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Biomedicines
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Molecular and Pathological Mechanisms of Adult Gliomas
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Molecular and Pathological Mechanisms of Adult Gliomas

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 32000

Special Issue Editor

Dr. Sevin Turcan

E-Mail Website
Guest Editor
Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany
Interests: neuro-oncology; brain tumors; cancer genomics; epigenetics; bioinformatics

Special Issue Information

Dear Colleagues,

Gliomas are the most common primary brain tumors in adults. Largely due to their infiltrative and heterogeneous nature, these tumors are challenging to treat and frequently recur. Over the last decade, significant progress has been made to map the molecular alterations in gliomas, and the next challenge is to understand the role of these alterations in glioma biology. Furthermore, emerging studies have highlighted that gliomas are not just a single entity but rather interact with their complex microenvironment to modulate their behavior.

The aim of this Special Issue is to provide a broad overview of molecular and pathological mechanisms that drive gliomas with a particular focus on several areas: genetic/epigenetic drivers of brain tumors, bioinformatic/deep learning approaches to identify molecular markers, high-resolution microscopy approaches to study gliomas, the influence of glioma microenvironment on tumor progression/therapy response, and glioma–brain interactions. Overall, the goal is to highlight progress made in preclinical and translational research to improve our understanding of glioma biology. We invite both original research and review articles highlighting recent advances in the glioma field.

Dr. Sevin Turcan
Guest Editor

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neuro-oncology
  • brain tumors
  • glioma invasion
  • glioma genetics/epigenetics
  • tumor microenvironment

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Published Papers (6 papers)

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Research

Jump to: Review

20 pages, 3450 KiB  
Article
Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms
by Ege Ülgen, Sıla Karacan, Umut Gerlevik, Özge Can, Kaya Bilguvar, Yavuz Oktay, Cemaliye B. Akyerli, Şirin K. Yüksel, Ayça E. Danyeli, Tarık Tihan, O. Uğur Sezerman, M. Cengiz Yakıcıer, M. Necmettin Pamir and Koray Özduman
Biomedicines 2020, 8(12), 574; https://doi.org/10.3390/biomedicines8120574 - 7 Dec 2020
Cited by 5 | Viewed by 4094
Abstract
Little is known about the mutational processes that shape the genetic landscape of gliomas. Numerous mutational processes leave marks on the genome in the form of mutations, copy number alterations, rearrangements or their combinations. To explore gliomagenesis, we hypothesized that gliomas with different [...] Read more.
Little is known about the mutational processes that shape the genetic landscape of gliomas. Numerous mutational processes leave marks on the genome in the form of mutations, copy number alterations, rearrangements or their combinations. To explore gliomagenesis, we hypothesized that gliomas with different underlying oncogenic mechanisms would have differences in the burden of various forms of these genomic alterations. This was an analysis on adult diffuse gliomas, but IDH-mutant gliomas as well as diffuse midline gliomas H3-K27M were excluded to search for the possible presence of new entities among the very heterogenous group of IDH-WT glioblastomas. The cohort was divided into two molecular subsets: (1) Molecularly-defined GBM (mGBM) as those that carried molecular features of glioblastomas (including TERT promoter mutations, 7/10 pattern, or EGFR-amplification), and (2) those who did not (others). Whole exome sequencing was performed for 37 primary tumors and matched blood samples as well as 8 recurrences. Single nucleotide variations (SNV), short insertion or deletions (indels) and copy number alterations (CNA) were quantified using 5 quantitative metrics (SNV burden, indel burden, copy number alteration frequency-wGII, chromosomal arm event ratio-CAER, copy number amplitude) as well as 4 parameters that explored underlying oncogenic mechanisms (chromothripsis, double minutes, microsatellite instability and mutational signatures). Findings were validated in the TCGA pan-glioma cohort. mGBM and “Others” differed significantly in their SNV (only in the TCGA cohort) and CNA metrics but not indel burden. SNV burden increased with increasing age at diagnosis and at recurrences and was driven by mismatch repair deficiency. On the contrary, indel and CNA metrics remained stable over increasing age at diagnosis and with recurrences. Copy number alteration frequency (wGII) correlated significantly with chromothripsis while CAER and CN amplitude correlated significantly with the presence of double minutes, suggesting separate underlying mechanisms for different forms of CNA. Full article
(This article belongs to the Special Issue Molecular and Pathological Mechanisms of Adult Gliomas)
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21 pages, 7982 KiB  
Article
Molecular Mechanisms of KDELC2 on Glioblastoma Tumorigenesis and Temozolomide Resistance
by Yu-Ling Tsai, Hsin-Han Chang, Ying-Chuan Chen, Yu-Chan Chang, Ying Chen and Wen-Chiuan Tsai
Biomedicines 2020, 8(9), 339; https://doi.org/10.3390/biomedicines8090339 - 10 Sep 2020
Cited by 15 | Viewed by 3486
Abstract
The activation of the Notch pathway induces glioblastoma (GBM) development. Since KDEL (Lys-Asp-Glu-Leu) containing 2 (KDELC2) is involved in the Notch pathway, the detailed mechanism is still undetermined. The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases revealed that KDELC2 [...] Read more.
The activation of the Notch pathway induces glioblastoma (GBM) development. Since KDEL (Lys-Asp-Glu-Leu) containing 2 (KDELC2) is involved in the Notch pathway, the detailed mechanism is still undetermined. The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases revealed that KDELC2 mRNA was associated with oncologic factors of GBM. U87, LN229, LNZ308, U118MG, and GBM8401 cells showed higher KDELC2 expression than normal brain tissues. The results of MTT, wound healing, and invasion assays proved that KDELC2 knockdown suppressed GBM-aggressive behaviors. The inhibitory properties of GBM stemness and angiogenesis under KDELC2 knockdown were evaluated by tumor spheroid and tube formation assays. Suppression of KDELC2 downregulated Notch factors’ expressions, including KDELC1, pofut1, Notch receptors 1–3, and HES-1. Immunoblot assay showed that KDELC2 knockdown promoted tumor apoptosis by downregulating PI3k/mTOR/Akt, MAPK/ERK, and NF-kB pathways. The combination of KDELC2 knockdown and temozolomide (TMZ) treatment had an optimal therapeutic effect by suppressing MGMT expression. Results of an orthotopic xenograft animal model and human tissue confirmed that KDELC2 correlated with glioma proliferation, advanced grades, and poor prognosis. Therefore, KDELC2 might be a potential pharmacological target to inhibit tumorigenesis, epithelial–mesenchymal transition, angiogenesis, and chemo-resistance of GBM. Full article
(This article belongs to the Special Issue Molecular and Pathological Mechanisms of Adult Gliomas)
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Review

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21 pages, 2023 KiB  
Review
IDH Mutations in Glioma: Double-Edged Sword in Clinical Applications?
by Alisan Kayabolen, Ebru Yilmaz and Tugba Bagci-Onder
Biomedicines 2021, 9(7), 799; https://doi.org/10.3390/biomedicines9070799 - 10 Jul 2021
Cited by 52 | Viewed by 8596
Abstract
Discovery of point mutations in the genes encoding isocitrate dehydrogenases (IDH) in gliomas about a decade ago has challenged our view of the role of metabolism in tumor progression and provided a new stratification strategy for malignant gliomas. IDH enzymes catalyze the conversion [...] Read more.
Discovery of point mutations in the genes encoding isocitrate dehydrogenases (IDH) in gliomas about a decade ago has challenged our view of the role of metabolism in tumor progression and provided a new stratification strategy for malignant gliomas. IDH enzymes catalyze the conversion of isocitrate to alpha-ketoglutarate (α-KG), an intermediate in the citric acid cycle. Specific mutations in the genes encoding IDHs cause neomorphic enzymatic activity that produces D-2-hydroxyglutarate (2-HG) and result in the inhibition of α-KG-dependent enzymes such as histone and DNA demethylases. Thus, chromatin structure and gene expression profiles in IDH-mutant gliomas appear to be different from those in IDH-wildtype gliomas. IDH mutations are highly common in lower grade gliomas (LGG) and secondary glioblastomas, and they are among the earliest genetic events driving tumorigenesis. Therefore, inhibition of mutant IDH enzymes in LGGs is widely accepted as an attractive therapeutic strategy. On the other hand, the metabolic consequences derived from IDH mutations lead to selective vulnerabilities within tumor cells, making them more sensitive to several therapeutic interventions. Therefore, instead of shutting down mutant IDH enzymes, exploiting the selective vulnerabilities caused by them might be another attractive and promising strategy. Here, we review therapeutic options and summarize current preclinical and clinical studies on IDH-mutant gliomas. Full article
(This article belongs to the Special Issue Molecular and Pathological Mechanisms of Adult Gliomas)
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20 pages, 1061 KiB  
Review
Opposed Interplay between IDH1 Mutations and the WNT/β-Catenin Pathway: Added Information for Glioma Classification
by Alexandre Vallée, Yves Lecarpentier and Jean-Noël Vallée
Biomedicines 2021, 9(6), 619; https://doi.org/10.3390/biomedicines9060619 - 30 May 2021
Cited by 8 | Viewed by 4240
Abstract
Gliomas are the main common primary intraparenchymal brain tumor in the central nervous system (CNS), with approximately 7% of the death caused by cancers. In the WHO 2016 classification, molecular dysregulations are part of the definition of particular brain tumor entities for the [...] Read more.
Gliomas are the main common primary intraparenchymal brain tumor in the central nervous system (CNS), with approximately 7% of the death caused by cancers. In the WHO 2016 classification, molecular dysregulations are part of the definition of particular brain tumor entities for the first time. Nevertheless, the underlying molecular mechanisms remain unclear. Several studies have shown that 75% to 80% of secondary glioblastoma (GBM) showed IDH1 mutations, whereas only 5% of primary GBM have IDH1 mutations. IDH1 mutations lead to better overall survival in gliomas patients. IDH1 mutations are associated with lower stimulation of the HIF-1α a, aerobic glycolysis and angiogenesis. The stimulation of HIF-1α and the process of angiogenesis appears to be activated only when hypoxia occurs in IDH1-mutated gliomas. In contrast, the observed upregulation of the canonical WNT/β-catenin pathway in gliomas is associated with proliferation, invasion, aggressive-ness and angiogenesis.. Molecular pathways of the malignancy process are involved in early stages of WNT/β-catenin pathway-activated-gliomas, and this even under normoxic conditions. IDH1 mutations lead to decreased activity of the WNT/β-catenin pathway and its enzymatic targets. The opposed interplay between IDH1 mutations and the canonical WNT/β-catenin pathway in gliomas could participate in better understanding of the observed evolution of different tumors and could reinforce the glioma classification. Full article
(This article belongs to the Special Issue Molecular and Pathological Mechanisms of Adult Gliomas)
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22 pages, 2199 KiB  
Review
Targeting Protein Kinase C in Glioblastoma Treatment
by Noelia Geribaldi-Doldán, Irati Hervás-Corpión, Ricardo Gómez-Oliva, Samuel Domínguez-García, Félix A. Ruiz, Irene Iglesias-Lozano, Livia Carrascal, Ricardo Pardillo-Díaz, José L. Gil-Salú, Pedro Nunez-Abades, Luis M. Valor and Carmen Castro
Biomedicines 2021, 9(4), 381; https://doi.org/10.3390/biomedicines9040381 - 4 Apr 2021
Cited by 13 | Viewed by 4834
Abstract
Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor and is associated with a poor prognosis. Despite the use of combined treatment approaches, recurrence is almost inevitable and survival longer than 14 or 15 months after diagnosis is low. It is [...] Read more.
Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor and is associated with a poor prognosis. Despite the use of combined treatment approaches, recurrence is almost inevitable and survival longer than 14 or 15 months after diagnosis is low. It is therefore necessary to identify new therapeutic targets to fight GBM progression and recurrence. Some publications have pointed out the role of glioma stem cells (GSCs) as the origin of GBM. These cells, with characteristics of neural stem cells (NSC) present in physiological neurogenic niches, have been proposed as being responsible for the high resistance of GBM to current treatments such as temozolomide (TMZ). The protein Kinase C (PKC) family members play an essential role in transducing signals related with cell cycle entrance, differentiation and apoptosis in NSC and participate in distinct signaling cascades that determine NSC and GSC dynamics. Thus, PKC could be a suitable druggable target to treat recurrent GBM. Clinical trials have tested the efficacy of PKCβ inhibitors, and preclinical studies have focused on other PKC isozymes. Here, we discuss the idea that other PKC isozymes may also be involved in GBM progression and that the development of a new generation of effective drugs should consider the balance between the activation of different PKC subtypes. Full article
(This article belongs to the Special Issue Molecular and Pathological Mechanisms of Adult Gliomas)
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19 pages, 1464 KiB  
Review
Isocitrate Dehydrogenase Mutations in Glioma: Genetics, Biochemistry, and Clinical Indications
by Yang Liu, Fengchao Lang, Fu-Ju Chou, Kareem A. Zaghloul and Chunzhang Yang
Biomedicines 2020, 8(9), 294; https://doi.org/10.3390/biomedicines8090294 - 20 Aug 2020
Cited by 46 | Viewed by 5870
Abstract
Mutations in isocitrate dehydrogenase (IDH) are commonly observed in lower-grade glioma and secondary glioblastomas. IDH mutants confer a neomorphic enzyme activity that converts α-ketoglutarate to an oncometabolite D-2-hydroxyglutarate, which impacts cellular epigenetics and metabolism. IDH mutation establishes distinctive patterns in metabolism, [...] Read more.
Mutations in isocitrate dehydrogenase (IDH) are commonly observed in lower-grade glioma and secondary glioblastomas. IDH mutants confer a neomorphic enzyme activity that converts α-ketoglutarate to an oncometabolite D-2-hydroxyglutarate, which impacts cellular epigenetics and metabolism. IDH mutation establishes distinctive patterns in metabolism, cancer biology, and the therapeutic sensitivity of glioma. Thus, a deeper understanding of the roles of IDH mutations is of great value to improve the therapeutic efficacy of glioma and other malignancies that share similar genetic characteristics. In this review, we focused on the genetics, biochemistry, and clinical impacts of IDH mutations in glioma. Full article
(This article belongs to the Special Issue Molecular and Pathological Mechanisms of Adult Gliomas)
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