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Glioblastoma: Recapitulating the Key Breakthroughs and Future Perspective

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 93182

Special Issue Editors

Department of Stereotactic and Functional Neurosurgery, University Hospital of Bonn, 53127 Bonn, Germany
Interests: neuro-oncology; glioblastoma; stereotaxic & functional neurosurgery; cancer stem cells
Special Issues, Collections and Topics in MDPI journals
Department of Neurological Surgery, Mayo Clinic, Jacksonville, FL 32224, USA
Interests: neuro-oncology; glioblastoma; cancer stem cells; adult neurogenesis
Special Issues, Collections and Topics in MDPI journals
Department of Neurosurgery, University Hospital Bonn, 53127 Bonn, Germany
Interests: neuro-oncology; glioblastoma; stereotaxic & functional neurosurgery; cancer stem cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Glioblastoma remains the most common and aggressive malignant primary brain tumour. Despite several therapeutic advances and broader understanding towards the complex interplay of glioblastoma genome and epigenome, as well as host immune system, the survival improvement in GBM patients appear to have reached a plateau and relapses continue to be the biggest clinical challenge.

In this special issue, experts in the field will review the current diagnostic, therapeutic and experimental models in GBM. Of interest are the research articles (in-vivo, in-vitro) that may help to further refine the understanding of tumour heterogeneity/microenvironment, the diverse molecular signature in GBM subtypes (epigenome, immune landscape, dysregulation of phylogenetically conserved signalling pathways, etc.) and the relative contribution of glioma stem cells (GSCs). In addition, the review articles highlighting new findings in the above areas and underlining the similarities or cross-comparisons between GBM and other human cancers are also welcome. In the prospective articles, manuscripts that address the key challenges in paediatric glioblastoma that need to be considered when applying treatment strategies purely based on adult glioblastoma trials, and the negative results while pursuing a strong scientific hypothesis in GBM will be of interest.

Prof. Dr. Jaroslaw Maciaczyk
Dr. Hugo Guerrero‐Cazares
Dr. Amit Sharma
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
  • glioma stem cells
  • signalling pathways
  • epigenomics
  • tumour heterogeneity
  • tumour microenvironment

Published Papers (33 papers)

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Editorial

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5 pages, 226 KiB  
Editorial
Editorial to Special Issue “Glioblastoma: Recapitulating the Key Breakthroughs and Future Perspective”
by Amit Sharma, Hugo Guerrero-Cázares and Jarek Maciaczyk
Int. J. Mol. Sci. 2023, 24(3), 2548; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032548 - 29 Jan 2023
Viewed by 1419
Abstract
Glioblastoma (GBM) remains the most common and aggressive malignant primary brain tumor [...] Full article

Research

Jump to: Editorial, Review, Other

20 pages, 2207 KiB  
Article
TRPML2 Mucolipin Channels Drive the Response of Glioma Stem Cells to Temozolomide and Affect the Overall Survival in Glioblastoma Patients
by Maria Beatrice Morelli, Massimo Nabissi, Consuelo Amantini, Federica Maggi, Lucia Ricci-Vitiani, Roberto Pallini and Giorgio Santoni
Int. J. Mol. Sci. 2022, 23(23), 15356; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315356 - 05 Dec 2022
Cited by 1 | Viewed by 1148
Abstract
The survival of patients with glioblastoma (GBM) is poor. The main cause is the presence of glioma stem cells (GSCs), exceptionally resistant to temozolomide (TMZ) treatment. This last may be related to the heterogeneous expression of ion channels, among them TRPML2. Its mRNA [...] Read more.
The survival of patients with glioblastoma (GBM) is poor. The main cause is the presence of glioma stem cells (GSCs), exceptionally resistant to temozolomide (TMZ) treatment. This last may be related to the heterogeneous expression of ion channels, among them TRPML2. Its mRNA expression was evaluated in two different neural stem cell (NS/PC) lines and sixteen GBM stem-like cells by qRT-PCR. The response to TMZ was evaluated in undifferentiated or differentiated GSCs, and in TRPML2-induced or silenced GSCs. The relationship between TRPML2 expression and responsiveness to TMZ treatment was evaluated by MTT assay showing that increased TRPML2 mRNA levels are associated with resistance to TMZ. This research was deepened by qRT-PCR and western blot analysis. PI3K/AKT and JAK/STAT pathways as well as ABC and SLC drug transporters were involved. Finally, the relationship between TRPML2 expression and overall survival (OS) and progression-free survival (PFS) in patient-derived GSCs was evaluated by Kaplan–Meier analysis. The expression of TRPML2 mRNA correlates with worse OS and PFS in GBM patients. Thus, the expression of TRPML2 in GSCs influences the responsiveness to TMZ in vitro and affects OS and PFS in GBM patients. Full article
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21 pages, 5350 KiB  
Article
The Chromatin-Oxygen Sensor Gene KDM5C Associates with Novel Hypoxia-Related Signatures in Glioblastoma Multiforme
by Denise Drongitis, Lucia Verrillo, Pasqualino De Marinis, Pasquale Orabona, Agnese Caiola, Giacinto Turitto, Alessandra Alfieri, Sara Bruscella, Marisa Gentile, Vania Moriello, Ettore Sannino, Ines Di Muccio, Valerio Costa, Maria Giuseppina Miano and Alberto de Bellis
Int. J. Mol. Sci. 2022, 23(18), 10250; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810250 - 06 Sep 2022
Cited by 3 | Viewed by 2121
Abstract
Glioblastoma multiforme (GBM) is a fatal brain tumor without effective drug treatment. In this study, we highlight, for the first time, the contribution of chromatin remodeling gene Lysine (K)-specific demethylase 5C (KDM5C) in GBM via an extensive analysis of clinical, expression, [...] Read more.
Glioblastoma multiforme (GBM) is a fatal brain tumor without effective drug treatment. In this study, we highlight, for the first time, the contribution of chromatin remodeling gene Lysine (K)-specific demethylase 5C (KDM5C) in GBM via an extensive analysis of clinical, expression, and functional data, integrated with publicly available omic datasets. The expression analysis on GBM samples (N = 37) revealed two informative subtypes, namely KDM5CHigh and KDM5CLow, displaying higher/lower KDM5C levels compared to the controls. The former subtype displays a strong downregulation of brain-derived neurotrophic factor (BDNF)—a negative KDM5C target—and a robust overexpression of hypoxia-inducible transcription factor-1A (HIF1A) gene, a KDM5C modulator. Additionally, a significant co-expression among the prognostic markers HIF1A, Survivin, and p75 was observed. These results, corroborated by KDM5C overexpression and hypoxia-related functional assays in T98G cells, suggest a role for the HIF1A-KDM5C axis in the hypoxic response in this tumor. Interestingly, fluorescence-guided surgery on GBM sections further revealed higher KDM5C and HIF1A levels in the tumor rim niche compared to the adjacent tumor margin, indicating a regionally restricted hyperactivity of this regulatory axis. Analyzing the TCGA expression and methylation data, we found methylation changes between the subtypes in the genes, accounting for the hypoxia response, stem cell differentiation, and inflammation. High NANOG and IL6 levels highlight a distinctive stem cell-like and proinflammatory signature in the KDM5CHigh subgroup and GBM niches. Taken together, our results indicate HIF1A-KDM5C as a new, relevant cancer axis in GBM, opening a new, interesting field of investigation based on KDM5C as a potential therapeutic target of the hypoxic microenvironment in GBM. Full article
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17 pages, 3953 KiB  
Article
Coexpression of TRPML1 and TRPML2 Mucolipin Channels Affects the Survival of Glioblastoma Patients
by Giorgio Santoni, Federica Maggi, Consuelo Amantini, Antonietta Arcella, Oliviero Marinelli, Massimo Nabissi, Matteo Santoni and Maria Beatrice Morelli
Int. J. Mol. Sci. 2022, 23(14), 7741; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147741 - 13 Jul 2022
Cited by 3 | Viewed by 1689
Abstract
Among brain cancers, glioblastoma (GBM) is the most malignant glioma with an extremely poor prognosis. It is characterized by high cell heterogeneity, which can be linked to its high malignancy. We have previously demonstrated that TRPML1 channels affect the OS of GBM patients. [...] Read more.
Among brain cancers, glioblastoma (GBM) is the most malignant glioma with an extremely poor prognosis. It is characterized by high cell heterogeneity, which can be linked to its high malignancy. We have previously demonstrated that TRPML1 channels affect the OS of GBM patients. Herein, by RT-PCR, FACS and Western blot, we demonstrated that TRPML1 and TRPML2 channels are differently expressed in GBM patients and cell lines. Moreover, these channels partially colocalized in ER and lysosomal compartments in GBM cell lines, as evaluated by confocal analysis. Interestingly, the silencing of TRPML1 or TRPML2 by RNA interference results in the decrease in the other receptor at protein level. Moreover, the double knockdown of TRPML1 and TRPML2 leads to increased GBM cell survival with respect to single-channel-silenced cells, and improves migration and invasion ability of U251 cells. Finally, the Kaplan–Meier survival analysis demonstrated that patients with high TRPML2 expression in absence of TRPML1 expression strongly correlates with short OS, whereas high TRPML1 associated with low TRPML2 mRNA expression correlates with longer OS in GBM patients. The worst OS in GBM patients is associated with the loss of both TRPML1 and TRPML2 channels. Full article
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23 pages, 11188 KiB  
Article
Next-Generation Grade and Survival Expression Biomarkers of Human Gliomas Based on Algorithmically Reconstructed Molecular Pathways
by Marianna A. Zolotovskaia, Max A. Kovalenko, Victor S. Tkachev, Alexander M. Simonov, Maxim I. Sorokin, Ella Kim, Denis V. Kuzmin, Betul Karademir-Yilmaz and Anton A. Buzdin
Int. J. Mol. Sci. 2022, 23(13), 7330; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137330 - 30 Jun 2022
Cited by 4 | Viewed by 1956
Abstract
In gliomas, expression of certain marker genes is strongly associated with survival and tumor type and often exceeds histological assessments. Using a human interactome model, we algorithmically reconstructed 7494 new-type molecular pathways that are centered each on an individual protein. Each single-gene expression [...] Read more.
In gliomas, expression of certain marker genes is strongly associated with survival and tumor type and often exceeds histological assessments. Using a human interactome model, we algorithmically reconstructed 7494 new-type molecular pathways that are centered each on an individual protein. Each single-gene expression and gene-centric pathway activation was tested as a survival and tumor grade biomarker in gliomas and their diagnostic subgroups (IDH mutant or wild type, IDH mutant with 1p/19q co-deletion, MGMT promoter methylated or unmethylated), including the three major molecular subtypes of glioblastoma (proneural, mesenchymal, classical). We used three datasets from The Cancer Genome Atlas and the Chinese Glioma Genome Atlas, which in total include 527 glioblastoma and 1097 low grade glioma profiles. We identified 2724 such gene and 2418 pathway survival biomarkers out of total 17,717 genes and 7494 pathways analyzed. We then assessed tumor grade and molecular subtype biomarkers and with the threshold of AUC > 0.7 identified 1322/982 gene biomarkers and 472/537 pathway biomarkers. This suggests roughly two times greater efficacy of the reconstructed pathway approach compared to gene biomarkers. Thus, we conclude that activation levels of algorithmically reconstructed gene-centric pathways are a potent class of new-generation diagnostic and prognostic biomarkers for gliomas. Full article
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20 pages, 4228 KiB  
Article
Chronically Radiation-Exposed Survivor Glioblastoma Cells Display Poor Response to Chk1 Inhibition under Hypoxia
by Nareg Pinarbasi-Degirmenci, Ilknur Sur-Erdem, Vuslat Akcay, Yasemin Bolukbasi, Ugur Selek, Ihsan Solaroglu and Tugba Bagci-Onder
Int. J. Mol. Sci. 2022, 23(13), 7051; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137051 - 24 Jun 2022
Cited by 4 | Viewed by 2752
Abstract
Glioblastoma is the most malignant primary brain tumor, and a cornerstone in its treatment is radiotherapy. However, tumor cells surviving after irradiation indicates treatment failure; therefore, better understanding of the mechanisms regulating radiotherapy response is of utmost importance. In this study, we generated [...] Read more.
Glioblastoma is the most malignant primary brain tumor, and a cornerstone in its treatment is radiotherapy. However, tumor cells surviving after irradiation indicates treatment failure; therefore, better understanding of the mechanisms regulating radiotherapy response is of utmost importance. In this study, we generated clinically relevant irradiation-exposed models by applying fractionated radiotherapy over a long time and selecting irradiation-survivor (IR-Surv) glioblastoma cells. We examined the transcriptomic alterations, cell cycle and growth rate changes and responses to secondary radiotherapy and DNA damage response (DDR) modulators. Accordingly, IR-Surv cells exhibited slower growth and partly retained their ability to resist secondary irradiation. Concomitantly, IR-Surv cells upregulated the expression of DDR-related genes, such as CHK1, ATM, ATR, and MGMT, and had better DNA repair capacity. IR-Surv cells displayed downregulation of hypoxic signature and lower induction of hypoxia target genes, compared to naïve glioblastoma cells. Moreover, Chk1 inhibition alone or in combination with irradiation significantly reduced cell viability in both naïve and IR-Surv cells. However, IR-Surv cells’ response to Chk1 inhibition markedly decreased under hypoxic conditions. Taken together, we demonstrate the utility of combining DDR inhibitors and irradiation as a successful approach for both naïve and IR-Surv glioblastoma cells as long as cells are refrained from hypoxic conditions. Full article
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14 pages, 16886 KiB  
Article
Novel Antibody–Peptide Binding Assay Indicates Presence of Immunoglobulins against EGFR Phospho-Site S1166 in High-Grade Glioma
by Lona Zeneyedpour, Christoph Stingl, Johan M. Kros, Peter A. E. Sillevis Smitt and Theo M. Luider
Int. J. Mol. Sci. 2022, 23(9), 5061; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095061 - 02 May 2022
Cited by 2 | Viewed by 2107
Abstract
We investigated the feasibility of detecting the presence of specific autoantibodies against potential tumor-associated peptide antigens by enriching these antibody–peptide complexes using Melon Gel resin and mass spectrometry. Our goal was to find tumor-associated phospho-sites that trigger immunoreactions and raise autoantibodies that are [...] Read more.
We investigated the feasibility of detecting the presence of specific autoantibodies against potential tumor-associated peptide antigens by enriching these antibody–peptide complexes using Melon Gel resin and mass spectrometry. Our goal was to find tumor-associated phospho-sites that trigger immunoreactions and raise autoantibodies that are detectable in plasma of glioma patients. Such immunoglobulins can potentially be used as targets in immunotherapy. To that aim, we describe a method to detect the presence of antibodies in biological samples that are specific to selected clinically relevant peptides. The method is based on the formation of antibody–peptide complexes by mixing patient plasma with a glioblastoma multiforme (GBM) derived peptide library, enrichment of antibodies and antibody–peptide complexes, the separation of peptides after they are released from immunoglobulins by molecular weight filtration and finally mass spectrometric quantification of these peptides. As proof of concept, we successfully applied the method to dinitrophenyl (DNP)-labeled α-casein peptides mixed with anti-DNP. Further, we incubated human plasma with a phospho-peptide library and conducted targeted analysis on EGFR and GFAP phospho-peptides. As a result, immunoaffinity against phospho-peptide GSHQIS[+80]LDNPDYQQDFFPK (EGFR phospho-site S1166) was detected in high-grade glioma (HGG) patient plasma but not in healthy donor plasma. For the GFAP phospho-sites selected, such immunoaffinity was not observed. Full article
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16 pages, 3410 KiB  
Article
Crosstalk between β-Catenin and CCL2 Drives Migration of Monocytes towards Glioblastoma Cells
by Philippe Aretz, Donata Maciaczyk, Suad Yusuf, Rüdiger V. Sorg, Daniel Hänggi, Hongjia Liu, Hongde Liu, Tikam Chand Dakal, Amit Sharma, Ramakrishna Bethanabatla, Silke Neumann and Jarek Maciaczyk
Int. J. Mol. Sci. 2022, 23(9), 4562; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094562 - 20 Apr 2022
Cited by 10 | Viewed by 2195
Abstract
Isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) is a fast growing and highly heterogeneous tumor, often characterized by the presence of glioblastoma stem cells (GSCs). The plasticity of GSCs results in therapy resistance and impairs anti-tumor immune response by influencing immune cells in the tumor [...] Read more.
Isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) is a fast growing and highly heterogeneous tumor, often characterized by the presence of glioblastoma stem cells (GSCs). The plasticity of GSCs results in therapy resistance and impairs anti-tumor immune response by influencing immune cells in the tumor microenvironment (TME). Previously, β-catenin was associated with stemness in GBM as well as with immune escape mechanisms. Here, we investigated the effect of β-catenin on attracting monocytes towards GBM cells. In addition, we evaluated whether CCL2 is involved in β-catenin crosstalk between monocytes and tumor cells. Our analysis revealed that shRNA targeting β-catenin in GBMs reduces monocytes attraction and impacts CCL2 secretion. The addition of recombinant CCL2 restores peripheral blood mononuclear cells (PBMC) migration towards medium (TCM) conditioned by shβ-catenin GBM cells. CCL2 knockdown in GBM cells shows similar effects and reduces monocyte migration to a similar extent as β-catenin knockdown. When investigating the effect of CCL2 on β-catenin activity, we found that CCL2 modulates components of the Wnt/β-catenin pathway and alters the clonogenicity of GBM cells. In addition, the pharmacological β-catenin inhibitor MSAB reduces active β-catenin, downregulates the expression of associated genes and alters CCL2 secretion. Taken together, we showed that β-catenin plays an important role in attracting monocytes towards GBM cells in vitro. We hypothesize that the interactions between β-catenin and CCL2 contribute to maintenance of GSCs via modulating immune cell interaction and promoting GBM growth and recurrence. Full article
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22 pages, 5494 KiB  
Article
GZ17-6.02 Inhibits the Growth of EGFRvIII+ Glioblastoma
by Justin Choi, Zachary A. Bordeaux, Jaimie McKeel, Cory Nanni, Nishadh Sutaria, Gabriella Braun, Cole Davis, Meghan N. Miller, Martin P. Alphonse, Shawn G. Kwatra, Cameron E. West and Madan M. Kwatra
Int. J. Mol. Sci. 2022, 23(8), 4174; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084174 - 10 Apr 2022
Cited by 5 | Viewed by 3164
Abstract
Epidermal Growth Factor Receptor (EGFR) is amplified in over 50% of glioblastomas and promotes tumor formation and progression. However, attempts to treat glioblastoma with EGFR tyrosine kinase inhibitors have been unsuccessful thus far. The current standard of care is especially poor in patients [...] Read more.
Epidermal Growth Factor Receptor (EGFR) is amplified in over 50% of glioblastomas and promotes tumor formation and progression. However, attempts to treat glioblastoma with EGFR tyrosine kinase inhibitors have been unsuccessful thus far. The current standard of care is especially poor in patients with a constitutively active form of EGFR, EGFRvIII, which is associated with shorter survival time. This study examined the effect of GZ17-6.02, a novel anti-cancer agent undergoing phase 1 studies, on two EGFRvIII+ glioblastoma stem cells: D10-0171 and D317. In vitro analyses showed that GZ17-6.02 inhibited the growth of both D10-0171 and D317 cells with IC50 values of 24.84 and 28.28 µg/mL respectively. RNA sequencing and reverse phase protein array analyses revealed that GZ17-6.02 downregulates pathways primarily related to steroid synthesis and cell cycle progression. Interestingly, G17-6.02’s mechanism of action involves the downregulation of the recently identified glioblastoma super-enhancer genes WSCD1, EVOL2, and KLHDC8A. Finally, a subcutaneous xenograft model showed that GZ17-6.02 inhibits glioblastoma growth in vivo. We conclude that GZ17-6.02 is a promising combination drug effective at inhibiting the growth of a subset of glioblastomas and our data warrants further preclinical studies utilizing xenograft models to identify patients that may respond to this drug. Full article
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27 pages, 7860 KiB  
Article
Investigating Glioblastoma Multiforme Sub-Proteomes: A Computational Study of CUSA Fluid Proteomic Data
by Fabiana Moresi, Diana Valeria Rossetti, Federica Vincenzoni, Giorgia Antonia Simboli, Giuseppe La Rocca, Alessandro Olivi, Andrea Urbani, Giovanni Sabatino and Claudia Desiderio
Int. J. Mol. Sci. 2022, 23(4), 2058; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042058 - 12 Feb 2022
Cited by 5 | Viewed by 2030
Abstract
Based on our previous proteomic study on Cavitating Ultrasound Aspirator (CUSA) fluid pools of Newly Diagnosed (ND) and Recurrent (R) glioblastomas (GBMs) of tumor core and periphery, as defined by 5-aminolevulinc acid (5-ALA) metabolite fluorescence, this work aims to apply a bioinformatic approach [...] Read more.
Based on our previous proteomic study on Cavitating Ultrasound Aspirator (CUSA) fluid pools of Newly Diagnosed (ND) and Recurrent (R) glioblastomas (GBMs) of tumor core and periphery, as defined by 5-aminolevulinc acid (5-ALA) metabolite fluorescence, this work aims to apply a bioinformatic approach to investigate specifically into three sub-proteomes, i.e., Not Detected in Brain (NB), Cancer Related (CR) and Extracellular Vesicles (EVs) proteins following selected database classification. The study of these yet unexplored specific datasets aims to understand the high infiltration capability and relapse rate that characterizes this aggressive brain cancer. Out of the 587 proteins highly confidently identified in GBM CUSA pools, 53 proteins were classified as NB. Their gene ontology (GO) analysis showed the over-representation of blood coagulation and plasminogen activating cascade pathways, possibly compatible with Blood Brain Barrier damage in tumor disease and surgery bleeding. However, the NB group also included non-blood proteins and, specifically, histones correlated with oncogenesis. Concerning CR proteins, 159 proteins were found in the characterized GBM proteome. Their GO analysis highlighted the over-representation of many pathways, primarily glycolysis. Interestingly, while CR proteins were identified in ND-GBM exclusively in the tumor zones (fluorescence positive core and periphery zones) as predictable, conversely, in R-GBM they were unexpectedly characterized prevalently in the healthy zone (fluorescence negative tumor periphery). Relative to EVs protein classification, 60 proteins were found. EVs are over-released in tumor disease and are important in the transport of biological macromolecules. Furthermore, the presence of EVs in numerous body fluids makes them a possible low-invasive source of brain tumor biomarkers to be investigated. These results give new hints on the molecular features of GBM in trying to understand its aggressive behavior and open to more in-depth investigations to disclose potential disease biomarkers. Full article
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22 pages, 5885 KiB  
Article
Up-Regulation of Cyclooxygenase-2 (COX-2) Expression by Temozolomide (TMZ) in Human Glioblastoma (GBM) Cell Lines
by Francesca Lombardi, Francesca Rosaria Augello, Serena Artone, Mitilda Karoli Gugu, Maria Grazia Cifone, Benedetta Cinque and Paola Palumbo
Int. J. Mol. Sci. 2022, 23(3), 1545; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031545 - 28 Jan 2022
Cited by 9 | Viewed by 3180
Abstract
TMZ-resistance remains a main limitation in glioblastoma (GBM) treatment. TMZ is an alkylating agent whose cytotoxicity is modulated by O6-methylguanine-DNA methyltransferase (MGMT), whose expression is determined by MGMT gene promoter methylation status. The inflammatory marker COX-2 has been implicated in GBM tumorigenesis, progression, [...] Read more.
TMZ-resistance remains a main limitation in glioblastoma (GBM) treatment. TMZ is an alkylating agent whose cytotoxicity is modulated by O6-methylguanine-DNA methyltransferase (MGMT), whose expression is determined by MGMT gene promoter methylation status. The inflammatory marker COX-2 has been implicated in GBM tumorigenesis, progression, and stemness. COX-2 inhibitors are considered a GBM add-on treatment due to their ability to increase TMZ-sensitivity. We investigated the effect of TMZ on COX-2 expression in GBM cell lines showing different COX-2 levels and TMZ sensitivity (T98G and U251MG). β-catenin, MGMT, and SOX-2 expression was analyzed. The effects of NS398, COX-2 inhibitor, alone or TMZ-combined, were studied evaluating cell proliferation by the IncuCyte® system, cell cycle/apoptosis, and clonogenic potential. COX-2, β-catenin, MGMT, and SOX-2 expression was evaluated by RT-PCR, Western blotting, and immunofluorescence and PGE2 by ELISA. Our findings, sustaining the role of COX-2/PGE2 system in TMZ-resistance of GBM, show, for the first time, a relevant, dose-dependent up-regulation of COX-2 expression and activity in TMZ-treated T98G that, in turn, correlated with chemoresistance. Similarly, all the COX-2-dependent signaling pathways involved in TMZ-resistance also resulted in being up-modulated after treatment with TMZ. NS398+TMZ was able to reduce cell proliferation and induce cell cycle arrest and apoptosis. Moreover, NS398+TMZ counteracted the resistance in T98G preventing the TMZ-induced COX-2, β-catenin, MGMT, and SOX-2 up-regulation. Full article
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17 pages, 2642 KiB  
Article
Somatostatin Receptor Splicing Variant sst5TMD4 Overexpression in Glioblastoma Is Associated with Poor Survival, Increased Aggressiveness Features, and Somatostatin Analogs Resistance
by Antonio C. Fuentes-Fayos, Miguel E. G-García, Jesús M. Pérez-Gómez, Annabel Peel, Cristóbal Blanco-Acevedo, Juan Solivera, Alejandro Ibáñez-Costa, Manuel D. Gahete, Justo P. Castaño and Raúl M. Luque
Int. J. Mol. Sci. 2022, 23(3), 1143; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031143 - 20 Jan 2022
Cited by 5 | Viewed by 2688
Abstract
Glioblastoma (GBM) is the most malignant and lethal brain tumor. Current standard treatment consists of surgery followed by radiotherapy/chemotherapy; however, this is only a palliative approach with a mean post-operative survival of scarcely ~12–15 months. Thus, the identification of novel therapeutic targets to [...] Read more.
Glioblastoma (GBM) is the most malignant and lethal brain tumor. Current standard treatment consists of surgery followed by radiotherapy/chemotherapy; however, this is only a palliative approach with a mean post-operative survival of scarcely ~12–15 months. Thus, the identification of novel therapeutic targets to treat this devastating pathology is urgently needed. In this context, the truncated splicing variant of the somatostatin receptor subtype 5 (sst5TMD4), which is produced by aberrant alternative splicing, has been demonstrated to be overexpressed and associated with increased aggressiveness features in several tumors. However, the presence, functional role, and associated molecular mechanisms of sst5TMD4 in GBM have not been yet explored. Therefore, we performed a comprehensive analysis to characterize the expression and pathophysiological role of sst5TMD4 in human GBM. sst5TMD4 was significantly overexpressed (at mRNA and protein levels) in human GBM tissue compared to non-tumor (control) brain tissue. Remarkably, sst5TMD4 expression was significantly associated with poor overall survival and recurrent tumors in GBM patients. Moreover, in vitro sst5TMD4 overexpression (by specific plasmid) increased, whereas sst5TMD4 silencing (by specific siRNA) decreased, key malignant features (i.e., proliferation and migration capacity) of GBM cells (U-87 MG/U-118 MG models). Furthermore, sst5TMD4 overexpression in GBM cells altered the activity of multiple key signaling pathways associated with tumor aggressiveness/progression (AKT/JAK-STAT/NF-κB/TGF-β), and its silencing sensitized GBM cells to the antitumor effect of pasireotide (a somatostatin analog). Altogether, these results demonstrate that sst5TMD4 is overexpressed and associated with enhanced malignancy features in human GBMs and reveal its potential utility as a novel diagnostic/prognostic biomarker and putative therapeutic target in GBMs. Full article
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13 pages, 1309 KiB  
Article
Regulation of the Receptor Tyrosine Kinase AXL in Response to Therapy and Its Role in Therapy Resistance in Glioblastoma
by Lea Scherschinski, Markus Prem, Irina Kremenetskaia, Ingeborg Tinhofer, Peter Vajkoczy, Anna-Gila Karbe and Julia Sophie Onken
Int. J. Mol. Sci. 2022, 23(2), 982; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020982 - 17 Jan 2022
Cited by 12 | Viewed by 2218
Abstract
The receptor tyrosine kinase AXL (RTK-AXL) is implicated in therapy resistance and tumor progression in glioblastoma multiforme (GBM). Here, we investigated therapy-induced receptor modifications and how endogenous RTK-AXL expression and RTK-AXL inhibition contribute to therapy resistance in GBM. GBM cell lines U118MG and [...] Read more.
The receptor tyrosine kinase AXL (RTK-AXL) is implicated in therapy resistance and tumor progression in glioblastoma multiforme (GBM). Here, we investigated therapy-induced receptor modifications and how endogenous RTK-AXL expression and RTK-AXL inhibition contribute to therapy resistance in GBM. GBM cell lines U118MG and SF126 were exposed to temozolomide (TMZ) and radiation (RTX). Receptor modifications in response to therapy were investigated on protein and mRNA levels. TMZ-resistant and RTK-AXL overexpressing cell lines were exposed to increasing doses of TMZ and RTX, with and without RTK-AXL tyrosine kinase inhibitor (TKI). Colorimetric microtiter (MTT) assay and colony formation assay (CFA) were used to assess cell viability. Results showed that the RTK-AXL shedding product, C-terminal AXL (CT-AXL), rises in response to repeated TMZ doses and under hypoxia, acts as a surrogate marker for radio-resistance. Endogenous RTX-AXL overexpression leads to therapy resistance, whereas combination therapy of TZM and RTX with TKI R428 significantly increases therapeutic effects. This data proves the role of RTK-AXL in acquired and intrinsic therapy resistance. By demonstrating that therapy resistance may be overcome by combining AXL TKI with standard treatments, we have provided a rationale for future study designs investigating AXL TKIs in GBM. Full article
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8 pages, 1503 KiB  
Article
HIF2α Upregulates the Migration Factor ODZ1 under Hypoxia in Glioblastoma Stem Cells
by María Carcelén, Carlos Velásquez, Veronica Vidal, Olga Gutierrez and Jose L. Fernandez-Luna
Int. J. Mol. Sci. 2022, 23(2), 741; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020741 - 11 Jan 2022
Cited by 3 | Viewed by 1634
Abstract
Background: Glioblastoma (GBM) remains a major clinical challenge due to its invasive capacity, resistance to treatment, and recurrence. We have previously shown that ODZ1 contributes to glioblastoma invasion and that ODZ1 mRNA levels can be upregulated by epigenetic mechanisms in response to hypoxia. [...] Read more.
Background: Glioblastoma (GBM) remains a major clinical challenge due to its invasive capacity, resistance to treatment, and recurrence. We have previously shown that ODZ1 contributes to glioblastoma invasion and that ODZ1 mRNA levels can be upregulated by epigenetic mechanisms in response to hypoxia. Herein, we have further studied the transcriptional regulation of ODZ1 in GBM stem cells (GSCs) under hypoxic conditions and analyzed whether HIF2α has any role in this regulation. Methods: We performed the experiments in three primary GSC cell lines established from tumor specimens. GSCs were cultured under hypoxia, treated with HIF regulators (DMOG, chetomin), or transfected with specific siRNAs, and the expression levels of ODZ1 and HIF2α were analyzed. In addition, the response of the ODZ1 promoter cloned into a luciferase reporter plasmid to the activation of HIF was also studied. Results: The upregulation of both mRNA and protein levels of HIF2α under hypoxia conditions correlated with the expression of ODZ1 mRNA. Moreover, the knockdown of HIF2α by siRNAs downregulated the expression of ODZ1. We found, in the ODZ1 promoter, a HIF consensus binding site (GCGTG) 1358 bp from the transcription start site (TSS) and a HIF-like site (CCGTG) 826 bp from the TSS. Luciferase assays revealed that the stabilization of HIF by DMOG resulted in the increased activity of the ODZ1 promoter. Conclusions: Our data indicate that the HIF2α-mediated upregulation of ODZ1 helps strengthen the transcriptional control of this migration factor under hypoxia in glioblastoma stem cells. The discovery of this novel transcriptional pathway identifies new targets to develop strategies that may avoid GBM tumor invasion and recurrence. Full article
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16 pages, 3116 KiB  
Article
Chemoattraction of Neoplastic Glial Cells with CXCL10, CCL2 and CCL11 as a Paradigm for a Promising Therapeutic Approach for Primary Brain Tumors
by Laurence Déry, Gabriel Charest, Brigitte Guérin, Mohsen Akbari and David Fortin
Int. J. Mol. Sci. 2021, 22(22), 12150; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212150 - 10 Nov 2021
Cited by 4 | Viewed by 2447
Abstract
Chemoattraction is a normal and essential process, but it can also be involved in tumorigenesis. This phenomenon plays a key role in glioblastoma (GBM). The GBM tumor cells are extremely difficult to eradicate, due to their strong capacity to migrate into the brain [...] Read more.
Chemoattraction is a normal and essential process, but it can also be involved in tumorigenesis. This phenomenon plays a key role in glioblastoma (GBM). The GBM tumor cells are extremely difficult to eradicate, due to their strong capacity to migrate into the brain parenchyma. Consequently, a complete resection of the tumor is rarely a possibility, and recurrence is inevitable. To overcome this problem, we proposed to exploit this behavior by using three chemoattractants: CXCL10, CCL2 and CCL11, released by a biodegradable hydrogel (GlioGel) to produce a migration of tumor cells toward a therapeutic trap. To investigate this hypothesis, the agarose drop assay was used to test the chemoattraction capacity of these three chemokines on murine F98 and human U87MG cell lines. We then studied the potency of this approach in vivo in the well-established syngeneic F98-Fischer glioma-bearing rat model using GlioGel containing different mixtures of the chemoattractants. In vitro assays resulted in an invasive cell rate 2-fold higher when chemokines were present in the environment. In vivo experiments demonstrated the capacity of these specific chemoattractants to strongly attract neoplastic glioblastoma cells. The use of this strong locomotion ability to our end is a promising avenue in the establishment of a new therapeutic approach in the treatment of primary brain tumors. Full article
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13 pages, 1884 KiB  
Article
Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts
by Masashi Okada, Shuhei Suzuki, Keita Togashi, Asuka Sugai, Masahiro Yamamoto and Chifumi Kitanaka
Int. J. Mol. Sci. 2021, 22(21), 11633; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111633 - 27 Oct 2021
Cited by 13 | Viewed by 2006
Abstract
Glioblastoma (GBM) is one of the deadliest of all human cancers. Developing therapies targeting GBM cancer stem cells or glioma stem cells (GSCs), which are deemed responsible for the malignancy of GBM due to their therapy resistance and tumor-initiating capacity, is considered key [...] Read more.
Glioblastoma (GBM) is one of the deadliest of all human cancers. Developing therapies targeting GBM cancer stem cells or glioma stem cells (GSCs), which are deemed responsible for the malignancy of GBM due to their therapy resistance and tumor-initiating capacity, is considered key to improving the dismal prognosis of GBM patients. In this study, we found that folate antagonists, such as methotrexate (MTX) and pemetrexed, are selectively cytotoxic to GSCs, but not to their differentiated counterparts, normal fibroblasts, or neural stem cells in vitro, and that the high sensitivity of GCSs to anti-folates may be due to the increased expression of RFC-1/SLC19A1, the reduced folate carrier that transports MTX into cells, in GSCs. Of note, in an in vivo serial transplantation model, MTX alone failed to exhibit anti-GSC effects but promoted the anti-GSC effects of CEP1347, an inducer of GSC differentiation. This suggests that folate metabolism, which plays an essential role specifically in GSCs, is a promising target of anti-GSC therapy, and that the combination of cytotoxic and differentiation therapies may be a novel and promising approach to effectively eliminate cancer stem cells. Full article
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21 pages, 5212 KiB  
Article
PIM1 Inhibition Affects Glioblastoma Stem Cell Behavior and Kills Glioblastoma Stem-like Cells
by Carolin Seifert, Ellen Balz, Susann Herzog, Anna Korolev, Sebastian Gaßmann, Heiko Paland, Matthias A. Fink, Markus Grube, Sascha Marx, Gabriele Jedlitschky, Mladen V. Tzvetkov, Bernhard H. Rauch, Henry W. S. Schroeder and Sandra Bien-Möller
Int. J. Mol. Sci. 2021, 22(20), 11126; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011126 - 15 Oct 2021
Cited by 8 | Viewed by 2287
Abstract
Despite comprehensive therapy and extensive research, glioblastoma (GBM) still represents the most aggressive brain tumor in adults. Glioma stem cells (GSCs) are thought to play a major role in tumor progression and resistance of GBM cells to radiochemotherapy. The PIM1 kinase has become [...] Read more.
Despite comprehensive therapy and extensive research, glioblastoma (GBM) still represents the most aggressive brain tumor in adults. Glioma stem cells (GSCs) are thought to play a major role in tumor progression and resistance of GBM cells to radiochemotherapy. The PIM1 kinase has become a focus in cancer research. We have previously demonstrated that PIM1 is involved in survival of GBM cells and in GBM growth in a mouse model. However, little is known about the importance of PIM1 in cancer stem cells. Here, we report on the role of PIM1 in GBM stem cell behavior and killing. PIM1 inhibition negatively regulates the protein expression of the stem cell markers CD133 and Nestin in GBM cells (LN-18, U-87 MG). In contrast, CD44 and the astrocytic differentiation marker GFAP were up-regulated. Furthermore, PIM1 expression was increased in neurospheres as a model of GBM stem-like cells. Treatment of neurospheres with PIM1 inhibitors (TCS PIM1-1, Quercetagetin, and LY294002) diminished the cell viability associated with reduced DNA synthesis rate, increased caspase 3 activity, decreased PCNA protein expression, and reduced neurosphere formation. Our results indicate that PIM1 affects the glioblastoma stem cell behavior, and its inhibition kills glioblastoma stem-like cells, pointing to PIM1 targeting as a potential anti-glioblastoma therapy. Full article
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15 pages, 3691 KiB  
Article
Androgen Receptor Activation in Glioblastoma Can Be Achieved by Ligand-Independent Signaling through EGFR—A Potential Therapeutic Target
by Nomi Zalcman, Mijal Gutreiman, Tal Shahar, Michael Weller and Iris Lavon
Int. J. Mol. Sci. 2021, 22(20), 10954; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222010954 - 11 Oct 2021
Cited by 9 | Viewed by 2315
Abstract
Androgen receptor (AR) is a ligand-mediated transcription factor that belongs to the superfamily of steroid receptors. AR is overexpressed in most glioblastomas and is a potential therapeutic target. In prostate and breast cancers, AR activation can be achieved also by a ligand-independent signaling [...] Read more.
Androgen receptor (AR) is a ligand-mediated transcription factor that belongs to the superfamily of steroid receptors. AR is overexpressed in most glioblastomas and is a potential therapeutic target. In prostate and breast cancers, AR activation can be achieved also by a ligand-independent signaling through receptor tyrosine kinases such as epidermal growth factor receptor (EGFR). Considering its major role in glioblastoma, we explored whether EGFR is involved in AR signaling in this tumor. Analysis of mRNA expression in 28 glioblastoma samples with quantitative real-time reverse-transcription polymerase chain reaction revealed a positive and significant correlation between AR and EGFR mRNA expression levels (R = 0.47, p = 0.0092), which was validated by The Cancer Genome Atlas dataset (n = 671) analysis (R = 0.3, p = 0.00006). Using Western blotting and immunofluorescence staining, we showed that the transduced overexpression of EGFR or its variant EGFRvIII in the U87MG cells induced AR protein overexpression and nuclear translocation and Protein kinase B (AKT) S473 and AR S210/213 phosphorylation. The EGFR kinase inhibitor afatinib and the AKT inhibitor MK2206 reduced AR nuclear translocation. Afatinib diminished AKT phosphorylation at 30 min and 6 h in the EGFR- and EGFRvIII-overexpressing cells, respectively, and decreased AR phosphorylation in EGFR-overexpressing cells at 4 h. Afatinib or MK2206 combination therapy with the AR antagonist enzalutamide in the EGFR and EGFRvIII-overexpressing cells had synergistic efficacy. Our findings suggest that EGFR signaling is involved in AR activation in glioblastoma and buttresses the concept of combining an EGFR signaling inhibitor with AR antagonists as a potential glioblastoma treatment. Full article
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26 pages, 11814 KiB  
Article
Preclinical Evaluation of Sodium Selenite in Mice: Toxicological and Tumor Regression Studies after Striatum Implantation of Human Glioblastoma Stem Cells
by Louis Larrouquère, Sylvie Berthier, Benoit Chovelon, Catherine Garrel, Véronique Vacchina, Hugues Paucot, Jean Boutonnat, Patrice Faure and Florence Hazane-Puch
Int. J. Mol. Sci. 2021, 22(19), 10646; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910646 - 30 Sep 2021
Cited by 2 | Viewed by 1782
Abstract
Glioblastoma (GBM) is the most aggressive malignant glioma, with a very poor prognosis; as such, efforts to explore new treatments and GBM’s etiology are a priority. We previously described human GBM cells (R2J-GS) as exhibiting the properties of cancer stem cells (growing in [...] Read more.
Glioblastoma (GBM) is the most aggressive malignant glioma, with a very poor prognosis; as such, efforts to explore new treatments and GBM’s etiology are a priority. We previously described human GBM cells (R2J-GS) as exhibiting the properties of cancer stem cells (growing in serum-free medium and proliferating into nude mice when orthotopically grafted). Sodium selenite (SS)—an in vitro attractive agent for cancer therapy against GBM—was evaluated in R2J-GS cells. To go further, we launched a preclinical study: SS was given orally, in an escalation-dose study (2.25 to 10.125 mg/kg/day, 5 days on, 2 days off, and 5 days on), to evaluate (1) the absorption of selenium in plasma and organs (brain, kidney, liver, and lung) and (2) the SS toxicity. A 6.75 mg/kg SS dose was chosen to perform a tumor regression assay, followed by MRI, in R2J-GS cells orthotopically implanted in nude mice, as this dose was nontoxic and increased brain selenium concentration. A group receiving TMZ (5 mg/kg) was led in parallel. Although not reaching statistical significance, the group of mice treated with SS showed a slower tumor growth vs. the control group (p = 0.08). No difference was observed between the TMZ and control groups. We provide new insights of the mechanisms of SS and its possible use in chemotherapy. Full article
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Review

Jump to: Editorial, Research, Other

28 pages, 5531 KiB  
Review
Recapitulating the Key Advances in the Diagnosis and Prognosis of High-Grade Gliomas: Second Half of 2021 Update
by Guido Frosina
Int. J. Mol. Sci. 2023, 24(7), 6375; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076375 - 28 Mar 2023
Cited by 3 | Viewed by 1426
Abstract
High-grade gliomas (World Health Organization grades III and IV) are the most frequent and fatal brain tumors, with median overall survivals of 24–72 and 14–16 months, respectively. We reviewed the progress in the diagnosis and prognosis of high-grade gliomas published in the second [...] Read more.
High-grade gliomas (World Health Organization grades III and IV) are the most frequent and fatal brain tumors, with median overall survivals of 24–72 and 14–16 months, respectively. We reviewed the progress in the diagnosis and prognosis of high-grade gliomas published in the second half of 2021. A literature search was performed in PubMed using the general terms “radio* and gliom*” and a time limit from 1 July 2021 to 31 December 2021. Important advances were provided in both imaging and non-imaging diagnoses of these hard-to-treat cancers. Our prognostic capacity also increased during the second half of 2021. This review article demonstrates slow, but steady improvements, both scientifically and technically, which express an increased chance that patients with high-grade gliomas may be correctly diagnosed without invasive procedures. The prognosis of those patients strictly depends on the final results of that complex diagnostic process, with widely varying survival rates. Full article
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19 pages, 1588 KiB  
Review
Protein Quality Control in Glioblastoma: A Review of the Current Literature with New Perspectives on Therapeutic Targets
by Angela Rocchi, Hassen S. Wollebo and Kamel Khalili
Int. J. Mol. Sci. 2022, 23(17), 9734; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179734 - 27 Aug 2022
Cited by 1 | Viewed by 1971
Abstract
Protein quality control allows eukaryotes to maintain proteostasis under the stress of constantly changing conditions. In this review, we discuss the current literature on PQC, highlighting flaws that must exist for malignancy to occur. At the nidus of PQC, the expression of BAG1-6 [...] Read more.
Protein quality control allows eukaryotes to maintain proteostasis under the stress of constantly changing conditions. In this review, we discuss the current literature on PQC, highlighting flaws that must exist for malignancy to occur. At the nidus of PQC, the expression of BAG1-6 reflects the cell environment; each isoform directs proteins toward different, parallel branches of the quality control cascade. The sum of these branches creates a net shift toward either homeostasis or apoptosis. With an established role in ALP, Bag3 is necessary for cell survival in stress conditions including those of the cancerous niche (i.e., hypoxia, hypermutation). Evidence suggests that excessive Bag3–HSP70 activity not only sustains, but also propagates cancers. Its role is anti-apoptotic—which allows malignant cells to persist—and intercellular—with the production of infectious ‘oncosomes’ enabling cancer expansion and recurrence. While Bag3 has been identified as a key prognostic indicator in several cancer types, its investigation is limited regarding glioblastoma. The cochaperone HSP70 has been strongly linked with GBM, while ALP inhibitors have been shown to improve GBM susceptibility to chemotherapeutics. Given the highly resilient, frequently recurrent nature of GBM, the targeting of Bag3 is a necessary consideration for the successful and definitive treatment of GBM. Full article
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30 pages, 861 KiB  
Review
Molecular and Circulating Biomarkers in Patients with Glioblastoma
by Nadia Senhaji, Asmae Squalli Houssaini, Salma Lamrabet, Sara Louati and Sanae Bennis
Int. J. Mol. Sci. 2022, 23(13), 7474; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137474 - 05 Jul 2022
Cited by 17 | Viewed by 2833
Abstract
Glioblastoma is the most aggressive malignant tumor of the central nervous system with a low survival rate. The difficulty of obtaining this tumor material represents a major limitation, making the real-time monitoring of tumor progression difficult, especially in the events of recurrence or [...] Read more.
Glioblastoma is the most aggressive malignant tumor of the central nervous system with a low survival rate. The difficulty of obtaining this tumor material represents a major limitation, making the real-time monitoring of tumor progression difficult, especially in the events of recurrence or resistance to treatment. The identification of characteristic biomarkers is indispensable for an accurate diagnosis, the rigorous follow-up of patients, and the development of new personalized treatments. Liquid biopsy, as a minimally invasive procedure, holds promise in this regard. The purpose of this paper is to summarize the current literature regarding the identification of molecular and circulating glioblastoma biomarkers and the importance of their integration as a valuable tool to improve patient care. Full article
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35 pages, 3511 KiB  
Review
Glioblastoma Treatment: State-of-the-Art and Future Perspectives
by Alejandro Rodríguez-Camacho, José Guillermo Flores-Vázquez, Júlia Moscardini-Martelli, Jorge Alejandro Torres-Ríos, Alejandro Olmos-Guzmán, Cindy Sharon Ortiz-Arce, Dharely Raquel Cid-Sánchez, Samuel Rosales Pérez, Monsserrat Del Sagrario Macías-González, Laura Crystell Hernández-Sánchez, Juan Carlos Heredia-Gutiérrez, Gabriel Alejandro Contreras-Palafox, José de Jesús Emilio Suárez-Campos, Miguel Ángel Celis-López, Guillermo Axayacalt Gutiérrez-Aceves and Sergio Moreno-Jiménez
Int. J. Mol. Sci. 2022, 23(13), 7207; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137207 - 29 Jun 2022
Cited by 34 | Viewed by 5751
Abstract
(1) Background: Glioblastoma is the most frequent and lethal primary tumor of the central nervous system. Through many years, research has brought various advances in glioblastoma treatment. At this time, glioblastoma management is based on maximal safe surgical resection, radiotherapy, and chemotherapy with [...] Read more.
(1) Background: Glioblastoma is the most frequent and lethal primary tumor of the central nervous system. Through many years, research has brought various advances in glioblastoma treatment. At this time, glioblastoma management is based on maximal safe surgical resection, radiotherapy, and chemotherapy with temozolomide. Recently, bevacizumab has been added to the treatment arsenal for the recurrent scenario. Nevertheless, patients with glioblastoma still have a poor prognosis. Therefore, many efforts are being made in different clinical research areas to find a new alternative to improve overall survival, free-progression survival, and life quality in glioblastoma patients. (2) Methods: Our objective is to recap the actual state-of-the-art in glioblastoma treatment, resume the actual research and future perspectives on immunotherapy, as well as the new synthetic molecules and natural compounds that represent potential future therapies at preclinical stages. (3) Conclusions: Despite the great efforts in therapeutic research, glioblastoma management has suffered minimal changes, and the prognosis remains poor. Combined therapeutic strategies and delivery methods, including immunotherapy, synthetic molecules, natural compounds, and glioblastoma stem cell inhibition, may potentiate the standard of care therapy and represent the next step in glioblastoma management research. Full article
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17 pages, 339 KiB  
Review
Immunotherapy in Glioblastoma: Current Approaches and Future Perspectives
by Ugur Sener, Michael W. Ruff and Jian L. Campian
Int. J. Mol. Sci. 2022, 23(13), 7046; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137046 - 24 Jun 2022
Cited by 19 | Viewed by 5116
Abstract
Glioblastoma (GBM) is the most common malignant brain tumor. Despite multimodality treatment with surgical resection, radiation therapy, chemotherapy, and tumor treating fields, recurrence is universal, median observed survival is low at 8 months and 5-year overall survival is poor at 7%. Immunotherapy aims [...] Read more.
Glioblastoma (GBM) is the most common malignant brain tumor. Despite multimodality treatment with surgical resection, radiation therapy, chemotherapy, and tumor treating fields, recurrence is universal, median observed survival is low at 8 months and 5-year overall survival is poor at 7%. Immunotherapy aims to generate a tumor-specific immune response to selectively eliminate tumor cells. In treatment of GBM, immunotherapy approaches including use of checkpoint inhibitors, chimeric antigen receptor (CAR) T-Cell therapy, vaccine-based approaches, viral vector therapies, and cytokine-based treatment has been studied. While there have been no major breakthroughs to date and broad implementation of immunotherapy for GBM remains elusive, multiple studies are underway. In this review, we discuss immunotherapy approaches to GBM with an emphasis on molecularly informed approaches. Full article
24 pages, 2003 KiB  
Review
Glycan-Lectin Interactions as Novel Immunosuppression Drivers in Glioblastoma
by Angelica Pace, Fabio Scirocchi, Chiara Napoletano, Ilaria Grazia Zizzari, Luca D’Angelo, Antonio Santoro, Marianna Nuti, Hassan Rahimi and Aurelia Rughetti
Int. J. Mol. Sci. 2022, 23(11), 6312; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23116312 - 05 Jun 2022
Cited by 5 | Viewed by 3602
Abstract
Despite diagnostic and therapeutic improvements, glioblastoma (GB) remains one of the most threatening brain tumor in adults, underlining the urgent need of new therapeutic targets. Lectins are glycan-binding proteins that regulate several biological processes through the recognition of specific sugar motifs. Lectins and [...] Read more.
Despite diagnostic and therapeutic improvements, glioblastoma (GB) remains one of the most threatening brain tumor in adults, underlining the urgent need of new therapeutic targets. Lectins are glycan-binding proteins that regulate several biological processes through the recognition of specific sugar motifs. Lectins and their ligands are found on immune cells, endothelial cells and, also, tumor cells, pointing out a strong correlation among immunity, tumor microenvironment and vascularization. In GB, altered glycans and lectins contribute to tumor progression and immune evasion, shaping the tumor-immune landscape promoting immunosuppressive cell subsets, such as myeloid-derived suppressor cells (MDSCs) and M2-macrophages, and affecting immunoeffector populations, such as CD8+ T cells and dendritic cells (DCs). Here, we discuss the latest knowledge on the immune cells, immune related lectin receptors (C-type lectins, Siglecs, galectins) and changes in glycosylation that are involved in immunosuppressive mechanisms in GB, highlighting their interest as possible novel therapeutical targets. Full article
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17 pages, 1255 KiB  
Review
Recent Development in NKT-Based Immunotherapy of Glioblastoma: From Bench to Bedside
by Yutao Li, Amit Sharma, Jarek Maciaczyk and Ingo G. H. Schmidt-Wolf
Int. J. Mol. Sci. 2022, 23(3), 1311; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031311 - 24 Jan 2022
Cited by 11 | Viewed by 3484
Abstract
Glioblastoma multiforme (GBM) is an aggressive and dismal disease with a median overall survival of around 15 months and a 5-year survival rate of 7.2%. Owing to genetic mutations, drug resistance, disruption to the blood–brain barrier (BBB)/blood–brain tumor barrier (BBTB), and the complexity [...] Read more.
Glioblastoma multiforme (GBM) is an aggressive and dismal disease with a median overall survival of around 15 months and a 5-year survival rate of 7.2%. Owing to genetic mutations, drug resistance, disruption to the blood–brain barrier (BBB)/blood–brain tumor barrier (BBTB), and the complexity of the immunosuppressive environment, the therapeutic approaches to GBM represent still major challenges. Conventional therapies, including surgery, radiotherapy, and standard chemotherapy with temozolomide, have not resulted in satisfactory improvements in the overall survival of GBM patients. Among cancer immunotherapeutic approaches, we propose that adjuvant NKT immunotherapy with invariant NKT (iNKT) and cytokine-induced killer (CIK) cells may improve the clinical scenario of this devastating disease. Considering this, herein, we discuss the current strategies of NKT therapy for GBM based primarily on in vitro/in vivo experiments, clinical trials, and the combinatorial approaches with future therapeutic potential. Full article
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19 pages, 3468 KiB  
Review
Neurofibromatosis Type 1 Gene Alterations Define Specific Features of a Subset of Glioblastomas
by Maximilian Scheer, Sandra Leisz, Eberhard Sorge, Olha Storozhuk, Julian Prell, Ivy Ho and Anja Harder
Int. J. Mol. Sci. 2022, 23(1), 352; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010352 - 29 Dec 2021
Cited by 6 | Viewed by 2613
Abstract
Neurofibromatosis type 1 (NF1) gene mutations or alterations occur within neurofibromatosis type 1 as well as in many different malignant tumours on the somatic level. In glioblastoma, NF1 loss of function plays a major role in inducing the mesenchymal (MES) subtype [...] Read more.
Neurofibromatosis type 1 (NF1) gene mutations or alterations occur within neurofibromatosis type 1 as well as in many different malignant tumours on the somatic level. In glioblastoma, NF1 loss of function plays a major role in inducing the mesenchymal (MES) subtype and, therefore defining the most aggressive glioblastoma. This is associated with an immune signature and mediated via the NF1–MAPK–FOSL1 axis. Specifically, increased invasion seems to be regulated via mutations in the leucine-rich domain (LRD) of the NF1 gene product neurofibromin. Novel targets for therapy may arise from neurofibromin deficiency-associated cellular mechanisms that are summarised in this review. Full article
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13 pages, 1455 KiB  
Review
Targeting AVIL, a New Cytoskeleton Regulator in Glioblastoma
by Robert Cornelison, Laine Marrah, Drew Horter, Sarah Lynch and Hui Li
Int. J. Mol. Sci. 2021, 22(24), 13635; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413635 - 20 Dec 2021
Cited by 3 | Viewed by 2419
Abstract
Glioblastoma (GBM) is the most common adult neural malignancy and the deadliest. The standard of care is optimal, safe, cytoreductive surgery followed by combined radiation therapy and alkylating chemotherapy with temozolomide. Recurrence is common and therapeutic options in the recurrent setting are limited. [...] Read more.
Glioblastoma (GBM) is the most common adult neural malignancy and the deadliest. The standard of care is optimal, safe, cytoreductive surgery followed by combined radiation therapy and alkylating chemotherapy with temozolomide. Recurrence is common and therapeutic options in the recurrent setting are limited. The dismal prognosis of GBM has led to novel treatments being a serious roadblock in the field, with most new treatments failing to show efficacy. Targeted therapies have shown some success in many cancers, but GBM remains one of the most difficult to treat, especially in recurrence. New chemotherapeutic directions need to be explored, possibly expanding the targeted chemotherapy spectrum in previously unforeseen ways. In this perspective paper, we will explain why AVIL, an actin-binding protein recently found to be overexpressed in GBM and a driving force for GBM, could prove versatile in the fight against cancer. By looking at AVIL and its potential to regulate FOXM1 and LIN28B, we will be able to highlight a way to improve outcomes for GBM patients who normally have very little hope. Full article
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22 pages, 9929 KiB  
Review
Hippo Pathway in Regulating Drug Resistance of Glioblastoma
by Giacomo Casati, Laura Giunti, Anna Lisa Iorio, Arianna Marturano, Luisa Galli and Iacopo Sardi
Int. J. Mol. Sci. 2021, 22(24), 13431; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413431 - 14 Dec 2021
Cited by 12 | Viewed by 4250
Abstract
Glioblastoma (GBM) represents the most common and malignant tumor of the Central Nervous System (CNS), affecting both children and adults. GBM is one of the deadliest tumor types and it shows a strong multidrug resistance (MDR) and an immunosuppressive microenvironment which remain a [...] Read more.
Glioblastoma (GBM) represents the most common and malignant tumor of the Central Nervous System (CNS), affecting both children and adults. GBM is one of the deadliest tumor types and it shows a strong multidrug resistance (MDR) and an immunosuppressive microenvironment which remain a great challenge to therapy. Due to the high recurrence of GBM after treatment, the understanding of the chemoresistance phenomenon and how to stimulate the antitumor immune response in this pathology is crucial. The deregulation of the Hippo pathway is involved in tumor genesis, chemoresistance and immunosuppressive nature of GBM. This pathway is an evolutionarily conserved signaling pathway with a kinase cascade core, which controls the translocation of YAP (Yes-Associated Protein)/TAZ (Transcriptional Co-activator with PDZ-binding Motif) into the nucleus, leading to regulation of organ size and growth. With this review, we want to highlight how chemoresistance and tumor immunosuppression work in GBM and how the Hippo pathway has a key role in them. We linger on the role of the Hippo pathway evaluating the effect of its de-regulation among different human cancers. Moreover, we consider how different pathways are cross-linked with the Hippo signaling in GBM genesis and the hypothetical mechanisms responsible for the Hippo pathway activation in GBM. Furthermore, we describe various drugs targeting the Hippo pathway. In conclusion, all the evidence described largely support a strong involvement of the Hippo pathway in gliomas progression, in the activation of chemoresistance mechanisms and in the development of an immunosuppressive microenvironment. Therefore, this pathway is a promising target for the treatment of high grade gliomas and in particular of GBM. Full article
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26 pages, 3860 KiB  
Review
Design of Biopolymer-Based Interstitial Therapies for the Treatment of Glioblastoma
by Erik S. Pena, Elizabeth G. Graham-Gurysh, Eric M. Bachelder and Kristy M. Ainslie
Int. J. Mol. Sci. 2021, 22(23), 13160; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222313160 - 06 Dec 2021
Cited by 17 | Viewed by 5162
Abstract
Glioblastoma multiforme (GBM) is the most common form of primary brain cancer and has the highest morbidity rate and current treatments result in a bleak 5-year survival rate of 5.6%. Interstitial therapy is one option to increase survival. Drug delivery by interstitial therapy [...] Read more.
Glioblastoma multiforme (GBM) is the most common form of primary brain cancer and has the highest morbidity rate and current treatments result in a bleak 5-year survival rate of 5.6%. Interstitial therapy is one option to increase survival. Drug delivery by interstitial therapy most commonly makes use of a polymer implant encapsulating a drug which releases as the polymer degrades. Interstitial therapy has been extensively studied as a treatment option for GBM as it provides several advantages over systemic administration of chemotherapeutics. Primarily, it can be applied behind the blood–brain barrier, increasing the number of possible chemotherapeutic candidates that can be used and reducing systemic levels of the therapy while concentrating it near the cancer source. With interstitial therapy, multiple drugs can be released locally into the brain at the site of resection as the polymer of the implant degrades, and the release profile of these drugs can be tailored to optimize combination therapy or maintain synergistic ratios. This can bypass the blood–brain barrier, alleviate systemic toxicity, and resolve drug resistance in the tumor. However, tailoring drug release requires appropriate consideration of the complex relationship between the drug, polymer, and formulation method. Drug physicochemical properties can result in intermolecular bonding with the polymeric matrix and affect drug distribution in the implant depending on the formulation method used. This review is focused on current works that have applied interstitial therapy towards GBM, discusses polymer and formulation methods, and provides design considerations for future implantable biodegradable materials. Full article
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17 pages, 1375 KiB  
Review
Estrogen Receptors as Molecular Targets of Endocrine Therapy for Glioblastoma
by Andrea Magali González-Mora and Patricia Garcia-Lopez
Int. J. Mol. Sci. 2021, 22(22), 12404; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212404 - 17 Nov 2021
Cited by 9 | Viewed by 2627
Abstract
Hormonal factors may participate in the development and progression of glioblastoma, the most aggressive primary tumor of the central nervous system. Many studies have been conducted on the possible involvement of estrogen receptors (ERs) in gliomas. Since there is a tendency for a [...] Read more.
Hormonal factors may participate in the development and progression of glioblastoma, the most aggressive primary tumor of the central nervous system. Many studies have been conducted on the possible involvement of estrogen receptors (ERs) in gliomas. Since there is a tendency for a reduced expression of ERs as the degree of malignancy of such tumors increases, it is important to understand the role of these receptors in the progression and treatment of this disease. ERs belong to the family of nuclear receptors, although they can also be in the plasmatic membrane, cytoplasm and mitochondria. They are classified as estrogen receptors alpha and beta (ER⍺ and ERβ), each with different isoforms that have a distinct function in the organism. ERs regulate multiple physiological and pathological processes through the activation of genomic and nongenomic pathways in the cell. Nevertheless, the role of each isoform in the development and progression of glioblastoma is not completely clear. Diverse in vitro and in vivo studies have shown encouraging results for endocrine therapy as a treatment for gliomas. At the same time, many questions have arisen concerning the nature of ERs as well as the mechanism of action of the proposed drugs. Hence, the aim of the current review is to describe the drugs that could possibly be utilized in endocrine therapy for the treatment of high-grade gliomas, analyze their interaction with ERs, and explore the involvement of these drugs and receptors in resistance to standard chemotherapy. Full article
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16 pages, 1886 KiB  
Review
C3G Protein, a New Player in Glioblastoma
by Sara Manzano, Alvaro Gutierrez-Uzquiza, Paloma Bragado, Angel M Cuesta, Carmen Guerrero and Almudena Porras
Int. J. Mol. Sci. 2021, 22(18), 10018; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221810018 - 16 Sep 2021
Cited by 4 | Viewed by 2422
Abstract
C3G (RAPGEF1) is a guanine nucleotide exchange factor (GEF) for GTPases from the Ras superfamily, mainly Rap1, although it also acts through GEF-independent mechanisms. C3G regulates several cellular functions. It is expressed at relatively high levels in specific brain areas, playing important roles [...] Read more.
C3G (RAPGEF1) is a guanine nucleotide exchange factor (GEF) for GTPases from the Ras superfamily, mainly Rap1, although it also acts through GEF-independent mechanisms. C3G regulates several cellular functions. It is expressed at relatively high levels in specific brain areas, playing important roles during embryonic development. Recent studies have uncovered different roles for C3G in cancer that are likely to depend on cell context, tumour type, and stage. However, its role in brain tumours remained unknown until very recently. We found that C3G expression is downregulated in GBM, which promotes the acquisition of a more mesenchymal phenotype, enhancing migration and invasion, but not proliferation. ERKs hyperactivation, likely induced by FGFR1, is responsible for this pro-invasive effect detected in C3G silenced cells. Other RTKs (Receptor Tyrosine Kinases) are also dysregulated and could also contribute to C3G effects. However, it remains undetermined whether Rap1 is a mediator of C3G actions in GBM. Various Rap1 isoforms can promote proliferation and invasion in GBM cells, while C3G inhibits migration/invasion. Therefore, other RapGEFs could play a major role regulating Rap1 activity in these tumours. Based on the information available, C3G could represent a new biomarker for GBM diagnosis, prognosis, and personalised treatment of patients in combination with other GBM molecular markers. The quantification of C3G levels in circulating tumour cells (CTCs) in the cerebrospinal liquid and/or circulating fluids might be a useful tool to improve GBM patient treatment and survival. Full article
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10 pages, 2467 KiB  
Case Report
Near-Complete Remission of Glioblastoma in a Patient Treated with an Allogenic Dendritic Cell-Based Vaccine: The Role of Tumor-Specific CD4+T-Cell Cytokine Secretion Pattern in Predicting Response and Recurrence
by Mariana P. Pinho, Guilherme A. Lepski, Roberta Rehder, Nadia E. Chauca-Torres, Gabriela C. M. Evangelista, Sarah F. Teixeira, Elizabeth A. Flatow, Jaqueline V. de Oliveira, Carla S. Fogolin, Nataly Peres, Analía Arévalo, Venâncio Alves, José A. M. Barbuto and Patricia C. Bergami-Santos
Int. J. Mol. Sci. 2022, 23(10), 5396; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105396 - 12 May 2022
Cited by 4 | Viewed by 4261
Abstract
Immunotherapy has brought hope to the fight against glioblastoma, but its efficacy remains unclear. We present the case of CST, a 25-year-old female patient with a large right-hemisphere glioblastoma treated with a dendritic–tumor cell fusion vaccine. CST showed a near-complete tumor response, with [...] Read more.
Immunotherapy has brought hope to the fight against glioblastoma, but its efficacy remains unclear. We present the case of CST, a 25-year-old female patient with a large right-hemisphere glioblastoma treated with a dendritic–tumor cell fusion vaccine. CST showed a near-complete tumor response, with a marked improvement in her functional status and simultaneous increases in tumor-specific CD8+ and CD4+ T cells. Two months before recurrence, the frequency of tumor-specific T cells decreased, while that of IL-17 and CD4+ T cells increased. CST passed away 15 months after enrollment. In this illustrative case, the tumor-specific CD4+ T-cell numbers and phenotype behaved as treatment efficacy biomarkers, highlighting the key role of the latter in glioblastoma immunotherapy. Full article
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