cohort and cell lines, no significant differences in OS and treatment response were observed. At the gene level, the high expression of ATP23, RAD51C and RPA3 independently associated with poor prognosis in glioblastoma patients. Finally, we observed a substantial upregulation of DDR genes after treatment with TMZ and/or RT, particularly in RT-treated glioblastoma cells, peaking within 24 h after treatment. Our results confirm the potential influence of DDR genes in patient outcome. The observation of DDR genes in response to TMZ and RT gives insight into the global response of DDR pathways after adjuvant treatment in glioblastoma, which may have utility in determining DDR targets for inhibition. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma II)

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18 pages, 2834 KiB

Open AccessArticle

Single-Cell Molecular Characterization to Partition the Human Glioblastoma Tumor Microenvironment Genetic Background

by Francesca Lessi, Sara Franceschi, Mariangela Morelli, Michele Menicagli, Francesco Pasqualetti, Orazio Santonocito, Carlo Gambacciani, Francesco Pieri, Filippo Aquila, Paolo Aretini and Chiara Maria Mazzanti

Cells 2022, 11(7), 1127; https://doi.org/10.3390/cells11071127 - 26 Mar 2022

Cited by 3 | Viewed by 2498

Abstract

Background: Glioblastoma (GB) is a devastating primary brain malignancy. The recurrence of GB is inevitable despite the standard treatment of surgery, chemotherapy, and radiation, and the median survival is limited to around 15 months. The barriers to treatment include the complex interactions among [...] Read more.

Background: Glioblastoma (GB) is a devastating primary brain malignancy. The recurrence of GB is inevitable despite the standard treatment of surgery, chemotherapy, and radiation, and the median survival is limited to around 15 months. The barriers to treatment include the complex interactions among the different cellular components inhabiting the tumor microenvironment. The complex heterogeneous nature of GB cells is helped by the local inflammatory tumor microenvironment, which mostly induces tumor aggressiveness and drug resistance. Methods: By using fluorescent multiple labeling and a DEPArray cell separator, we recovered several single cells or groups of single cells from populations of different origins from IDH-WT GB samples. From each GB sample, we collected astrocytes-like (GFAP+), microglia-like (IBA1+), stem-like cells (CD133+), and endothelial-like cells (CD105+) and performed Copy Number Aberration (CNA) analysis with a low sequencing depth. The same tumors were subjected to a bulk CNA analysis. Results: The tumor partition in its single components allowed single-cell molecular subtyping which revealed new aspects of the GB altered genetic background. Conclusions: Nowadays, single-cell approaches are leading to a new understanding of GB physiology and disease. Moreover, single-cell CNAs resource will permit new insights into genome heterogeneity, mutational processes, and clonal evolution in malignant tissues. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma II)

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21 pages, 5938 KiB

Open AccessArticle

Combining HDAC and MEK Inhibitors with Radiation against Glioblastoma-Derived Spheres

by Eno I. Essien, Thomas P. Hofer, Michael J. Atkinson and Nataša Anastasov

Cells 2022, 11(5), 775; https://doi.org/10.3390/cells11050775 - 23 Feb 2022

Cited by 10 | Viewed by 2736

Abstract

Glioblastoma stem-like cells (GSLCs) in glioblastoma limit effective treatment and promote therapeutic resistance and tumor recurrence. Using a combined radiation and drug-screening platform, we tested the combination of a histone deacetylase inhibitor (HDACi) and MAPK/ERK kinase inhibitor (MEKi) with radiation to predict the [...] Read more.

Glioblastoma stem-like cells (GSLCs) in glioblastoma limit effective treatment and promote therapeutic resistance and tumor recurrence. Using a combined radiation and drug-screening platform, we tested the combination of a histone deacetylase inhibitor (HDACi) and MAPK/ERK kinase inhibitor (MEKi) with radiation to predict the efficacy against GSLCs. To mimic a stem-like phenotype, glioblastoma-derived spheres were used and treated with a combination of HDACi (MS-275) and MEKi (TAK-733 or trametinib) with 4 Gy irradiation. The sphere-forming ability after the combined radiochemotherapy was investigated using a sphere formation assay, while the expression levels of the GSLC markers (CD44, Nestin and SOX2) after treatment were analyzed using Western blotting and flow cytometry. The combined radiochemotherapy treatment inhibited the sphere formation in both glioblastoma-derived spheres, decreased the expression of the GSLC markers in a cell-line dependent manner and increased the dead cell population. Finally, we showed that the combined treatment with radiation was more effective at reducing the GSLC markers compared to the standard treatment of temozolomide and radiation. These results suggest that combining HDAC and MEK inhibition with radiation may offer a new strategy to improve the treatment of glioblastoma. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma II)

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18 pages, 2851 KiB

Open AccessArticle

Interaction of Glia Cells with Glioblastoma and Melanoma Cells under the Influence of Phytocannabinoids

by Urszula Hohmann, Christoph Walsleben, Chalid Ghadban, Frank Kirchhoff, Faramarz Dehghani and Tim Hohmann

Cells 2022, 11(1), 147; https://doi.org/10.3390/cells11010147 - 03 Jan 2022

Cited by 6 | Viewed by 2735

Abstract

Brain tumor heterogeneity and progression are subject to complex interactions between tumor cells and their microenvironment. Glioblastoma and brain metastasis can contain 30–40% of tumor-associated macrophages, microglia, and astrocytes, affecting migration, proliferation, and apoptosis. Here, we analyzed interactions between glial cells and LN229 [...] Read more.

Brain tumor heterogeneity and progression are subject to complex interactions between tumor cells and their microenvironment. Glioblastoma and brain metastasis can contain 30–40% of tumor-associated macrophages, microglia, and astrocytes, affecting migration, proliferation, and apoptosis. Here, we analyzed interactions between glial cells and LN229 glioblastoma or A375 melanoma cells in the context of motility and cell–cell interactions in a 3D model. Furthermore, the effects of phytocannabinoids, cannabidiol (CBD), tetrahydrocannabidiol (THC), or their co-application were analyzed. Co-culture of tumor cells with glial cells had little effect on 3D spheroid formation, while treatment with cannabinoids led to significantly larger spheroids. The addition of astrocytes blocked cannabinoid-induced effects. None of the interventions affected cell death. Furthermore, glial cell-conditioned media led to a significant slowdown in collective, but not single-cell migration speed. Taken together, glial cells in glioblastoma and brain metastasis micromilieu impact the tumor spheroid formation, cell spreading, and motility. Since the size of spheroid remained unaffected in glial cell tumor co-cultures, phytocannabinoids increased the size of spheroids without any effects on migration. This aspect might be of relevance since phytocannabinoids are frequently used in tumor therapy for side effects. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma II)

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15 pages, 3354 KiB

Open AccessArticle

Corosolic Acid Attenuates the Invasiveness of Glioblastoma Cells by Promoting CHIP-Mediated AXL Degradation and Inhibiting GAS6/AXL/JAK Axis

by Li-Wei Sun, Shao-Hsuan Kao, Shun-Fa Yang, Shang-Wun Jhang, Yi-Chen Lin, Chien-Min Chen and Yi-Hsien Hsieh

Cells 2021, 10(11), 2919; https://doi.org/10.3390/cells10112919 - 28 Oct 2021

Cited by 10 | Viewed by 2556

Abstract

Corosolic acid (CA), a bioactive compound obtained from Actinidia chinensis, has potential anti-cancer activities. Glioblastoma (GBM) is a malignant brain tumor and whether CA exerts anti-cancer activity on GBM remains unclear. This study was aimed to explore the anticancer activity and its underlying [...] Read more.

Corosolic acid (CA), a bioactive compound obtained from Actinidia chinensis, has potential anti-cancer activities. Glioblastoma (GBM) is a malignant brain tumor and whether CA exerts anti-cancer activity on GBM remains unclear. This study was aimed to explore the anticancer activity and its underlying mechanism of CA in GBM cells. Our findings showed that CA ≤ 20 μM did not affect cell viability and cell proliferative rate of normal astrocyte and four GBM cells. Notably, 10 or 20 μM CA significantly inhibited cell migration and invasion of three GBM cells, decreased the protein level of F-actin and disrupted F-actin polymerization in these GBM cells. Further investigation revealed that CA decreased AXL level by promoting ubiquitin-mediated proteasome degradation and upregulating the carboxyl terminus of Hsc70-interacting protein (CHIP), an inducer of AXL polyubiquitination. CHIP knock-down restored the CA-reduced AXL and invasiveness of GBM cells. Additionally, we observed that CA-reduced Growth arrest-specific protein 6 (GAS6) and inhibited JAK2/MEK/ERK activation, and GAS6 pre-treatment restored attenuated JAK2/MEK/ERK activation and invasiveness of GBM cells. Furthermore, molecular docking analysis revealed that CA might bind to GAS6 and AXL. These findings collectively indicate that CA attenuates the invasiveness of GBM cells, attributing to CHIP upregulation and binding to GAS6 and AXL and subsequently promoting AXL degradation and downregulating GAS6-mediated JAK2/MEK/ERK cascade. Conclusively, this suggests that CA has potential anti-metastatic activity on GBM cells by targeting the CHIP/GAS6/AXL axis. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma II)

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13 pages, 4340 KiB

Open AccessArticle

Inhibition of FABP6 Reduces Tumor Cell Invasion and Angiogenesis through the Decrease in MMP-2 and VEGF in Human Glioblastoma Cells

by Feng-Cheng Pai, Hsiang-Wei Huang, Yu-Ling Tsai, Wen-Chiuan Tsai, Yu-Chen Cheng, Hsin-Han Chang and Ying Chen

Cells 2021, 10(10), 2782; https://doi.org/10.3390/cells10102782 - 17 Oct 2021

Cited by 12 | Viewed by 2910

Abstract

Malignant glioma is one of the most lethal cancers with rapid progression, high recurrence, and poor prognosis in the central nervous system. Fatty acid-binding protein 6 (FABP6) is a bile acid carrier protein that is overexpressed in colorectal cancer. This study aimed to [...] Read more.

Malignant glioma is one of the most lethal cancers with rapid progression, high recurrence, and poor prognosis in the central nervous system. Fatty acid-binding protein 6 (FABP6) is a bile acid carrier protein that is overexpressed in colorectal cancer. This study aimed to assess the involvement of FABP6 expression in the progression of malignant glioma. Immunohistochemical analysis revealed that FABP6 expression was higher in glioma than in normal brain tissue. After the knockdown of FABP6, a decrease in the migration and invasion abilities of glioma cells was observed. The phosphorylation of the myosin light chain was inhibited, which may be associated with migration ability. Moreover, expression levels of invasion-related proteins, matrix metalloproteinase-2 (MMP-2) and cathepsin B, were reduced. Furthermore, tube formation was inhibited in the human umbilical vein endothelial cells with a decreased concentration of vascular endothelial growth factor (VEGF) in the conditioned medium after the knockdown of FABP6. The phosphorylation of the extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p65 were also decreased after FABP6 reduction. Finally, the bioluminescent images and immunostaining of MMP-2, cluster of differentiation 31 (CD31), and the VEGF receptor 1 (VEGFR1) revealed attenuated tumor progression in the combination of the FABP6-knocked-down and temozolomide (TMZ)-treated group in an orthotopic xenograft mouse tumor model. This is the first study that revealed the impact of FABP6 on the invasion, angiogenesis, and progression of glioma. The results of this study show that FABP6 may be a potential therapeutic target combined with TMZ for malignant gliomas. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma II)

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Review

Jump to: Editorial, Research

25 pages, 1667 KiB

Open AccessReview

A Comprehensive Review of miRNAs and Their Epigenetic Effects in Glioblastoma

by Hera Hasan, Mohammad Afzal, Javier S. Castresana and Mehdi H. Shahi

Cells 2023, 12(12), 1578; https://doi.org/10.3390/cells12121578 - 07 Jun 2023

Cited by 2 | Viewed by 1526

Abstract

Glioblastoma is the most aggressive form of brain tumor originating from glial cells with a maximum life expectancy of 14.6 months. Despite the establishment of multiple promising therapies, the clinical outcome of glioblastoma patients is abysmal. Drug resistance has been identified as a [...] Read more.

Glioblastoma is the most aggressive form of brain tumor originating from glial cells with a maximum life expectancy of 14.6 months. Despite the establishment of multiple promising therapies, the clinical outcome of glioblastoma patients is abysmal. Drug resistance has been identified as a major factor contributing to the failure of current multimodal therapy. Epigenetic modification, especially DNA methylation has been identified as a major regulatory mechanism behind glioblastoma progression. In addition, miRNAs, a class of non-coding RNA, have been found to play a role in the regulation as well as in the diagnosis of glioblastoma. The relationship between epigenetics, drug resistance, and glioblastoma progression has been clearly demonstrated. MGMT hypermethylation, leading to a lack of MGMT expression, is associated with a cytotoxic effect of TMZ in GBM, while resistance to TMZ frequently appears in MGMT non-methylated GBM. In this review, we will elaborate on known miRNAs linked to glioblastoma; their distinctive oncogenic or tumor suppressor roles; and how epigenetic modification of miRNAs, particularly via methylation, leads to their upregulation or downregulation in glioblastoma. Moreover, we will try to identify those miRNAs that might be potential regulators of MGMT expression and their role as predictors of tumor response to temozolomide treatment. Although we do not impact clinical data and survival, we open possible experimental approaches to treat GBM, although they should be further validated with clinically oriented studies. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma II)

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15 pages, 1692 KiB

Open AccessReview

Utility of the Cerebral Organoid Glioma ‘GLICO’ Model for Screening Applications

by Freya R. Weth, Lifeng Peng, Erin Paterson, Swee T. Tan and Clint Gray

Cells 2023, 12(1), 153; https://doi.org/10.3390/cells12010153 - 30 Dec 2022

Cited by 6 | Viewed by 2731

Abstract

Glioblastoma, a grade IV astrocytoma, is regarded as the most aggressive primary brain tumour with an overall median survival of 16.0 months following the standard treatment regimen of surgical resection, followed by radiotherapy and chemotherapy with temozolomide. Despite such intensive treatment, the tumour [...] Read more.

Glioblastoma, a grade IV astrocytoma, is regarded as the most aggressive primary brain tumour with an overall median survival of 16.0 months following the standard treatment regimen of surgical resection, followed by radiotherapy and chemotherapy with temozolomide. Despite such intensive treatment, the tumour almost invariably recurs. This poor prognosis has most commonly been attributed to the initiation, propagation, and differentiation of cancer stem cells. Despite the unprecedented advances in biomedical research over the last decade, the current in vitro models are limited at preserving the inter- and intra-tumoural heterogeneity of primary tumours. The ability to understand and manipulate complex cancers such as glioblastoma requires disease models to be clinically and translationally relevant and encompass the cellular heterogeneity of such cancers. Therefore, brain cancer research models need to aim to recapitulate glioblastoma stem cell function, whilst remaining amenable for analysis. Fortunately, the recent development of 3D cultures has overcome some of these challenges, and cerebral organoids are emerging as cutting-edge tools in glioblastoma research. The opportunity to generate cerebral organoids via induced pluripotent stem cells, and to perform co-cultures with patient-derived cancer stem cells (GLICO model), has enabled the analysis of cancer development in a context that better mimics brain tissue architecture. In this article, we review the recent literature on the use of patient-derived glioblastoma organoid models and their applicability for drug screening, as well as provide a potential workflow for screening using the GLICO model. The proposed workflow is practical for use in most laboratories with accessible materials and equipment, a good first pass, and no animal work required. This workflow is also amenable for analysis, with separate measures of invasion, growth, and viability. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma II)

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52 pages, 6709 KiB

Open AccessReview

Current Opportunities for Targeting Dysregulated Neurodevelopmental Signaling Pathways in Glioblastoma

by Danijela Drakulic, Marija Schwirtlich, Isidora Petrovic, Marija Mojsin, Milena Milivojevic, Natasa Kovacevic-Grujicic and Milena Stevanovic

Cells 2022, 11(16), 2530; https://doi.org/10.3390/cells11162530 - 15 Aug 2022

Cited by 8 | Viewed by 3245

Abstract

Glioblastoma (GBM) is the most common and highly lethal type of brain tumor, with poor survival despite advances in understanding its complexity. After current standard therapeutic treatment, including tumor resection, radiotherapy and concomitant chemotherapy with temozolomide, the median overall survival of patients with [...] Read more.

Glioblastoma (GBM) is the most common and highly lethal type of brain tumor, with poor survival despite advances in understanding its complexity. After current standard therapeutic treatment, including tumor resection, radiotherapy and concomitant chemotherapy with temozolomide, the median overall survival of patients with this type of tumor is less than 15 months. Thus, there is an urgent need for new insights into GBM molecular characteristics and progress in targeted therapy in order to improve clinical outcomes. The literature data revealed that a number of different signaling pathways are dysregulated in GBM. In this review, we intended to summarize and discuss current literature data and therapeutic modalities focused on targeting dysregulated signaling pathways in GBM. A better understanding of opportunities for targeting signaling pathways that influences malignant behavior of GBM cells might open the way for the development of novel GBM-targeted therapies. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma II)

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23 pages, 3484 KiB

Open AccessReview

Ribosomes and Ribosomal Proteins Promote Plasticity and Stemness Induction in Glioma Cells via Reprogramming

by Takuichiro Hide, Ichiyo Shibahara, Madoka Inukai, Ryota Shigeeda and Toshihiro Kumabe

Cells 2022, 11(14), 2142; https://doi.org/10.3390/cells11142142 - 07 Jul 2022

Cited by 5 | Viewed by 2949

Abstract

Glioblastoma multiforme (GBM) is a lethal tumor that develops in the adult brain. Despite advances in therapeutic strategies related to surgical resection and chemo-radiotherapy, the overall survival of patients with GBM remains unsatisfactory. Genetic research on mutation, amplification, and deletion in GBM cells [...] Read more.

Glioblastoma multiforme (GBM) is a lethal tumor that develops in the adult brain. Despite advances in therapeutic strategies related to surgical resection and chemo-radiotherapy, the overall survival of patients with GBM remains unsatisfactory. Genetic research on mutation, amplification, and deletion in GBM cells is important for understanding the biological aggressiveness, diagnosis, and prognosis of GBM. However, the efficacy of drugs targeting the genetic abnormalities in GBM cells is limited. Investigating special microenvironments that induce chemo-radioresistance in GBM cells is critical to improving the survival and quality of life of patients with GBM. GBM cells acquire and maintain stem-cell-like characteristics via their intrinsic potential and extrinsic factors from their special microenvironments. The acquisition of stem-cell-like phenotypes and aggressiveness may be referred to as a reprogramming of GBM cells. In addition to protein synthesis, deregulation of ribosome biogenesis is linked to several diseases including cancer. Ribosomal proteins possess both tumor-promotive and -suppressive functions as extra-ribosomal functions. Incorporation of ribosomes and overexpression of ribosomal protein S6 reprogram and induce stem-cell-like phenotypes in GBM cells. Herein, we review recent literature and our published data on the acquisition of aggressiveness by GBM and discuss therapeutic options through reprogramming. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma II)

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28 pages, 3671 KiB

Open AccessFeature PaperReview

Role of Circular RNA in Brain Tumor Development

by Swalih P. Ahmed, Javier S. Castresana and Mehdi H. Shahi

Cells 2022, 11(14), 2130; https://doi.org/10.3390/cells11142130 - 06 Jul 2022

Cited by 11 | Viewed by 3131

Abstract

Central nervous system tumors are a leading cause of cancer-related death in children and adults, with medulloblastoma (MB) and glioblastoma (GBM) being the most prevalent malignant brain tumors, respectively. Despite tremendous breakthroughs in neurosurgery, radiation, and chemotherapeutic techniques, cell heterogeneity and various genetic [...] Read more.

Central nervous system tumors are a leading cause of cancer-related death in children and adults, with medulloblastoma (MB) and glioblastoma (GBM) being the most prevalent malignant brain tumors, respectively. Despite tremendous breakthroughs in neurosurgery, radiation, and chemotherapeutic techniques, cell heterogeneity and various genetic mutations impacting cell cycle control, cell proliferation, apoptosis, and cell invasion result in unwanted resistance to treatment approaches, with a 5-year survival rate of 70–80% for medulloblastoma, and the median survival time for patients with glioblastoma is only 15 months. Developing new medicines and utilizing combination medications may be viewed as excellent techniques for battling MB and GBM. Circular RNAs (circRNAs) can affect cancer-developing processes such as cell proliferation, cell apoptosis, invasion, and chemoresistance in this regard. As a result, several compounds have been introduced as prospective therapeutic targets in the fight against MB and GBM. The current study aims to elucidate the fundamental molecular and cellular mechanisms underlying the pathogenesis of GBM in conjunction with circRNAs. Several mechanisms were examined in detail, including PI3K/Akt/mTOR signaling, Wnt/-catenin signaling, angiogenic processes, and metastatic pathways, in order to provide a comprehensive knowledge of the involvement of circRNAs in the pathophysiology of MB and GBM. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma II)

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