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Molecular and Cellular Mechanisms of Cancers: Glioblastoma
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Molecular and Cellular Mechanisms of Cancers: Glioblastoma

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 90217

Special Issue Editors

Prof. Dr. Javier S. Castresana

E-Mail Website
Guest Editor
Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain
Interests: glioblastoma genetics and epigenetics; brain tumor stem cells; experimental treatments against glioblastoma cells; resistance to therapy
Special Issues, Collections and Topics in MDPI journals
Dr. Bárbara Meléndez

E-Mail Website
Guest Editor
Molecular Pathology Research Unit, Virgen de la Salud Hospital, 45005 Toledo, Spain
Interests: glioblastoma; brain tumor genetics; brain tumor epigenetics; brain tumor molecular pathology; liquid biopsy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Glioblastoma is the most aggressive brain tumor and one of the tumors with a worst clinical prognosis, with overall survival data of less than two years from diagnosis. Surgically, glioblastoma is difficult to be removed, due to its infiltrative pattern, which added to the fact that brain tumor stem cells may exist within it, make glioblastoma relapse very frequent. Radiotherapy and chemotherapy are also used against this tumor. Temozolomide is the chosen chemotherapy, especially for those patients who do not express MGMT, mostly due to MGMT promoter hypermethylation. But radiotherapy and temozolomide resistance appear as well. Molecular subtypes of glioblastoma have been established with the aim of assigning particular therapies to particular tumors. More research is needed, both at the genetic and epigenetic levels, in order to guarantee specific treatments to succeed.

We invite all scientists working on glioblastoma to participate in this special issue. Original research articles, reviews, or shorter perspective articles on all aspects related to the molecular and cellular mechanisms of glioblastoma biology and therapy are welcome. Articles with insights from a cell and molecular biological perspective are especially welcome. Relevant topics include, but are not limited to: genetic and epigenetic profiles, brain tumor stem cells, epithelial-to-mesenchymal transition, angiogenesis, migration and invasion, resistance to therapy, molecular and cellular heterogeneity, and any other topics related to the genetics and epigenetics of glioblastoma.

Prof. Javier S. Castresana
Dr. Bárbara Meléndez
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • glioblastoma genetics and epigenetics
  • brain tumor stem cells
  • epithelial-to-mesenchymal transition
  • angiogenesis
  • glioblastoma migration and invasion
  • glioblastoma therapy
  • resistance to therapy
  • molecular and cellular heterogeneity

Related Special Issues

Published Papers (21 papers)

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Editorial

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4 pages, 227 KiB  
Editorial
Molecular and Cellular Mechanisms of Glioblastoma
by Javier S. Castresana and Bárbara Meléndez
Cells 2021, 10(6), 1456; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061456 - 10 Jun 2021
Cited by 1 | Viewed by 1685
Abstract
Glioblastoma is the most malignant primary brain tumor [...] Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)

Research

Jump to: Editorial, Review

23 pages, 3439 KiB  
Article
Beyond the Warburg Effect: Oxidative and Glycolytic Phenotypes Coexist within the Metabolic Heterogeneity of Glioblastoma
by Tomás Duraj, Noemí García-Romero, Josefa Carrión-Navarro, Rodrigo Madurga, Ana Ortiz de Mendivil, Ricardo Prat-Acin, Lina Garcia-Cañamaque and Angel Ayuso-Sacido
Cells 2021, 10(2), 202; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020202 - 20 Jan 2021
Cited by 47 | Viewed by 5988
Abstract
Glioblastoma (GBM) is the most aggressive primary brain tumor, with a median survival at diagnosis of 16–20 months. Metabolism represents a new attractive therapeutic target; however, due to high intratumoral heterogeneity, the application of metabolic drugs in GBM is challenging. We characterized the [...] Read more.
Glioblastoma (GBM) is the most aggressive primary brain tumor, with a median survival at diagnosis of 16–20 months. Metabolism represents a new attractive therapeutic target; however, due to high intratumoral heterogeneity, the application of metabolic drugs in GBM is challenging. We characterized the basal bioenergetic metabolism and antiproliferative potential of metformin (MF), dichloroacetate (DCA), sodium oxamate (SOD) and diazo-5-oxo-L-norleucine (DON) in three distinct glioma stem cells (GSCs) (GBM18, GBM27, GBM38), as well as U87MG. GBM27, a highly oxidative cell line, was the most resistant to all treatments, except DON. GBM18 and GBM38, Warburg-like GSCs, were sensitive to MF and DCA, respectively. Resistance to DON was not correlated with basal metabolic phenotypes. In combinatory experiments, radiomimetic bleomycin exhibited therapeutically relevant synergistic effects with MF, DCA and DON in GBM27 and DON in all other cell lines. MF and DCA shifted the metabolism of treated cells towards glycolysis or oxidation, respectively. DON consistently decreased total ATP production. Our study highlights the need for a better characterization of GBM from a metabolic perspective. Metabolic therapy should focus on both glycolytic and oxidative subpopulations of GSCs. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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17 pages, 3459 KiB  
Article
Nanotherapeutic Modulation of Human Neural Cells and Glioblastoma in Organoids and Monocultures
by Issan Zhang, Paula Lépine, Chanshuai Han, María Lacalle-Aurioles, Carol X.-Q. Chen, Rainer Haag, Thomas M. Durcan and Dusica Maysinger
Cells 2020, 9(11), 2434; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9112434 - 07 Nov 2020
Cited by 10 | Viewed by 3555
Abstract
Inflammatory processes in the brain are orchestrated by microglia and astrocytes in response to activators such as pathogen-associated molecular patterns, danger-associated molecular patterns and some nanostructures. Microglia are the primary immune responders in the brain and initiate responses amplified by astrocytes through intercellular [...] Read more.
Inflammatory processes in the brain are orchestrated by microglia and astrocytes in response to activators such as pathogen-associated molecular patterns, danger-associated molecular patterns and some nanostructures. Microglia are the primary immune responders in the brain and initiate responses amplified by astrocytes through intercellular signaling. Intercellular communication between neural cells can be studied in cerebral organoids, co-cultures or in vivo. We used human cerebral organoids and glioblastoma co-cultures to study glia modulation by dendritic polyglycerol sulfate (dPGS). dPGS is an extensively studied nanostructure with inherent anti-inflammatory properties. Under inflammatory conditions, lipocalin-2 levels in astrocytes are markedly increased and indirectly enhanced by soluble factors released from hyperactive microglia. dPGS is an effective anti-inflammatory modulator of these markers. Our results show that dPGS can enter neural cells in cerebral organoids and glial cells in monocultures in a time-dependent manner. dPGS markedly reduces lipocalin-2 abundance in the neural cells. Glioblastoma tumoroids of astrocytic origin respond to activated microglia with enhanced invasiveness, whereas conditioned media from dPGS-treated microglia reduce tumoroid invasiveness. Considering that many nanostructures have only been tested in cancer cells and rodent models, experiments in human 3D cerebral organoids and co-cultures are complementary in vitro models to evaluate nanotherapeutics in the pre-clinical setting. Thoroughly characterized organoids and standardized procedures for their preparation are prerequisites to gain information of translational value in nanomedicine. This study provides data for a well-characterized dendrimer (dPGS) that modulates the activation state of human microglia implicated in brain tumor invasiveness. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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19 pages, 3388 KiB  
Article
Identification of New Genetic Clusters in Glioblastoma Multiforme: EGFR Status and ADD3 Losses Influence Prognosis
by Lara Navarro, Teresa San-Miguel, Javier Megías, Nuria Santonja, Silvia Calabuig, Lisandra Muñoz-Hidalgo, Pedro Roldán, Miguel Cerdá-Nicolás and Concha López-Ginés
Cells 2020, 9(11), 2429; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9112429 - 06 Nov 2020
Cited by 3 | Viewed by 2082
Abstract
Glioblastoma multiforme (GB) is one of the most aggressive tumors. Despite continuous efforts to improve its clinical management, there is still no strategy to avoid a rapid and fatal outcome. EGFR amplification is the most characteristic alteration of these tumors. Although effective therapy [...] Read more.
Glioblastoma multiforme (GB) is one of the most aggressive tumors. Despite continuous efforts to improve its clinical management, there is still no strategy to avoid a rapid and fatal outcome. EGFR amplification is the most characteristic alteration of these tumors. Although effective therapy against it has not yet been found in GB, it may be central to classifying patients. We investigated somatic-copy number alterations (SCNA) by multiplex ligation-dependent probe amplification in a series of 137 GB, together with the detection of EGFRvIII and FISH analysis for EGFR amplification. Publicly available data from 604 patients were used as a validation cohort. We found statistical associations between EGFR amplification and/or EGFRvIII, and SCNA in CDKN2A, MSH6, MTAP and ADD3. Interestingly, we found that both EGFRvIII and losses on ADD3 were independent markers of bad prognosis (p = 0.028 and 0.014, respectively). Finally, we got an unsupervised hierarchical classification that differentiated three clusters of patients based on their genetic alterations. It offered a landscape of EGFR co-alterations that may improve the comprehension of the mechanisms underlying GB aggressiveness. Our findings can help in defining different genetic profiles, which is necessary to develop new and different approaches in the management of our patients. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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25 pages, 9015 KiB  
Article
Combinatory Treatment of Canavanine and Arginine Deprivation Efficiently Targets Human Glioblastoma Cells via Pleiotropic Mechanisms
by Olena Karatsai, Pavel Shliaha, Ole N. Jensen, Oleh Stasyk and Maria Jolanta Rędowicz
Cells 2020, 9(10), 2217; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9102217 - 30 Sep 2020
Cited by 7 | Viewed by 3255
Abstract
Glioblastomas are the most frequent and aggressive form of primary brain tumors with no efficient cure. However, they often exhibit specific metabolic shifts that include deficiency in the biosynthesis of and dependence on certain exogenous amino acids. Here, we evaluated, in vitro, a [...] Read more.
Glioblastomas are the most frequent and aggressive form of primary brain tumors with no efficient cure. However, they often exhibit specific metabolic shifts that include deficiency in the biosynthesis of and dependence on certain exogenous amino acids. Here, we evaluated, in vitro, a novel combinatory antiglioblastoma approach based on arginine deprivation and canavanine, an arginine analogue of plant origin, using two human glioblastoma cell models, U251MG and U87MG. The combinatory treatment profoundly affected cell viability, morphology, motility and adhesion, destabilizing the cytoskeleton and mitochondrial network, and induced apoptotic cell death. Importantly, the effects were selective toward glioblastoma cells, as they were not pronounced for primary rat glial cells. At the molecular level, canavanine inhibited prosurvival kinases such as FAK, Akt and AMPK. Its effects on protein synthesis and stress response pathways were more complex and dependent on exposure time. We directly observed canavanine incorporation into nascent proteins by using quantitative proteomics. Although canavanine in the absence of arginine readily incorporated into polypeptides, no motif preference for such incorporation was observed. Our findings provide a strong rationale for further developing the proposed modality based on canavanine and arginine deprivation as a potential antiglioblastoma metabolic therapy independent of the blood–brain barrier. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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23 pages, 9509 KiB  
Article
Estradiol Induces Epithelial to Mesenchymal Transition of Human Glioblastoma Cells
by Ana M. Hernández-Vega, Aylin Del Moral-Morales, Carmen J. Zamora-Sánchez, Ana G. Piña-Medina, Aliesha González-Arenas and Ignacio Camacho-Arroyo
Cells 2020, 9(9), 1930; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9091930 - 21 Aug 2020
Cited by 23 | Viewed by 3467
Abstract
The mesenchymal phenotype of glioblastoma multiforme (GBM), the most frequent and malignant brain tumor, is associated with the worst prognosis. The epithelial–mesenchymal transition (EMT) is a cell plasticity mechanism involved in GBM malignancy. In this study, we determined 17β-estradiol (E2)-induced EMT by changes [...] Read more.
The mesenchymal phenotype of glioblastoma multiforme (GBM), the most frequent and malignant brain tumor, is associated with the worst prognosis. The epithelial–mesenchymal transition (EMT) is a cell plasticity mechanism involved in GBM malignancy. In this study, we determined 17β-estradiol (E2)-induced EMT by changes in cell morphology, expression of EMT markers, and cell migration and invasion assays in human GBM-derived cell lines. E2 (10 nM) modified the shape and size of GBM cells due to a reorganization of actin filaments. We evaluated EMT markers expression by RT-qPCR, Western blot, and immunofluorescence.We found that E2 upregulated the expression of the mesenchymal markers, vimentin, and N-cadherin. Scratch and transwell assays showed that E2 increased migration and invasion of GBM cells. The estrogen receptor-α (ER-α)-selective agonist 4,4’,4’’-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT, 10 nM) affected similarly to E2 in terms of the expression of EMT markers and cell migration, and the treatment with the ER-α antagonist methyl-piperidino-pyrazole (MPP, 1 μM) blocked E2 and PPT effects. ER-β-selective agonist diarylpropionitrile (DNP, 10 nM) and antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazole[1,5-a]pyrimidin-3-yl]phenol (PHTPP, 1 μM) showed no effects on EMT marker expression. These data suggest that E2 induces EMT activation through ER-α in human GBM-derived cells. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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21 pages, 6188 KiB  
Article
Targeting BC200/miR218-5p Signaling Axis for Overcoming Temozolomide Resistance and Suppressing Glioma Stemness
by Yu-Kai Su, Jia Wei Lin, Jing-Wen Shih, Hao-Yu Chuang, Iat-Hang Fong, Chi-Tai Yeh and Chien-Min Lin
Cells 2020, 9(8), 1859; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9081859 - 08 Aug 2020
Cited by 14 | Viewed by 2986
Abstract
Background: Glioblastoma (GB) is one of the most common (~30%) and lethal cancers of the central nervous system. Although new therapies are emerging, chemoresistance to treatment is one of the major challenges in cancer treatment. Brain cytoplasmic 200 (BC200) RNA, also known [...] Read more.
Background: Glioblastoma (GB) is one of the most common (~30%) and lethal cancers of the central nervous system. Although new therapies are emerging, chemoresistance to treatment is one of the major challenges in cancer treatment. Brain cytoplasmic 200 (BC200) RNA, also known as BCYRN1, is a long noncoding RNA (lncRNA) that has recently emerged as one of the crucial members of the lncRNA family. BC200 atypical expression is observed in many human cancers. BC200 expression is higher in invasive cancers than in benign tumors. However, the clinical significance of BC200 and its effect on GB multiforme is still unexplored and remains unclear. Methods: BC200 expression in GB patients and cell lines were investigated through RT-qPCR, immunoblotting, and immunohistochemistry analysis. The biological importance of BC200 was investigated in vitro and in vivo through knockdown and overexpression. Bioinformatic analysis was performed to determine miRNAs associated with BC200 RNA. Results: Our findings revealed that in GB patients, BC200 RNA expression was higher in blood and tumor tissues than in normal tissues. BC200 RNA expression have a statistically significant difference between the IDH1 and P53 status. Moreover, the BC200 RNA expression was higher than both p53, a prognostic marker of glioma, and Ki-67, a reliable indicator of tumor cell proliferation activity. Overexpression and silencing of BC200 RNA both in vitro and in vivo significantly modulated the proliferation, self-renewal, pluripotency, and temozolomide (TMZ) chemo-resistance of GB cells. It was found that the expressions of BC200 were up-regulated and that of miR-218-5p were down-regulated in GB tissues and cells. miR-218-5p inhibited the expression of BC200. Conclusions: This study is the first to show that the molecular mechanism of BC200 promotes GB oncogenicity and TMZ resistance through miR-218-5p expression modulation. Thus, the noncoding RNA BC200/miR-218-5p signaling circuit is a potential clinical biomarker or therapeutic target for GB. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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21 pages, 7372 KiB  
Article
Time- and Dose-Dependent Effects of Ionizing Irradiation on the Membrane Expression of Hsp70 on Glioma Cells
by Helena Fellinger, Stefan Stangl, Alicia Hernandez Schnelzer, Melissa Schwab, Tommaso Di Genio, Marija Pieper, Caroline Werner, Maxim Shevtsov, Bernhard Haller and Gabriele Multhoff
Cells 2020, 9(4), 912; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9040912 - 08 Apr 2020
Cited by 7 | Viewed by 2787
Abstract
The major stress-inducible protein Hsp70 (HSPA1A) is overexpressed in the cytosol of many highly aggressive tumor cells including glioblastoma multiforme and presented on their plasma membrane. Depending on its intracellular or membrane localization, Hsp70 either promotes tumor growth or serves as a target [...] Read more.
The major stress-inducible protein Hsp70 (HSPA1A) is overexpressed in the cytosol of many highly aggressive tumor cells including glioblastoma multiforme and presented on their plasma membrane. Depending on its intracellular or membrane localization, Hsp70 either promotes tumor growth or serves as a target for natural killer (NK) cells. The kinetics of the membrane Hsp70 (mHsp70) density on human glioma cells (U87) was studied after different irradiation doses to define the optimal therapeutic window for Hsp70-targeting NK cells. To maintain the cells in the exponential growth phase during a cultivation period of 7 days, different initial cell counts were seeded. Although cytosolic Hsp70 levels remained unchanged on days 4 and 7 after a sublethal irradiation with 2, 4 and 6 Gy, a dose of 2 Gy resulted in an upregulated mHsp70 density in U87 cells which peaked on day 4 and started to decline on day 7. Higher radiation doses (4 Gy, 6 Gy) resulted in an earlier and more rapid onset of the mHsp70 expression on days 2 and 1, respectively, followed by a decline on day 5. Membrane Hsp70 levels were higher on cells in G2/M than in G1; however, an irradiation-induced cell cycle arrest on days 4 and 7 was not associated with an increase in the mHsp70 density. Extracellular Hsp70 concentrations in the supernatant of irradiated cells were significantly higher than sham (0 Gy) irradiated cells on days 4 and 7, but not on day 1. Functionally, elevated mHsp70 densities were associated with a significantly better lysis by Hsp70-targeting NK cells. In summary, the kinetics of changes in the mHsp70 density upon irradiation on tumor cells is time- and dose-dependent. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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17 pages, 4688 KiB  
Article
Cross Interaction between M2 Muscarinic Receptor and Notch1/EGFR Pathway in Human Glioblastoma Cancer Stem Cells: Effects on Cell Cycle Progression and Survival
by Ilaria Cristofaro, Francesco Alessandrini, Zaira Spinello, Claudia Guerriero, Mario Fiore, Elisa Caffarelli, Pietro Laneve, Luciana Dini, Luciano Conti and Ada Maria Tata
Cells 2020, 9(3), 657; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9030657 - 09 Mar 2020
Cited by 18 | Viewed by 2819
Abstract
Glioblastomas (GBM) are the most aggressive form of primary brain tumors in humans. A key feature of malignant gliomas is their cellular heterogeneity. In particular, the presence of an undifferentiated cell population of defined Glioblastoma Stem cells (GSCs) was reported. Increased expression of [...] Read more.
Glioblastomas (GBM) are the most aggressive form of primary brain tumors in humans. A key feature of malignant gliomas is their cellular heterogeneity. In particular, the presence of an undifferentiated cell population of defined Glioblastoma Stem cells (GSCs) was reported. Increased expression of anti-apoptotic and chemo-resistance genes in GCSs subpopulation favors their high resistance to a broad spectrum of drugs. Our previous studies showed the ability of M2 muscarinic receptors to negatively modulate the cell growth in GBM cell lines and in the GSCs. The aim of this study was to better characterize the inhibitory effects of M2 receptors on cell proliferation and survival in GSCs and investigate the molecular mechanisms underlying the M2-mediated cell proliferation arrest and decreased survival. Moreover, we also evaluated the ability of M2 receptors to interfere with Notch1 and EGFR pathways, whose activation promotes GSCs proliferation. Our data demonstrate that M2 receptors activation impairs cell cycle progression and survival in the primary GSC lines analyzed (GB7 and GB8). Moreover, we also demonstrated the ability of M2 receptor to inhibit Notch1 and EGFR expression, highlighting a molecular interaction between M2 receptor and the Notch-1/EGFR pathways also in GSCs. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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24 pages, 6142 KiB  
Article
Loss of 5′-Methylthioadenosine Phosphorylase (MTAP) is Frequent in High-Grade Gliomas; Nevertheless, it is Not Associated with Higher Tumor Aggressiveness
by Weder Pereira de Menezes, Viviane Aline Oliveira Silva, Izabela Natália Faria Gomes, Marcela Nunes Rosa, Maria Luisa Corcoll Spina, Adriana Cruvinel Carloni, Ana Laura Vieira Alves, Matias Melendez, Gisele Caravina Almeida, Luciane Sussuchi da Silva, Carlos Clara, Isabela Werneck da Cunha, Glaucia Noeli Maroso Hajj, Chris Jones, Lucas Tadeu Bidinotto and Rui Manuel Reis
Cells 2020, 9(2), 492; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9020492 - 20 Feb 2020
Cited by 19 | Viewed by 3947
Abstract
The 5’-methylthioadenosine phosphorylase (MTAP) gene is located in the chromosomal region 9p21. MTAP deletion is a frequent event in a wide variety of human cancers; however, its biological role in tumorigenesis remains unclear. The purpose of this study was to characterize the MTAP [...] Read more.
The 5’-methylthioadenosine phosphorylase (MTAP) gene is located in the chromosomal region 9p21. MTAP deletion is a frequent event in a wide variety of human cancers; however, its biological role in tumorigenesis remains unclear. The purpose of this study was to characterize the MTAP expression profile in a series of gliomas and to associate it with patients’ clinicopathological features. Moreover, we sought to evaluate, through glioma gene-edited cell lines, the biological impact of MTAP in gliomas. MTAP expression was evaluated in 507 glioma patients by immunohistochemistry (IHC), and the expression levels were associated with patients’ clinicopathological features. Furthermore, an in silico study was undertaken using genomic databases totalizing 350 samples. In glioma cell lines, MTAP was edited, and following MTAP overexpression and knockout (KO), a transcriptome analysis was performed by NanoString Pan-Cancer Pathways panel. Moreover, MTAP’s role in glioma cell proliferation, migration, and invasion was evaluated. Homozygous deletion of 9p21 locus was associated with a reduction of MTAP mRNA expression in the TCGA (The Cancer Genome Atlas) - glioblastoma dataset (p < 0.01). In addition, the loss of MTAP expression was markedly high in high-grade gliomas (46.6% of cases) determined by IHC and Western blotting (40% of evaluated cell lines). Reduced MTAP expression was associated with a better prognostic in the adult glioblastoma dataset (p < 0.001). Nine genes associated with five pathways were differentially expressed in MTAP-knockout (KO) cells, with six upregulated and three downregulated in MTAP. Analysis of cell proliferation, migration, and invasion did not show any significant differences between MTAP gene-edited and control cells. Our results integrating data from patients as well as in silico and in vitro models provide evidence towards the lack of strong biological importance of MTAP in gliomas. Despite the frequent loss of MTAP, it seems not to have a clinical impact in survival and does not act as a canonic tumor suppressor gene in gliomas. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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12 pages, 2504 KiB  
Article
WNK2 Inhibits Autophagic Flux in Human Glioblastoma Cell Line
by Ana Laura Vieira Alves, Angela Margarida Costa, Olga Martinho, Vinicius Duval da Silva, Peter Jordan, Viviane Aline Oliveira Silva and Rui Manuel Reis
Cells 2020, 9(2), 485; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9020485 - 20 Feb 2020
Cited by 5 | Viewed by 3350
Abstract
Autophagy is a cell-survival pathway with dual role in tumorigenesis, promoting either tumor survival or tumor death. WNK2 gene, a member of the WNK (with no lysine (K)) subfamily, acts as a tumor suppressor gene in gliomas, regulating cell migration and invasion; however, [...] Read more.
Autophagy is a cell-survival pathway with dual role in tumorigenesis, promoting either tumor survival or tumor death. WNK2 gene, a member of the WNK (with no lysine (K)) subfamily, acts as a tumor suppressor gene in gliomas, regulating cell migration and invasion; however, its role in autophagy process is poorly explored. The WNK2-methylated human glioblastoma cell line A172 WT (wild type) was compared to transfected clones A172 EV (empty vector), and A172 WNK2 (WNK2 overexpression) for the evaluation of autophagy using an inhibitor (bafilomycin A1—baf A1) and an inducer (everolimus) of autophagic flux. Western blot and immunofluorescence approaches were used to monitor autophagic markers, LC3A/B and SQSTM1/p62. A172 WNK2 cells presented a significant decrease in LC3B and p62 protein levels, and in LC3A/B ratio when compared with control cells, after treatment with baf A1 + everolimus, suggesting that WNK2 overexpression inhibits the autophagic flux in gliomas. The mTOR pathway was also evaluated under the same conditions, and the observed results suggest that the inhibition of autophagy mediated by WNK2 occurs through a mTOR-independent pathway. In conclusion, the evaluation of the autophagic process demonstrated that WNK2 inhibits the autophagic flux in glioblastoma cell line. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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15 pages, 2285 KiB  
Article
Q-Cell Glioblastoma Resource: Proteomics Analysis Reveals Unique Cell-States Are Maintained in 3D Culture
by Rochelle C. J. D’Souza, Carolin Offenhäuser, Jasmin Straube, Ulrich Baumgartner, Anja Kordowski, Yuchen Li, Brett W. Stringer, Hamish Alexander, Zarnie Lwin, Po-Ling Inglis, Rosalind L. Jeffree, Terrance G. Johns, Andrew W. Boyd and Bryan W. Day
Cells 2020, 9(2), 267; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9020267 - 21 Jan 2020
Cited by 11 | Viewed by 5485
Abstract
Glioblastoma (GBM) is a treatment-refractory central nervous system (CNS) tumour, and better therapies to treat this aggressive disease are urgently needed. Primary GBM models that represent the true disease state are essential to better understand disease biology and for accurate preclinical therapy assessment. [...] Read more.
Glioblastoma (GBM) is a treatment-refractory central nervous system (CNS) tumour, and better therapies to treat this aggressive disease are urgently needed. Primary GBM models that represent the true disease state are essential to better understand disease biology and for accurate preclinical therapy assessment. We have previously presented a comprehensive transcriptome characterisation of a panel (n = 12) of primary GBM models (Q-Cell). We have now generated a systematic, quantitative, and deep proteome abundance atlas of the Q-Cell models grown in 3D culture, representing 6167 human proteins. A recent study has highlighted the degree of functional heterogeneity that coexists within individual GBM tumours, describing four cellular states (MES-like, NPC-like, OPC-like and AC-like). We performed comparative proteomic analysis, confirming a good representation of each of the four cell-states across the 13 models examined. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified upregulation of a number of GBM-associated cancer pathway proteins. Bioinformatics analysis, using the OncoKB database, identified a number of functional actionable targets that were either uniquely or ubiquitously expressed across the panel. This study provides an in-depth proteomic analysis of the GBM Q-Cell resource, which should prove a valuable functional dataset for future biological and preclinical investigations. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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24 pages, 10525 KiB  
Article
Upregulation of Epithelial-To-Mesenchymal Transition Markers and P2X7 Receptors Is Associated to Increased Invasiveness Caused by P2X7 Receptor Stimulation in Human Glioblastoma Stem Cells
by Sihana Ziberi, Mariachiara Zuccarini, Marzia Carluccio, Patricia Giuliani, Lucia Ricci-Vitiani, Roberto Pallini, Francesco Caciagli, Patrizia Di Iorio and Renata Ciccarelli
Cells 2020, 9(1), 85; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9010085 - 29 Dec 2019
Cited by 30 | Viewed by 3384
Abstract
Glioblastoma (GBM) stem cells (GSCs), which contribute to GBM unfavorable prognosis, show high expression levels of ATP/P2X7 receptors (P2X7R). Here, we reported that cells exposure to 2’(3’)-O-(4-benzoylbenzoyl)-ATP (BzATP), a P2X7R agonist, up-regulated the expression of markers associated to epithelial-to-mesenchymal transition (EMT), [...] Read more.
Glioblastoma (GBM) stem cells (GSCs), which contribute to GBM unfavorable prognosis, show high expression levels of ATP/P2X7 receptors (P2X7R). Here, we reported that cells exposure to 2’(3’)-O-(4-benzoylbenzoyl)-ATP (BzATP), a P2X7R agonist, up-regulated the expression of markers associated to epithelial-to-mesenchymal transition (EMT), a process likely contributing to GSC malignancy, and increased GSC migration/invasiveness like the known EMT inducer, Transforming Growth Factor β1 (TGFβ1). These effects were coupled to phosphorylation of SMAD2, a downstream effector in the TGFβ pathway, suggesting its involvement in P2X7R-mediated activity in GSCs. All BzATP effects, including a decrease in the caspase 3/7 activity in GSC medium, were mostly counteracted by the P2X7R antagonist A438079. Finally, BzATP increased the subunit expression of two main human P2X7R splice variants, the full-length P2X7A and the truncated P2X7B, lacking the carboxylic tail, which have different functional properties depending on their arrangement. Since up-regulation of A/B subunits might favor their assembly into a heterotrimeric P2X7R with great sensitivity towards agonists and cell energy support, this is in line with increased EMT markers expression, cell migration/invasion and GSC survival observed following P2X7R stimulation. As in GBM microenvironment extracellular ATP levels may activate P2X7R, our data suggest a P2X7R role in GBM recurrence/invasiveness. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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9 pages, 1200 KiB  
Article
Identification of Astrocytoma Blood Serum Protein Profile
by Paulina Vaitkiene, Ruta Urbanaviciute, Povilas Grigas, Giedrius Steponaitis, Arimantas Tamasauskas and Daina Skiriutė
Cells 2020, 9(1), 16; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9010016 - 19 Dec 2019
Cited by 8 | Viewed by 2657
Abstract
High-grade astrocytomas are some of the most common and aggressive brain cancers, whose signs and symptoms are initially non-specific. Up to the present date, there are no diagnostic tools to observe the early onset of the disease. Here, we analyzed the combination of [...] Read more.
High-grade astrocytomas are some of the most common and aggressive brain cancers, whose signs and symptoms are initially non-specific. Up to the present date, there are no diagnostic tools to observe the early onset of the disease. Here, we analyzed the combination of blood serum proteins, which may play key roles in the tumorigenesis and the progression of glial tumors. Fifty-nine astrocytoma patients and 43 control serums were analyzed using Custom Human Protein Antibody Arrays, including ten targets: ANGPT1, AREG, IGF1, IP10, MMP2, NCAM1, OPN, PAI1, TGFβ1, and TIMP1. The decision tree analysis indicates that serums ANGPT1, TIMP1, IP10, and TGFβ1 are promising combinations of targets for glioma diagnostic applications. The accuracy of the decision tree algorithm was 73.5% (75/102), which correctly classified 79.7% (47/59) astrocytomas and 65.1% (28/43) healthy controls. The analysis revealed that the relative value of osteopontin (OPN) protein level alone predicted the 12-month survival of glioblastoma (GBM) patients with the specificity of 84%, while the inclusion of the IP10 protein increased model predictability to 92.3%. In conclusion, the serum protein profiles of ANGPT1, TIMP1, IP10, and TGFβ1 were associated with the presence of astrocytoma independent of its malignancy grade, while OPN and IP10 were associated with GBM patient survival. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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17 pages, 4091 KiB  
Article
Intracellular Redox-Balance Involvement in Temozolomide Resistance-Related Molecular Mechanisms in Glioblastoma
by Alessia Lo Dico, Daniela Salvatore, Cristina Martelli, Dario Ronchi, Cecilia Diceglie, Giovanni Lucignani and Luisa Ottobrini
Cells 2019, 8(11), 1315; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8111315 - 24 Oct 2019
Cited by 25 | Viewed by 4363
Abstract
Glioblastoma (GBM) is the most common astrocytic-derived brain tumor in adults, characterized by a poor prognosis mainly due to the resistance to the available therapy. The study of mitochondria-derived oxidative stress, and of the biological events that orbit around it, might help in [...] Read more.
Glioblastoma (GBM) is the most common astrocytic-derived brain tumor in adults, characterized by a poor prognosis mainly due to the resistance to the available therapy. The study of mitochondria-derived oxidative stress, and of the biological events that orbit around it, might help in the comprehension of the molecular mechanisms at the base of GBM responsiveness to Temozolomide (TMZ). Sensitive and resistant GBM cells were used to test the role of mitochondrial ROS release in TMZ-resistance. Chaperone-Mediated Autophagy (CMA) activation in relation to reactive oxygen species (ROS) release has been measured by monitoring the expression of specific genes. Treatments with H2O2 were used to test their potential in reverting resistance. Fluctuations of cytoplasmic ROS levels were accountable for CMA induction and cytotoxic effects observed in TMZ sensitive cells after treatment. On the other hand, in resistant cells, TMZ failed in producing an increase in cytoplasmic ROS levels and CMA activation, preventing GBM cell toxicity. By increasing oxidative stress, CMA activation was recovered, as also cell cytotoxicity, especially in combination with TMZ treatment. Herein, for the first time, it is shown the relation between mitochondrial ROS release, CMA activation and TMZ-responsiveness in GBM. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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Review

Jump to: Editorial, Research

15 pages, 3953 KiB  
Review
Energy Metabolism in IDH1 Wild-Type and IDH1-Mutated Glioblastoma Stem Cells: A Novel Target for Therapy?
by Cornelis J.F. van Noorden, Vashendriya V.V. Hira, Amber J. van Dijck, Metka Novak, Barbara Breznik and Remco J. Molenaar
Cells 2021, 10(3), 705; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10030705 - 22 Mar 2021
Cited by 16 | Viewed by 4489
Abstract
Cancer is a redox disease. Low levels of reactive oxygen species (ROS) are beneficial for cells and have anti-cancer effects. ROS are produced in the mitochondria during ATP production by oxidative phosphorylation (OXPHOS). In the present review, we describe ATP production in primary [...] Read more.
Cancer is a redox disease. Low levels of reactive oxygen species (ROS) are beneficial for cells and have anti-cancer effects. ROS are produced in the mitochondria during ATP production by oxidative phosphorylation (OXPHOS). In the present review, we describe ATP production in primary brain tumors, glioblastoma, in relation to ROS production. Differentiated glioblastoma cells mainly use glycolysis for ATP production (aerobic glycolysis) without ROS production, whereas glioblastoma stem cells (GSCs) in hypoxic periarteriolar niches use OXPHOS for ATP and ROS production, which is modest because of the hypoxia and quiescence of GSCs. In a significant proportion of glioblastoma, isocitrate dehydrogenase 1 (IDH1) is mutated, causing metabolic rewiring, and all cancer cells use OXPHOS for ATP and ROS production. Systemic therapeutic inhibition of glycolysis is not an option as clinical trials have shown ineffectiveness or unwanted side effects. We argue that systemic therapeutic inhibition of OXPHOS is not an option either because the anti-cancer effects of ROS production in healthy cells is inhibited as well. Therefore, we advocate to remove GSCs out of their hypoxic niches by the inhibition of their binding to niches to enable their differentiation and thus increase their sensitivity to radiotherapy and/or chemotherapy. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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22 pages, 947 KiB  
Review
Immunotherapy of Glioblastoma: Current Strategies and Challenges in Tumor Model Development
by Bernarda Majc, Metka Novak, Nataša Kopitar-Jerala, Anahid Jewett and Barbara Breznik
Cells 2021, 10(2), 265; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020265 - 29 Jan 2021
Cited by 46 | Viewed by 7565
Abstract
Glioblastoma is the most common brain malignant tumor in the adult population, and immunotherapy is playing an increasingly central role in the treatment of many cancers. Nevertheless, the search for effective immunotherapeutic approaches for glioblastoma patients continues. The goal of immunotherapy is to [...] Read more.
Glioblastoma is the most common brain malignant tumor in the adult population, and immunotherapy is playing an increasingly central role in the treatment of many cancers. Nevertheless, the search for effective immunotherapeutic approaches for glioblastoma patients continues. The goal of immunotherapy is to promote tumor eradication, boost the patient’s innate and adaptive immune responses, and overcome tumor immune resistance. A range of new, promising immunotherapeutic strategies has been applied for glioblastoma, including vaccines, oncolytic viruses, immune checkpoint inhibitors, and adoptive cell transfer. However, the main challenges of immunotherapy for glioblastoma are the intracranial location and heterogeneity of the tumor as well as the unique, immunosuppressive tumor microenvironment. Owing to the lack of appropriate tumor models, there are discrepancies in the efficiency of various immunotherapeutic strategies between preclinical studies (with in vitro and animal models) on the one hand and clinical studies (on humans) on the other hand. In this review, we summarize the glioblastoma characteristics that drive tolerance to immunotherapy, the currently used immunotherapeutic approaches against glioblastoma, and the most suitable tumor models to mimic conditions in glioblastoma patients. These models are improving and can more precisely predict patients’ responses to immunotherapeutic treatments, either alone or in combination with standard treatment. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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14 pages, 930 KiB  
Review
Hippo Signaling Pathway in Gliomas
by Konstantin Masliantsev, Lucie Karayan-Tapon and Pierre-Olivier Guichet
Cells 2021, 10(1), 184; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10010184 - 18 Jan 2021
Cited by 61 | Viewed by 7484
Abstract
The Hippo signaling pathway is a highly conserved pathway involved in tissue development and regeneration that controls organ size through the regulation of cell proliferation and apoptosis. The core Hippo pathway is composed of a block of kinases, MST1/2 (Mammalian STE20-like protein kinase [...] Read more.
The Hippo signaling pathway is a highly conserved pathway involved in tissue development and regeneration that controls organ size through the regulation of cell proliferation and apoptosis. The core Hippo pathway is composed of a block of kinases, MST1/2 (Mammalian STE20-like protein kinase 1/2) and LATS1/2 (Large tumor suppressor 1/2), which inhibits nuclear translocation of YAP/TAZ (Yes-Associated Protein 1/Transcriptional co-activator with PDZ-binding motif) and its downstream association with the TEAD (TEA domain) family of transcription factors. This pathway was recently shown to be involved in tumorigenesis and metastasis in several cancers such as lung, breast, or colorectal cancers but is still poorly investigated in brain tumors. Gliomas are the most common and the most lethal primary brain tumors representing about 80% of malignant central nervous system neoplasms. Despite intensive clinical protocol, the prognosis for patients remains very poor due to systematic relapse and treatment failure. Growing evidence demonstrating the role of Hippo signaling in cancer biology and the lack of efficient treatments for malignant gliomas support the idea that this pathway could represent a potential target paving the way for alternative therapeutics. Based on recent advances in the Hippo pathway deciphering, the main goal of this review is to highlight the role of this pathway in gliomas by a state-of-the-art synthesis. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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21 pages, 1204 KiB  
Review
Resistance Mechanisms and Barriers to Successful Immunotherapy for Treating Glioblastoma
by Jason Adhikaree, Julia Moreno-Vicente, Aanchal Preet Kaur, Andrew Mark Jackson and Poulam M. Patel
Cells 2020, 9(2), 263; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9020263 - 21 Jan 2020
Cited by 40 | Viewed by 5238
Abstract
Glioblastoma (GBM) is inevitably refractory to surgery and chemoradiation. The hope for immunotherapy has yet to be realised in the treatment of GBM. Immune checkpoint blockade antibodies, particularly those targeting the Programme death 1 (PD-1)/PD-1 ligand (PD-L1) pathway, have improved the prognosis in [...] Read more.
Glioblastoma (GBM) is inevitably refractory to surgery and chemoradiation. The hope for immunotherapy has yet to be realised in the treatment of GBM. Immune checkpoint blockade antibodies, particularly those targeting the Programme death 1 (PD-1)/PD-1 ligand (PD-L1) pathway, have improved the prognosis in a range of cancers. However, its use in combination with chemoradiation or as monotherapy has proved unsuccessful in treating GBM. This review focuses on our current knowledge of barriers to immunotherapy success in treating GBM, such as diminished pre-existing anti-tumour immunity represented by low levels of PD-L1 expression, low tumour mutational burden and a severely exhausted T-cell tumour infiltrate. Likewise, systemic T-cell immunosuppression is seen driven by tumoural factors and corticosteroid use. Furthermore, unique anatomical differences with primary intracranial tumours such as the blood-brain barrier, the type of antigen-presenting cells and lymphatic drainage contribute to differences in treatment success compared to extracranial tumours. There are, however, shared characteristics with those known in other tumours such as the immunosuppressive tumour microenvironment. We conclude with a summary of ongoing and future immune combination strategies in GBM, which are representative of the next wave in immuno-oncology therapeutics. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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13 pages, 1986 KiB  
Review
Extracellular Vesicle-Mediated Communication between the Glioblastoma and Its Microenvironment
by Esperanza R. Matarredona and Angel M. Pastor
Cells 2020, 9(1), 96; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9010096 - 30 Dec 2019
Cited by 59 | Viewed by 5333
Abstract
The glioblastoma is the most malignant form of brain cancer. Glioblastoma cells use multiple ways of communication with the tumor microenvironment in order to tune it for their own benefit. Among these, extracellular vesicles have emerged as a focus of study in the [...] Read more.
The glioblastoma is the most malignant form of brain cancer. Glioblastoma cells use multiple ways of communication with the tumor microenvironment in order to tune it for their own benefit. Among these, extracellular vesicles have emerged as a focus of study in the last few years. Extracellular vesicles contain soluble proteins, DNA, mRNA and non-coding RNAs with which they can modulate the phenotypes of recipient cells. In this review we summarize recent findings on the extracellular vesicles-mediated bilateral communication established between glioblastoma cells and their tumor microenvironment, and the impact of this dialogue for tumor progression and recurrence. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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29 pages, 1576 KiB  
Review
Relevance of Translation Initiation in Diffuse Glioma Biology and its Therapeutic Potential
by Digregorio Marina, Lombard Arnaud, Lumapat Paul Noel, Scholtes Felix, Rogister Bernard and Coppieters Natacha
Cells 2019, 8(12), 1542; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8121542 - 29 Nov 2019
Cited by 11 | Viewed by 5522
Abstract
Cancer cells are continually exposed to environmental stressors forcing them to adapt their protein production to survive. The translational machinery can be recruited by malignant cells to synthesize proteins required to promote their survival, even in times of high physiological and pathological stress. [...] Read more.
Cancer cells are continually exposed to environmental stressors forcing them to adapt their protein production to survive. The translational machinery can be recruited by malignant cells to synthesize proteins required to promote their survival, even in times of high physiological and pathological stress. This phenomenon has been described in several cancers including in gliomas. Abnormal regulation of translation has encouraged the development of new therapeutics targeting the protein synthesis pathway. This approach could be meaningful for glioma given the fact that the median survival following diagnosis of the highest grade of glioma remains short despite current therapy. The identification of new targets for the development of novel therapeutics is therefore needed in order to improve this devastating overall survival rate. This review discusses current literature on translation in gliomas with a focus on the initiation step covering both the cap-dependent and cap-independent modes of initiation. The different translation initiation protagonists will be described in normal conditions and then in gliomas. In addition, their gene expression in gliomas will systematically be examined using two freely available datasets. Finally, we will discuss different pathways regulating translation initiation and current drugs targeting the translational machinery and their potential for the treatment of gliomas. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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