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Special Issue "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 (30 September 2021).

Special Issue Editors

Prof. Dr. Jaroslaw Maciaczyk
E-Mail Website
Guest Editor
Div. of Stereotactic and Functional Neurosurgery, Dept. of Neurosurgery University Hospital Bonn, Bonn, Germany
Interests: neuro-oncology; glioblastoma; stereotaxic & functional neurosurgery; cancer stem cells
Dr. Hugo Guerrero‐Cazares
E-Mail Website
Guest Editor
Department of Neurological Surgery, Mayo Clinic, Jacksonville, FL, USA
Interests: neuro-oncology; glioblastoma; cancer stem cells; adult neurogenesis
Dr. Amit Sharma
E-Mail Website
Guest Editor
Div. of Stereotactic and Functional Neurosurgery, Dept. of Neurosurgery University Hospital Bonn, Bonn, Germany
Interests: neuro-oncology; glioblastoma; stereotaxic & functional neurosurgery; cancer stem cells

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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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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 (4 papers)

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Research

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Article
PIM1 Inhibition Affects Glioblastoma Stem Cell Behavior and Kills Glioblastoma Stem-like Cells
Int. J. Mol. Sci. 2021, 22(20), 11126; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011126 - 15 Oct 2021
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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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Article
Androgen Receptor Activation in Glioblastoma Can Be Achieved by Ligand-Independent Signaling through EGFR—A Potential Therapeutic Target
Int. J. Mol. Sci. 2021, 22(20), 10954; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222010954 - 11 Oct 2021
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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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Article
Preclinical Evaluation of Sodium Selenite in Mice: Toxicological and Tumor Regression Studies after Striatum Implantation of Human Glioblastoma Stem Cells
Int. J. Mol. Sci. 2021, 22(19), 10646; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910646 - 30 Sep 2021
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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

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Review
C3G Protein, a New Player in Glioblastoma
Int. J. Mol. Sci. 2021, 22(18), 10018; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221810018 - 16 Sep 2021
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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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