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Advances in Molecular Genetics of Brain Tumors

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 April 2022) | Viewed by 48280

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Nives Pećina-Šlaus

E-Mail Website
Guest Editor
Department of biology and Croatian Institute for Brain ResearchSchool of Medicine University of Zagreb, Šalata 3, 10000 Zagreb, Croatia
Interests: cancer genetics; brain tumors; Wnt signaling pathway; epithelial-to-mesenchymal transition; genomic instability; biomarkers
Dr. Ivana Jovčevska

E-Mail Website
Guest Editor
Medical Centre for Molecular Biology, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
Interests: glioblastoma; nanobodies; nanomedicine; proteomics; oncology; oncogenesis; genetics; transcriptomics

Special Issue Information

Dear colleagues,

we understand nowadays that cancer is not a single disease but rather a collection of diseases with specific genetic profiles. Genetic landscapes of cancer are formidable because they include malfunctioning of genes involved in a variety of vital cellular processes, including cell growth, proliferation, differentiation, apoptosis, mechanisms of DNA repair, cell mobility, angiogenesis, immune system. Therefore the field of cancer genomics is fast expanding and accumulating knowledge in order to develop novel and efficient therapeutic approaches. Brain tumors display a broad spectrum of clinical, histological and genetic features. The majority of brain tumors are unfortunately showing poor prognosis and survival. Taking into account the great heterogeneity of different brain tumor types and tumor cells even within the specific subtype, it is important to understand that their biology is still largely unexplained. It has long been known that cellular signaling networks interact and communicate and the malfunctioning of these interactions govern the brain tumorigenesis often preserving neoplastic cell phenotype.

The Special Issue intents to elucidate the diversity of problems and solutions behind brain tumors. The topics will cover events - molecular genetics, signaling pathways governing the mechanisms of tumor formation and invasion, DNA methylation, predictive biomarkers, diagnostic improvement, potential therapeutic targets, metastasis and recurrence, but also the difference in therapeutic response of specific clinical subtypes. Studies that bring results of large-scale analyses and system biology are also welcome. Besides the known driver genes and their mutations, some of which have already been comprehensively characterized, the investigation of genes harboring passenger mutations that are less known molecular players and probably contribute to tumor heterogeneity will also be one of the focuses of the issue.

The issue welcomes original work unraveling novel innovative studies on the genetics of brain tumors, but also reviews with a perspective points of view and interesting cases that can shed light on novel genetic events.

Prof. Nives Pećina‐Šlaus
Dr. Ivana Jovčevska
Guest Editors

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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

  • Brain tumors
  • Cellular signaling pathways
  • Tumor formation and invasion
  • Molecular genetics
  • Diagnostic and therapeutic biomarkers
  • Metastasis and recurrence
  • Epithelial-to-mesenchymal transition
  • Response to therapy
  • Large scale analysis
  • System biology
  • DNA Methylation

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Published Papers (15 papers)

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Editorial

Jump to: Research, Review

5 pages, 507 KiB  
Editorial
Different Approaches to Study Molecular Blueprint and Biological Behavior of Brain Tumors: Editorial to the Special Issue “Advances in Molecular Genetics of Brain Tumors”
by Nives Pećina-Šlaus and Ivana Jovčevska
Int. J. Mol. Sci. 2023, 24(2), 948; https://doi.org/10.3390/ijms24020948 - 4 Jan 2023
Viewed by 1601
Abstract
Cancer remains one of the leading causes of mortality worldwide [...] Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Brain Tumors)
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Research

Jump to: Editorial, Review

23 pages, 6466 KiB  
Article
Different Approaches for the Profiling of Cancer Pathway-Related Genes in Glioblastoma Cells
by Zuzana Majercikova, Katarina Dibdiakova, Michal Gala, Denis Horvath, Radovan Murin, Gabriel Zoldak and Jozef Hatok
Int. J. Mol. Sci. 2022, 23(18), 10883; https://doi.org/10.3390/ijms231810883 - 17 Sep 2022
Cited by 13 | Viewed by 3671
Abstract
Deregulation of signalling pathways that regulate cell growth, survival, metabolism, and migration can frequently lead to the progression of cancer. Brain tumours are a large group of malignancies characterised by inter- and intratumoral heterogeneity, with glioblastoma (GBM) being the most aggressive and fatal. [...] Read more.
Deregulation of signalling pathways that regulate cell growth, survival, metabolism, and migration can frequently lead to the progression of cancer. Brain tumours are a large group of malignancies characterised by inter- and intratumoral heterogeneity, with glioblastoma (GBM) being the most aggressive and fatal. The present study aimed to characterise the expression of cancer pathway-related genes (n = 84) in glial tumour cell lines (A172, SW1088, and T98G). The transcriptomic data obtained by the qRT-PCR method were compared to different control groups, and the most appropriate control for subsequent interpretation of the obtained results was chosen. We analysed three widely used control groups (non-glioma cells) in glioblastoma research: Human Dermal Fibroblasts (HDFa), Normal Human Astrocytes (NHA), and commercially available mRNAs extracted from healthy human brain tissues (hRNA). The gene expression profiles of individual glioblastoma cell lines may vary due to the selection of a different control group to correlate with. Moreover, we present the original multicriterial decision making (MCDM) for the possible characterization of gene expression profiles. We observed deregulation of 75 genes out of 78 tested in the A172 cell line, while T98G and SW1088 cells exhibited changes in 72 genes. By comparing the delta cycle threshold value of the tumour groups to the mean value of the three controls, only changes in the expression of 26 genes belonging to the following pathways were identified: angiogenesis FGF2; apoptosis APAF1, CFLAR, XIAP; cellular senescence BM1, ETS2, IGFBP5, IGFBP7, SOD1, TBX2; DNA damage and repair ERCC5, PPP1R15A; epithelial to mesenchymal transition SNAI3, SOX10; hypoxia ADM, ARNT, LDHA; metabolism ATP5A1, COX5A, CPT2, PFKL, UQCRFS1; telomeres and telomerase PINX1, TINF2, TNKS, and TNKS2. We identified a human astrocyte cell line and normal human brain tissue as the appropriate control group for an in vitro model, despite the small sample size. A different method of assessing gene expression levels produced the same disparities, highlighting the need for caution when interpreting the accuracy of tumorigenesis markers. Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Brain Tumors)
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10 pages, 490 KiB  
Communication
The Value of FET PET/CT in Recurrent Glioma with a Different IDH Mutation Status: The Relationship between Imaging and Molecular Biomarkers
by Marija Skoblar Vidmar, Andrej Doma, Uroš Smrdel, Katarina Zevnik and Andrej Studen
Int. J. Mol. Sci. 2022, 23(12), 6787; https://doi.org/10.3390/ijms23126787 - 17 Jun 2022
Cited by 12 | Viewed by 1978
Abstract
The evaluation of treatment response remains a challenge in glioma cases because the neuro oncological therapy can lead to the development of treatment-related changes (TRC) that mimic true progression (TP). Positron emission tomography (PET) using O-(2-[18F] fluoroethyl-)-L-tyrosine (18F-FET) has [...] Read more.
The evaluation of treatment response remains a challenge in glioma cases because the neuro oncological therapy can lead to the development of treatment-related changes (TRC) that mimic true progression (TP). Positron emission tomography (PET) using O-(2-[18F] fluoroethyl-)-L-tyrosine (18F-FET) has been shown to be a useful tool for detecting TRC and TP. We assessed the diagnostic performance of different 18F-FET PET segmentation approaches and different imaging biomarkers for differentiation between late TRC and TP in glioma patients. Isocitrate dehydrogenase (IDH) status was evaluated as a predictor of disease outcome. In our study, the proportion of TRC in IDH wild type (IDHwt) and IDH mutant (IDHm) subgroups was without significant difference. We found that the diagnostic value of static and dynamic biomarkers of 18F-FET PET for discrimination between TRC and TP depends on the IDH mutation status of the tumor. Dynamic 18F-FET PET acquisition proved helpful in the IDH wild type (IDHwt) subgroup, as opposed to the IDH mutant (IDHm) subgroup, providing an early indication to discontinue dynamic imaging in the IDHm subgroup. Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Brain Tumors)
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16 pages, 2378 KiB  
Article
The Use of Pro-Angiogenic and/or Pro-Hypoxic miRNAs as Tools to Monitor Patients with Diffuse Gliomas
by Guénaëlle Levallet, Fatéméh Dubois, Arthur Leclerc, Edwige Petit, Lien Bekaert, Maxime Faisant, Christian Creveuil, Evelyne Emery, Gérard Zalcman and Emmanuèle Lechapt-Zalcman
Int. J. Mol. Sci. 2022, 23(11), 6042; https://doi.org/10.3390/ijms23116042 - 27 May 2022
Cited by 1 | Viewed by 1828
Abstract
IDH (isocitrate dehydrogenase) mutation, hypoxia, and neo-angiogenesis, three hallmarks of diffuse gliomas, modulate the expression of small non-coding RNAs (miRNA). In this paper, we tested whether pro-angiogenic and/or pro-hypoxic miRNAs could be used to monitor patients with glioma. The miRNAs were extracted from [...] Read more.
IDH (isocitrate dehydrogenase) mutation, hypoxia, and neo-angiogenesis, three hallmarks of diffuse gliomas, modulate the expression of small non-coding RNAs (miRNA). In this paper, we tested whether pro-angiogenic and/or pro-hypoxic miRNAs could be used to monitor patients with glioma. The miRNAs were extracted from tumoral surgical specimens embedded in the paraffin of 97 patients with diffuse gliomas and, for 7 patients, from a blood sample too. The expression of 10 pro-angiogenic and/or pro-hypoxic miRNAs was assayed by qRT-PCR and normalized to the miRNA expression of non-tumoral brain tissues. We confirmed in vitro that IDH in hypoxia (1% O2, 24 h) alters pro-angiogenic and/or pro-hypoxic miRNA expression in HBT-14 (U-87 MG) cells. Then, we reported that the expression of these miRNAs is (i) strongly affected in patients with glioma compared to that in a non-tumoral brain; (ii) correlated with the histology/grade of glioma according to the 2016 WHO classification; and (iii) predicts the overall and/or progression-free survival of patients with glioma in univariate but not in a multivariate analysis after adjusting for sex, age at diagnosis, and WHO classification. Finally, the expression of miRNAs was found to be the same between the plasma and glial tumor of the same patient. This study highlights a panel of seven pro-angiogenic and/or pro-hypoxic miRNAs as a potential tool for monitoring patients with glioma. Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Brain Tumors)
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15 pages, 1542 KiB  
Article
Sedoheptulose Kinase SHPK Expression in Glioblastoma: Emerging Role of the Nonoxidative Pentose Phosphate Pathway in Tumor Proliferation
by Sara Franceschi, Francesca Lessi, Mariangela Morelli, Michele Menicagli, Francesco Pasqualetti, Paolo Aretini and Chiara Maria Mazzanti
Int. J. Mol. Sci. 2022, 23(11), 5978; https://doi.org/10.3390/ijms23115978 - 26 May 2022
Cited by 4 | Viewed by 2292
Abstract
Glioblastoma (GBM) is the most common form of malignant brain cancer and is considered the deadliest human cancer. Because of poor outcomes in this disease, there is an urgent need for progress in understanding the molecular mechanisms of GBM therapeutic resistance, as well [...] Read more.
Glioblastoma (GBM) is the most common form of malignant brain cancer and is considered the deadliest human cancer. Because of poor outcomes in this disease, there is an urgent need for progress in understanding the molecular mechanisms of GBM therapeutic resistance, as well as novel and innovative therapies for cancer prevention and treatment. The pentose phosphate pathway (PPP) is a metabolic pathway complementary to glycolysis, and several PPP enzymes have already been demonstrated as potential targets in cancer therapy. In this work, we aimed to evaluate the role of sedoheptulose kinase (SHPK), a key regulator of carbon flux that catalyzes the phosphorylation of sedoheptulose in the nonoxidative arm of the PPP. SHPK expression was investigated in patients with GBM using microarray data. SHPK was also overexpressed in GBM cells, and functional studies were conducted. SHPK expression in GBM shows a significant correlation with histology, prognosis, and survival. In particular, its increased expression is associated with a worse prognosis. Furthermore, its overexpression in GBM cells confirms an increase in cell proliferation. This work highlights for the first time the importance of SHPK in GBM for tumor progression and proposes this enzyme and the nonoxidative PPP as possible therapeutic targets. Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Brain Tumors)
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18 pages, 3713 KiB  
Article
Different Effects of RNAi-Mediated Downregulation or Chemical Inhibition of NAMPT in an Isogenic IDH Mutant and Wild-Type Glioma Cell Model
by Maximilian Clausing, Doreen William, Matthias Preussler, Julia Biedermann, Konrad Grützmann, Susan Richter, Frank Buchholz, Achim Temme, Evelin Schröck and Barbara Klink
Int. J. Mol. Sci. 2022, 23(10), 5787; https://doi.org/10.3390/ijms23105787 - 21 May 2022
Cited by 7 | Viewed by 2912
Abstract
The IDH1R132H mutation in glioma results in the neoenzymatic function of IDH1, leading to the production of the oncometabolite 2-hydroxyglutarate (2-HG), alterations in energy metabolism and changes in the cellular redox household. Although shifts in the redox ratio NADPH/NADP+ were described, [...] Read more.
The IDH1R132H mutation in glioma results in the neoenzymatic function of IDH1, leading to the production of the oncometabolite 2-hydroxyglutarate (2-HG), alterations in energy metabolism and changes in the cellular redox household. Although shifts in the redox ratio NADPH/NADP+ were described, the consequences for the NAD+ synthesis pathways and potential therapeutic interventions were largely unexplored. Here, we describe the effects of heterozygous IDH1R132H on the redox system in a CRISPR/Cas edited glioblastoma model and compare them with IDH1 wild-type (IDH1wt) cells. Besides an increase in 2-HG and decrease in NADPH, we observed an increase in NAD+ in IDH1R132H glioblastoma cells. RT-qPCR analysis revealed the upregulation of the expression of the NAD+ synthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT). Knockdown of NAMPT resulted in significantly reduced viability in IDH1R132H glioblastoma cells. Given this dependence of IDH1R132H cells on NAMPT expression, we explored the effects of the NAMPT inhibitors FK866, GMX1778 and GNE-617. Surprisingly, these agents were equally cytotoxic to IDH1R132H and IDH1wt cells. Altogether, our results indicate that targeting the NAD+ synthesis pathway is a promising therapeutic strategy in IDH mutant gliomas; however, the agent should be carefully considered since three small-molecule inhibitors of NAMPT tested in this study were not suitable for this purpose. Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Brain Tumors)
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16 pages, 2942 KiB  
Article
Circadian Gene cry Controls Tumorigenesis through Modulation of Myc Accumulation in Glioblastoma Cells
by Patricia Jarabo, Carmen de Pablo, Amanda González-Blanco and Sergio Casas-Tintó
Int. J. Mol. Sci. 2022, 23(4), 2043; https://doi.org/10.3390/ijms23042043 - 12 Feb 2022
Cited by 3 | Viewed by 2740
Abstract
Glioblastoma (GB) is the most frequent malignant brain tumor among adults and currently there is no effective treatment. This aggressive tumor grows fast and spreads through the brain causing death in 15 months. GB cells display a high mutation rate and generate a [...] Read more.
Glioblastoma (GB) is the most frequent malignant brain tumor among adults and currently there is no effective treatment. This aggressive tumor grows fast and spreads through the brain causing death in 15 months. GB cells display a high mutation rate and generate a heterogeneous population of tumoral cells that are genetically distinct. Thus, the contribution of genes and signaling pathways relevant for GB progression is of great relevance. We used a Drosophila model of GB that reproduces the features of human GB and describe the upregulation of the circadian gene cry in GB patients and in a Drosophila GB model. We studied the contribution of cry to the expansion of GB cells and the neurodegeneration and premature death caused by GB, and we determined that cry is required for GB progression. Moreover, we determined that the PI3K pathway regulates cry expression in GB cells, and in turn, cry is necessary and sufficient to promote Myc accumulation in GB. These results contribute to understanding the mechanisms underlying GB malignancy and lethality, and describe a novel role of Cry in GB cells. Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Brain Tumors)
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19 pages, 4247 KiB  
Article
The Different Temozolomide Effects on Tumorigenesis Mechanisms of Pediatric Glioblastoma PBT24 and SF8628 Cell Tumor in CAM Model and on Cells In Vitro
by Eligija Damanskienė, Ingrida Balnytė, Angelija Valančiūtė, Marta Maria Alonso, Aidanas Preikšaitis and Donatas Stakišaitis
Int. J. Mol. Sci. 2022, 23(4), 2001; https://doi.org/10.3390/ijms23042001 - 11 Feb 2022
Cited by 5 | Viewed by 2483
Abstract
It is necessary to elucidate the individual effects of temozolomide (TMZ) on carcinogenesis and tumor resistance to chemotherapy mechanisms. The study aimed to investigate the TMZ 50 and 100 μM dose effect difference between PBT24 and SF8628 cell line high-grade pediatric glioblastoma (phGBM) [...] Read more.
It is necessary to elucidate the individual effects of temozolomide (TMZ) on carcinogenesis and tumor resistance to chemotherapy mechanisms. The study aimed to investigate the TMZ 50 and 100 μM dose effect difference between PBT24 and SF8628 cell line high-grade pediatric glioblastoma (phGBM) xenografts in a chicken chorioallantoic membrane (CAM) model, on PCNA and EZH2 immunohistochemical expression in the tumor and on the expression of NKCC1, KCC2, E- and N-cadherin genes in TMZ-treated and control cell groups in vitro. TMZ at a 100 μg dose reduced the incidence of PBT24 xenograft invasion into the CAM, CAM thickening and the number of blood vessels in the CAM (p < 0.05), but did not affect the SF8628 tumor in the CAM model. The TMZ impact on PBT24 and SF8628 tumor PCNA expression was similarly significantly effective but did not alter EZH2 expression in the studied tumors. The TMZ at 50 μM caused significantly increased RNA expression of the NKCC1 gene in both studied cell types compared with controls (p < 0.05). The expression of the KCC2 gene was increased in PBT24 TMZ-treated cells (p < 0.05), and no TMZ effect was found in SF8628-treated cells. The study supports the suggestion that individual sensitivity to TMZ should be assessed when starting treatment. Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Brain Tumors)
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14 pages, 3084 KiB  
Article
A Novel Role of BIRC3 in Stemness Reprogramming of Glioblastoma
by Qiong Wu, Anders E. Berglund, Robert J. MacAulay and Arnold B. Etame
Int. J. Mol. Sci. 2022, 23(1), 297; https://doi.org/10.3390/ijms23010297 - 28 Dec 2021
Cited by 13 | Viewed by 2411
Abstract
Stemness reprogramming remains a largely unaddressed principal cause of lethality in glioblastoma (GBM). It is therefore of utmost importance to identify and target mechanisms that are essential for GBM stemness and self-renewal. Previously, we implicated BIRC3 as an essential mediator of therapeutic resistance [...] Read more.
Stemness reprogramming remains a largely unaddressed principal cause of lethality in glioblastoma (GBM). It is therefore of utmost importance to identify and target mechanisms that are essential for GBM stemness and self-renewal. Previously, we implicated BIRC3 as an essential mediator of therapeutic resistance and survival adaptation in GBM. In this study, we present novel evidence that BIRC3 has an essential noncanonical role in GBM self-renewal and stemness reprogramming. We demonstrate that BIRC3 drives stemness reprogramming of human GBM cell lines, mouse GBM cell lines and patient-derived GBM stem cells (GSCs) through regulation of BMP4 signaling axis. Specifically, BIRC3 induces stemness reprogramming in GBM through downstream inactivation of BMP4 signaling. RNA-Seq interrogation of the stemness reprogramming hypoxic (pseudopalisading necrosis and perinecrosis) niche in GBM patient tissues further validated the high BIRC3/low BMP4 expression correlation. BIRC3 knockout upregulated BMP4 expression and prevented stemness reprogramming of GBM models. Furthermore, siRNA silencing of BMP4 restored stemness reprogramming of BIRC3 knockout in GBM models. In vivo silencing of BIRC3 suppressed tumor initiation and progression in GBM orthotopic intracranial xenografts. The stemness reprograming of both GSCs and non-GSCs populations highlights the impact of BIRC3 on intra-tumoral cellular heterogeneity GBM. Our study has identified a novel function of BIRC3 that can be targeted to reverse stemness programming of GBM. Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Brain Tumors)
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12 pages, 5682 KiB  
Article
Profiling Glioblastoma Cases with an Expression of DCX, OLIG2 and NES
by Adrian Odrzywolski, Bożena Jarosz, Michał Kiełbus, Ilona Telejko, Dominik Ziemianek, Sebastian Knaga and Radosław Rola
Int. J. Mol. Sci. 2021, 22(24), 13217; https://doi.org/10.3390/ijms222413217 - 8 Dec 2021
Cited by 2 | Viewed by 2933
Abstract
Glioblastoma (GBM) remains the leading cause of cancer-related deaths with the lowest five-year survival rates among all of the human cancers. Multiple factors contribute to its poor outcome, including intratumor heterogeneity, along with migratory and invasive capacities of tumour cells. Over the last [...] Read more.
Glioblastoma (GBM) remains the leading cause of cancer-related deaths with the lowest five-year survival rates among all of the human cancers. Multiple factors contribute to its poor outcome, including intratumor heterogeneity, along with migratory and invasive capacities of tumour cells. Over the last several years Doublecortin (DCX) has been one of the debatable factors influencing GBM cells’ migration. To resolve DCX’s ambiguous role in GBM cells’ migration, we set to analyse the expression patterns of DCX along with Nestin (NES) and Oligodendrocyte lineage transcription factor 2 (OLIG2) in 17 cases of GBM, using immunohistochemistry, followed by an analysis of single-cell RNA-seq data. Our results showed that only a small subset of DCX positive (DCX+) cells was present in the tumour. Moreover, no particular pattern emerged when analysing DCX+ cells relative position to the tumour margin. By looking into single-cell RNA-seq data, the majority of DCX+ cells were classified as non-cancerous, with a small subset of cells that could be regarded as glioma stem cells. In conclusion, our findings support the notion that glioma cells express DCX; however, there is no clear evidence to prove that DCX participates in GBM cell migration. Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Brain Tumors)
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15 pages, 3155 KiB  
Article
Microglia-Derived Olfactomedin-like 3 Promotes Pro-Tumorigenic Microglial Function and Malignant Features of Glioma Cells
by Ryan G. Toedebusch, Christopher A. Lucchesi, Eshetu T. Debebe, Luke A. Wittenburg, Xinbin Chen and Christine M. Toedebusch
Int. J. Mol. Sci. 2021, 22(23), 13052; https://doi.org/10.3390/ijms222313052 - 2 Dec 2021
Cited by 9 | Viewed by 2798
Abstract
Under the influence of transforming growth factor-beta (TGFβ), glioma-associated microglia produce molecules that promote glioma growth and invasion. Olfactomedin-like 3 (Olfml3), a novel, secreted glycoprotein, is known to promote several non-CNS cancers. While it is a direct TGFβ1 target gene in [...] Read more.
Under the influence of transforming growth factor-beta (TGFβ), glioma-associated microglia produce molecules that promote glioma growth and invasion. Olfactomedin-like 3 (Olfml3), a novel, secreted glycoprotein, is known to promote several non-CNS cancers. While it is a direct TGFβ1 target gene in microglia, the role of microglia-derived OLFML3 in glioma progression is unknown. Here, we tested the hypotheses that microglial Olfml3 is integral to the pro-tumorigenic glioma-associated microglia phenotype and promotes glioma cell malignancy. Using an Olfml3 knockout microglial cell line (N9), we demonstrated that Olfml3 is a direct target gene of all TGFβ isoforms in murine microglia. Moreover, loss of Olfml3 attenuated TGFβ-induced restraint on microglial immune function and production of cytokines that are critical in promoting glioma cell malignancy. Importantly, microglia-derived OLFML3 directly contributes to glioma cell malignancy through increased migration and invasion. While exposure to conditioned medium (CM) from isogenic control microglia pre-treated with TGFβ increased mouse glioma cell (GL261) migration and invasion, this effect was abolished with exposure to CM from TGFβ-treated Olfml3-/- microglia. Taken together, our data suggest that Olfml3 may serve as a gatekeeper for TGFβ-induced microglial gene expression, thereby promoting the pro-tumorigenic microglia phenotype and glioma cell malignancy. Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Brain Tumors)
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12 pages, 2618 KiB  
Communication
Decoding the Role of DVL1 in Intracranial Meningioma
by Anja Bukovac, Katarina Dragičević, Anja Kafka, Darko Orešković, Sanja Cesarec-Augustinović and Nives Pećina-Šlaus
Int. J. Mol. Sci. 2021, 22(21), 11996; https://doi.org/10.3390/ijms222111996 - 5 Nov 2021
Cited by 2 | Viewed by 2449
Abstract
In the search for molecular candidates for targeted meningioma therapies, increasing attention has been paid to the role of signaling pathways in the development and progression of intracranial meningiomas. Although it is well known that the Wnt signaling pathway is involved in meningioma [...] Read more.
In the search for molecular candidates for targeted meningioma therapies, increasing attention has been paid to the role of signaling pathways in the development and progression of intracranial meningiomas. Although it is well known that the Wnt signaling pathway is involved in meningioma progression, the role of its central mediator, DVL1, is still unclear. In order to investigate the influence of DVL1 gene alterations on the progression of human intracranial meningioma, we focused on its central PDZ domain, which is responsible for DVL interaction with the Fzd receptor and the phosphorylation of DVL mediated through the casein kinases CK1 and CK2. A genetic analysis of genomic instability revealed the existence of microsatellite instability in 9.09% and the loss of heterozygosity in 6.06% of the samples. The sequencing of the PDZ gene region showed repetitive deletions of two bases located in intron 7 and exon 8, and a duplication in intron 8 in most samples, with different outcomes on the biological function of the DVL1 protein. Immunohistochemistry revealed that the nuclear expression of DVL1 was significantly correlated with a higher expression of active β-catenin (p = 0.029) and a higher meningioma grade (p = 0.030), which leads to the conclusion that it could be used as biomarker for meningioma progression and the activation of the Wnt signaling pathway. Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Brain Tumors)
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Review

Jump to: Editorial, Research

18 pages, 1057 KiB  
Review
Molecular Biomarkers in Glioblastoma: A Systematic Review and Meta-Analysis
by Heena Sareen, Yafeng Ma, Therese M. Becker, Tara L. Roberts, Paul de Souza and Branka Powter
Int. J. Mol. Sci. 2022, 23(16), 8835; https://doi.org/10.3390/ijms23168835 - 9 Aug 2022
Cited by 36 | Viewed by 5017
Abstract
Background: Glioblastoma (GBM) is a highly aggressive cancer with poor prognosis that needs better treatment modalities. Moreover, there is a lack of reliable biomarkers to predict the response and outcome of current or newly designed therapies. While several molecular markers have been proposed [...] Read more.
Background: Glioblastoma (GBM) is a highly aggressive cancer with poor prognosis that needs better treatment modalities. Moreover, there is a lack of reliable biomarkers to predict the response and outcome of current or newly designed therapies. While several molecular markers have been proposed as potential biomarkers for GBM, their uptake into clinical settings is slow and impeded by marker heterogeneity. Detailed assessment of prognostic and predictive value for biomarkers in well-defined clinical trial settings, if available, is scattered throughout the literature. Here we conducted a systematic review and meta-analysis to evaluate the prognostic and predictive significance of clinically relevant molecular biomarkers in GBM patients. Material and methods: A comprehensive literature search was conducted to retrieve publications from 3 databases (Pubmed, Cochrane and Embase) from January 2010 to December 2021, using specific terms. The combined hazard ratios (HR) and confidence intervals (95% CI) were used to evaluate the association of biomarkers with overall survival (OS) in GBM patients. Results: Twenty-six out of 1831 screened articles were included in this review. Nineteen articles were included in the meta-analyses, and 7 articles were quantitatively summarised. Fourteen studies with 1231 GBM patients showed a significant association of MGMT methylation with better OS with the pooled HR of 1.66 (95% CI 1.32–2.09, p < 0.0001, random effect). Five studies including 541 GBM patients analysed for the prognostic significance of IDH1 mutation showed significantly better OS in patients with IDH1 mutation with a pooled HR of 2.37 (95% CI 1.81–3.12; p < 0.00001]. Meta-analysis performed on 5 studies including 575 GBM patients presenting with either amplification or high expression of EGFR gene did not reveal any prognostic significance with a pooled HR of 1.31 (95% CI 0.96–1.79; p = 0.08). Conclusions: MGMT promoter methylation and IDH1 mutation are significantly associated with better OS in GBM patients. No significant associations were found between EGFR amplification or overexpression with OS. Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Brain Tumors)
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19 pages, 7285 KiB  
Review
Functional Precision Oncology: The Next Frontier to Improve Glioblastoma Outcome?
by Dena Panovska and Frederik De Smet
Int. J. Mol. Sci. 2022, 23(15), 8637; https://doi.org/10.3390/ijms23158637 - 3 Aug 2022
Cited by 6 | Viewed by 3337
Abstract
Glioblastoma remains the most malignant and intrinsically resistant brain tumour in adults. Despite intensive research over the past few decades, through which numerous potentially druggable targets have been identified, virtually all clinical trials of the past 20 years have failed to improve the [...] Read more.
Glioblastoma remains the most malignant and intrinsically resistant brain tumour in adults. Despite intensive research over the past few decades, through which numerous potentially druggable targets have been identified, virtually all clinical trials of the past 20 years have failed to improve the outcome for the vast majority of GBM patients. The observation that small subgroups of patients displayed a therapeutic response across several unsuccessful clinical trials suggests that the GBM patient population probably consists of multiple subgroups that probably all require a distinct therapeutic approach. Due to extensive inter- and intratumoral heterogeneity, assigning the right therapy to each patient remains a major challenge. Classically, bulk genetic profiling would be used to identify suitable therapies, although the success of this approach remains limited due to tumor heterogeneity and the absence of direct relationships between mutations and therapy responses in GBM. An attractive novel strategy aims at implementing methods for functional precision oncology, which refers to the evaluation of treatment efficacies and vulnerabilities of (ex vivo) living tumor cells in a highly personalized way. Such approaches are currently being implemented for other cancer types by providing rapid, translatable information to guide patient-tailored therapeutic selections. In this review, we discuss the current state of the art of transforming technologies, tools and challenges for functional precision oncology and how these could improve therapy selection for GBM patients. Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Brain Tumors)
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11 pages, 629 KiB  
Review
A Critical Overview of Targeted Therapies for Vestibular Schwannoma
by Ryota Tamura and Masahiro Toda
Int. J. Mol. Sci. 2022, 23(10), 5462; https://doi.org/10.3390/ijms23105462 - 13 May 2022
Cited by 20 | Viewed by 6921
Abstract
Vestibular schwannoma (VS) is a benign tumor that originates from Schwann cells in the vestibular component. Surgical treatment for VS has gradually declined over the past few decades, especially for small tumors. Gamma knife radiosurgery has become an accepted treatment for VS, with [...] Read more.
Vestibular schwannoma (VS) is a benign tumor that originates from Schwann cells in the vestibular component. Surgical treatment for VS has gradually declined over the past few decades, especially for small tumors. Gamma knife radiosurgery has become an accepted treatment for VS, with a high rate of tumor control. For neurofibromatosis type 2 (NF2)-associated VS resistant to radiotherapy, vascular endothelial growth factor (VEGF)-A/VEGF receptor (VEGFR)-targeted therapy (e.g., bevacizumab) may become the first-line therapy. Recently, a clinical trial using a VEGFR1/2 peptide vaccine was also conducted in patients with progressive NF2-associated schwannomas, which was the first immunotherapeutic approach for NF2 patients. Targeted therapies for the gene product of SH3PXD2A-HTRA1 fusion may be effective for sporadic VS. Several protein kinase inhibitors could be supportive to prevent tumor progression because merlin inhibits signaling by tyrosine receptor kinases and the activation of downstream pathways, including the Ras/Raf/MEK/ERK and PI3K/Akt/mTORC1 pathways. Tumor-microenvironment-targeted therapy may be supportive for the mainstays of management. The tumor-associated macrophage is the major component of immunosuppressive cells in schwannomas. Here, we present a critical overview of targeted therapies for VS. Multimodal therapy is required to manage patients with refractory VS. Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Brain Tumors)
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