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Biomolecular Characterization of Brain Gliomas and Molecular Alterations Caused by Therapy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 17748

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Special Issue Editor

Dr. Carsten Hagemann

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Guest Editor

Universitätsklinikum Würzburg, Wurzburg, Germany
Interests: neuro-oncology; tumor biology; glioblastoma multiforme; glioma; tumor treating fields (TTFields); drug delivery; cell signaling; blood–brain barrier

Special Issue Information

Dear Colleagues,

The World Health Organization (WHO) classifies glial tumors, which are a group of primary brain tumors, into different subgroups. There is a great variety in their developmental history and clinical behavior. For example, pilocytic astrocytomas WHO grade I are benign and mainly found in children, whereas low grade astrocytomas WHO grade II and III grow faster and more infiltrative. Formerly, gliomas were classified according to their histological appearance, while the recent update of the WHO classification in addition takes molecular markers into account. The mutation status of isocytrate dehydrogenase (IDH) distinguishes between a slowly growing subcategory of IDH-mutated gliomas WHO grade II and III and IDH-wildtype gliomas of the same grade. Whereas the former display a comparatively better prognosis, the latter show a growth pattern and patients’ clinical course that resembles those of glioblastoma multiforme (GBM). GBM is the most common and devastating form of primary brain tumor. Methylation of the O⁶-methylguanine DNA methyltransferase (MGMT) promoter is associated with improved response to temozolomide (TMZ) chemotherapy and has emerged as a strong prognostic factor for the clinical course of the patients. Microsurgical tumor resection, irradiation and concomitant, as well as adjuvant TMZ chemotherapy, are the current standards of care. Recently, the introduction of tumor treating fields (TTFields) has raised new hopes for an improvement of this standard therapy. TTFields directly influence a multitude of regulatory key molecules within the cancer cell, involved in the regulation of e.g., proliferation, migration, autophagy and apoptosis. Meanwhile, it has been shown that TMZ has the potential to induce hypermutation in a subset of IDH-mutant gliomas. However, how this affects the expression of the biomolecular signaling network in glioma cells remains elusive.

This Special Issue shall provide an introduction to the biomolecular characteristics of these central nervous system tumors. In this respect, reports on therapeutic and prognostic molecular biomarkers and the alterations therapy may provoke on biomolecules - and vice versa - are of particular interest.

Dr. Carsten Hagemann
Guest Editor

Manuscript Submission Information

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

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

gliomas
glioblastoma multiforme
therapeutic and prognostic biomarker expression
cell signaling
therapy effects on biomolecules and vice versa
molecular therapy mode of action

Published Papers (4 papers)

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Research

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15 pages, 2006 KiB

Open AccessArticle

Protocadherin Gamma C3 (PCDHGC3) Is Strongly Expressed in Glioblastoma and Its High Expression Is Associated with Longer Progression-Free Survival of Patients

by Jonas Feldheim, David Wend, Mara J. Lauer, Camelia M. Monoranu, Martin Glas, Christoph Kleinschnitz, Ralf-Ingo Ernestus, Barbara M. Braunger, Patrick Meybohm, Carsten Hagemann and Malgorzata Burek

Int. J. Mol. Sci. 2022, 23(15), 8101; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158101 - 22 Jul 2022

Cited by 3 | Viewed by 1765

Abstract

Protocadherins (PCDHs) belong to the cadherin superfamily and represent the largest subgroup of calcium-dependent adhesion molecules. In the genome, most PCDHs are arranged in three clusters, α, β, and γ on chromosome 5q31. PCDHs are highly expressed in the central nervous system (CNS). Several PCDHs have tumor suppressor functions, but their individual role in primary brain tumors has not yet been elucidated. Here, we examined the mRNA expression of PCDHGC3, a member of the PCDHγ cluster, in non-cancerous brain tissue and in gliomas of different World Health Organization (WHO) grades and correlated it with the clinical data of the patients. We generated a PCDHGC3 knockout U343 cell line and examined its growth rate and migration in a wound healing assay. We showed that PCDHGC3 mRNA and protein were significantly overexpressed in glioma tissue compared to a non-cancerous brain specimen. This could be confirmed in glioma cell lines. High PCDHGC3 mRNA expression correlated with longer progression-free survival (PFS) in glioma patients. PCDHGC3 knockout in U343 resulted in a slower growth rate but a significantly faster migration rate in the wound healing assay and decreased the expression of several genes involved in WNT signaling. PCDHGC3 expression should therefore be further investigated as a PFS-marker in gliomas. However, more studies are needed to elucidate the molecular mechanisms underlying the PCDHGC3 effects. Full article

(This article belongs to the Special Issue Biomolecular Characterization of Brain Gliomas and Molecular Alterations Caused by Therapy)

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19 pages, 3111 KiB

Open AccessArticle

Effects of Long-Term Temozolomide Treatment on Glioblastoma and Astrocytoma WHO Grade 4 Stem-like Cells

by Jonas Feldheim, Almuth F. Kessler, Julia J. Feldheim, Ellina Schulz, David Wend, Lazaros Lazaridis, Christoph Kleinschnitz, Martin Glas, Ralf-Ingo Ernestus, Sebastian Brandner, Camelia M. Monoranu, Mario Löhr and Carsten Hagemann

Int. J. Mol. Sci. 2022, 23(9), 5238; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095238 - 07 May 2022

Cited by 6 | Viewed by 3130

Abstract

Glioblastoma leads to a fatal course within two years in more than two thirds of patients. An essential cornerstone of therapy is chemotherapy with temozolomide (TMZ). The effect of TMZ is counteracted by the cellular repair enzyme O⁶-methylguanine-DNA methyltransferase (MGMT). The MGMT promoter methylation, the main regulator of MGMT expression, can change from primary tumor to recurrence, and TMZ may play a significant role in this process. To identify the potential mechanisms involved, three primary stem-like cell lines (one astrocytoma with the mutation of the isocitrate dehydrogenase (IDH), CNS WHO grade 4 (HGA)), and two glioblastoma (IDH-wildtype, CNS WHO grade 4) were treated with TMZ. The MGMT promoter methylation, migration, proliferation, and TMZ-response of the tumor cells were examined at different time points. The strong effects of TMZ treatment on the MGMT methylated cells were observed. Furthermore, TMZ led to a loss of the MGMT promoter hypermethylation and induced migratory rather than proliferative behavior. Cells with the unmethylated MGMT promoter showed more aggressive behavior after treatment, while HGA cells reacted heterogenously. Our study provides further evidence to consider the potential adverse effects of TMZ chemotherapy and a rationale for investigating potential relationships between TMZ treatment and change in the MGMT promoter methylation during relapse. Full article

(This article belongs to the Special Issue Biomolecular Characterization of Brain Gliomas and Molecular Alterations Caused by Therapy)

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10 pages, 4627 KiB

Open AccessCommunication

SOAT1: A Suitable Target for Therapy in High-Grade Astrocytic Glioma?

by Mario Löhr, Wolfgang Härtig, Almut Schulze, Matthias Kroiß, Silviu Sbiera, Constantin Lapa, Bianca Mages, Sabrina Strobel, Jennifer Elisabeth Hundt, Simone Bohnert, Stefan Kircher, Sudha Janaki-Raman and Camelia-Maria Monoranu

Int. J. Mol. Sci. 2022, 23(7), 3726; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073726 - 28 Mar 2022

Cited by 6 | Viewed by 2581

Abstract

Targeting molecular alterations as an effective treatment for isocitrate dehydrogenase-wildtype glioblastoma (GBM) patients has not yet been established. Sterol-O-Acyl Transferase 1 (SOAT1), a key enzyme in the conversion of endoplasmic reticulum cholesterol to esters for storage in lipid droplets (LD), serves as a target for the orphan drug mitotane to treat adrenocortical carcinoma. Inhibition of SOAT1 also suppresses GBM growth. Here, we refined SOAT1-expression in GBM and IDH-mutant astrocytoma, CNS WHO grade 4 (HGA), and assessed the distribution of LD in these tumors. Twenty-seven GBM and three HGA specimens were evaluated by multiple GFAP, Iba1, IDH1 R132H, and SOAT1 immunofluorescence labeling as well as Oil Red O staining. To a small extent SOAT1 was expressed by tumor cells in both tumor entities. In contrast, strong expression was observed in glioma-associated macrophages. Triple immunofluorescence labeling revealed, for the first time, evidence for SOAT1 colocalization with Iba1 and IDH1 R132H, respectively. Furthermore, a notable difference in the amount of LD between GBM and HGA was observed. Therefore, SOAT1 suppression might be a therapeutic option to target GBM and HGA growth and invasiveness. In addition, the high expression in cells related to neuroinflammation could be beneficial for a concomitant suppression of protumoral microglia/macrophages. Full article

(This article belongs to the Special Issue Biomolecular Characterization of Brain Gliomas and Molecular Alterations Caused by Therapy)

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Review

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32 pages, 1996 KiB

Open AccessReview

Prognostic and Predictive Biomarkers in Gliomas

by Paulina Śledzińska, Marek G. Bebyn, Jacek Furtak, Janusz Kowalewski and Marzena A. Lewandowska

Int. J. Mol. Sci. 2021, 22(19), 10373; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910373 - 26 Sep 2021

Cited by 106 | Viewed by 9268

Abstract

Gliomas are the most common central nervous system tumors. New technologies, including genetic research and advanced statistical methods, revolutionize the therapeutic approach to the patient and reveal new points of treatment options. Moreover, the 2021 World Health Organization Classification of Tumors of the Central Nervous System has fundamentally changed the classification of gliomas and incorporated many molecular biomarkers. Given the rapid progress in neuro-oncology, here we compile the latest research on prognostic and predictive biomarkers in gliomas. In adult patients, IDH mutations are positive prognostic markers and have the greatest prognostic significance. However, CDKN2A deletion, in IDH-mutant astrocytomas, is a marker of the highest malignancy grade. Moreover, the presence of TERT promoter mutations, EGFR alterations, or a combination of chromosome 7 gain and 10 loss upgrade IDH-wildtype astrocytoma to glioblastoma. In pediatric patients, H3F3A alterations are the most important markers which predict the worse outcome. MGMT promoter methylation has the greatest clinical significance in predicting responses to temozolomide (TMZ). Conversely, mismatch repair defects cause hypermutation phenotype predicting poor response to TMZ. Finally, we discussed liquid biopsies, which are promising diagnostic, prognostic, and predictive techniques, but further work is needed to implement these novel technologies in clinical practice. Full article

(This article belongs to the Special Issue Biomolecular Characterization of Brain Gliomas and Molecular Alterations Caused by Therapy)

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