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Tumors of the Nervous System: New Insights into Signaling, Genetics and Therapeutic Targeting 2.0

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

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 18979

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Dr. Sabrina Di Bartolomeo

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Guest Editor

Department of Biosciences and Territory, University of Molise, 86090 Pesche, Italy
Interests: glioma; autophagy; cell signalling; epigenetics; molecular mechanisms
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Brain tumors and other nervous system tumors are an extremely heterogeneous group of benign and malignant tumors characterized by different aggressiveness and variable clinical outcomes. Among them, the most common primary brain tumors in adults are gliomas, meningiomas and pituitary adenomas. Otherwise, medulloblastoma is the most common brain tumor in children. Despite their diversity, nervous system tumors share the tendency of being refractory to radical surgical resection, and radio-chemotherapy is often ineffective because of resistance mechanisms. For these reasons, clinical management of these kinds of tumors is frequently challenging and prognosis is still poor. In this scenario, precision medicine approaches are emerging as promising therapeutic avenues against nervous system tumors, and highlight the need to acquire an in-depth knowledge about the genetic mutations, signaling pathways, metabolic alterations and environmental effects involved in tumor biology and resistance to therapies.

This Special Issue focuses on the current understanding of signaling pathways, as well as genetic and epigenetic features involved in the pathogenesis of brain tumors and other nervous system tumors, with emphasis on the development of novel therapeutic approaches aimed at improving the current standard care. Original articles and up-to-date reviews are encouraged, in order to provide a comprehensive knowledge of the state of the art and future directions.

Dr. Sabrina Di Bartolomeo
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

brain tumors
gliomas
medulloblastomas
neuroblastoma
cell signaling
molecular mechanisms
genetic mutations
cancer therapy
drug resistance
drug repositioning

Published Papers (7 papers)

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Research

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15 pages, 39328 KiB

Open AccessArticle

Bromodomain and Extraterminal Domain (BET) Protein Inhibition Hinders Glioblastoma Progression by Inducing Autophagy-Dependent Differentiation

by Mayra Colardo, Deborah Gargano, Miriam Russo, Michele Petraroia, Daniele Pensabene, Giuseppina D’Alessandro, Antonio Santoro, Cristina Limatola, Marco Segatto and Sabrina Di Bartolomeo

Int. J. Mol. Sci. 2023, 24(8), 7017; https://doi.org/10.3390/ijms24087017 - 10 Apr 2023

Cited by 2 | Viewed by 1573

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive type of malignant primary brain tumor, and it is characterized by a high recurrence incidence and poor prognosis due to the presence of a highly heterogeneous mass of stem cells with self-renewal capacity and stemness maintenance ability. In recent years, the epigenetic landscape of GBM has been explored and many epigenetic alterations have been investigated. Among the investigated epigenetic abnormalities, the bromodomain and extra-terminal domain (BET) chromatin readers have been found to be significantly overexpressed in GBM. In this work, we investigated the effects of BET protein inhibition on GBM cell reprogramming. We found that the pan-BET pharmacological inhibitor JQ1 was able to promote a differentiation program in GBM cells, thus impairing cell proliferation and enhancing the toxicity of the drug Temozolomide (TMZ). Notably, the pro-differentiation capability of JQ1 was prevented in autophagy-defective models, suggesting that autophagy activation is necessary for BET protein activity in regulating glioma cell fate. Given the growing interest in epigenetic therapy, our results further support the possibility of introducing a BET-based approach in GBM clinical management. Full article

(This article belongs to the Special Issue Tumors of the Nervous System: New Insights into Signaling, Genetics and Therapeutic Targeting 2.0)

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15 pages, 1895 KiB

Open AccessArticle

Clinical, Histopathologic and Genetic Features of Rhabdoid Meningiomas

by Patricia Alejandra Garrido Ruiz, María González-Tablas, Alejandro Pasco Peña, María Victoria Zelaya Huerta, Javier Ortiz, Álvaro Otero, Luis Antonio Corchete, María Dolores Ludeña, María Cristina Caballero Martínez, Alicia Córdoba Iturriagagoitia, Inmaculada Catalina Fernández, Joaquín González-Carreró Fojón, Aurelio Hernández Laín, Alberto Orfao and María Dolores Tabernero

Int. J. Mol. Sci. 2023, 24(2), 1116; https://doi.org/10.3390/ijms24021116 - 06 Jan 2023

Cited by 3 | Viewed by 1591

Abstract

Rhabdoid meningiomas (RM) shows heterogeneous histological findings, and a wide variety of chromosomal copy number alterations (CNA) are associated with an unpredictable course of the disease. In this study, we analyzed a series of 305 RM samples from patients previously reported in the literature and 33 samples from 23 patients studied in our laboratory. Monosomy 22-involving the minimal but most common recurrent region loss of the 22q11.23 chromosomal region was the most observed chromosomal alteration, followed by losses of chromosomes 14, 1, 6, and 19, polysomies of chromosomes 17, 1q, and 20, and gains of 13q14.2, 10p13, and 21q21.2 chromosomal regions. Based on their CNA profile, RM could be classified into two genetic subgroups with distinct clinicopathologic features characterized by the presence of (1) chromosomal losses only and (2) combined losses and gains of several chromosomes. The latter displays a higher frequency of WHO grade 3 tumors and poorer clinical outcomes. Full article

(This article belongs to the Special Issue Tumors of the Nervous System: New Insights into Signaling, Genetics and Therapeutic Targeting 2.0)

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14 pages, 2639 KiB

Open AccessArticle

Menadione Potentiates Auranofin-Induced Glioblastoma Cell Death

by Monika Szeliga and Radosław Rola

Int. J. Mol. Sci. 2022, 23(24), 15712; https://doi.org/10.3390/ijms232415712 - 11 Dec 2022

Cited by 4 | Viewed by 1383

Abstract

Glioblastoma (GBM) is the most aggressive primary brain tumor. Recently, agents increasing the level of oxidative stress have been proposed as anticancer drugs. However, their efficacy may be lowered by the cytoprotective activity of antioxidant enzymes, often upregulated in neoplastic cells. Here, we assessed the mRNA and protein expression of thioredoxin reductase 1 (TrxR1), a master regulator of cellular redox homeostasis, in GBM and non-tumor brain tissues. Next, we examined the influence of an inhibitor of TrxR1, auranofin (AF), alone or in combination with a prooxidant menadione (MEN), on growth of GBM cell lines, patient-derived GBM cells and normal human astrocytes. We detected considerable amount of TrxR1 in the majority of GBM tissues. Treatment with AF decreased viability of GBM cells and their potential to form colonies and neurospheres. Moreover, it increased the intracellular level of reactive oxygen species (ROS). Pre-treatment with ROS scavenger prevented the AF-induced cell death, pointing to the important role of ROS in the reduction of cell viability. The cytotoxic effect of AF was potentiated by treatment with MEN. In conclusion, our results identify TrxR1 as an attractive drug target and highlights AF as an off-patent drug candidate in GBM therapy. Full article

(This article belongs to the Special Issue Tumors of the Nervous System: New Insights into Signaling, Genetics and Therapeutic Targeting 2.0)

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14 pages, 2947 KiB

Open AccessArticle

MicroRNA 3928 Suppresses Glioblastoma through Downregulation of Several Oncogenes and Upregulation of p53

by Elizabeth Q. X. Mulcahy, Ying Zhang, Rossymar R. Colόn, Shelby R. Cain, Myron K. Gibert, Jr., Collin J. Dube, Markus Hafner and Roger Abounader

Int. J. Mol. Sci. 2022, 23(7), 3930; https://doi.org/10.3390/ijms23073930 - 01 Apr 2022

Cited by 7 | Viewed by 2092

Abstract

Glioblastoma (GBM) is the most frequent and lethal primary malignant brain tumor. Despite decades of research, therapeutic advances that significantly prolong life are non-existent. In recent years, microRNAs (miRNAs) have been a focus of study in the pathobiology of cancer because of their ability to simultaneously regulate multiple genes. The aim of this study was to determine the functional and mechanistic effects of miR-3928 in GBM both in vitro and in vivo. To the best of our knowledge, this is the first article investigating the role of miR-3928 in GBM. We measured endogenous miR-3928 expression levels in a panel of patient-derived GBM tissue samples and cell lines. We found that GBM tissue samples and cell lines express lower levels of miR-3928 than normal brain cortex and astrocytes, respectively. Therefore, we hypothesized that miR-3928 is a tumor suppressive microRNA. We verified this hypothesis by showing that exogenous expression of miR-3928 has a strong inhibitory effect on both cell growth and invasiveness of GBM cells. Stable ex vivo overexpression of miR-3928 in GBM cells led to a reduction in tumor size in nude mice xenografts. We identified many targets (MDM2, CD44, DDX3X, HMGA2, CCND1, BRAF, ATOH8, and BMI1) of miR-3928. Interestingly, inhibition of the oncogene MDM2 also led to an upregulation of wild-type p53 expression and phosphorylation. In conclusion, we find that miR-3928, through the downregulation of several oncogenes and upregulation and activation of wild-type p53, is a strong tumor suppressor in GBM. Furthermore, the fact that miR-3928 can target many important dysregulated proteins in GBM suggests it might be a “master” regulatory microRNA that could be therapeutically exploited. Full article

(This article belongs to the Special Issue Tumors of the Nervous System: New Insights into Signaling, Genetics and Therapeutic Targeting 2.0)

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Review

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32 pages, 2254 KiB

Open AccessReview

Non-Canonical Splicing and Its Implications in Brain Physiology and Cancer

by Consuelo Pitolli, Alberto Marini, Claudio Sette and Vittoria Pagliarini

Int. J. Mol. Sci. 2022, 23(5), 2811; https://doi.org/10.3390/ijms23052811 - 04 Mar 2022

Cited by 10 | Viewed by 5604

Abstract

The advance of experimental and computational techniques has allowed us to highlight the existence of numerous different mechanisms of RNA maturation, which have been so far unknown. Besides canonical splicing, consisting of the removal of introns from pre-mRNA molecules, non-canonical splicing events may occur to further increase the regulatory and coding potential of the human genome. Among these, splicing of microexons, recursive splicing and biogenesis of circular and chimeric RNAs through back-splicing and trans-splicing processes, respectively, all contribute to expanding the repertoire of RNA transcripts with newly acquired regulatory functions. Interestingly, these non-canonical splicing events seem to occur more frequently in the central nervous system, affecting neuronal development and differentiation programs with important implications on brain physiology. Coherently, dysregulation of non-canonical RNA processing events is associated with brain disorders, including brain tumours. Herein, we summarize the current knowledge on molecular and regulatory mechanisms underlying canonical and non-canonical splicing events with particular emphasis on cis-acting elements and trans-acting factors that all together orchestrate splicing catalysis reactions and decisions. Lastly, we review the impact of non-canonical splicing on brain physiology and pathology and how unconventional splicing mechanisms may be targeted or exploited for novel therapeutic strategies in cancer. Full article

(This article belongs to the Special Issue Tumors of the Nervous System: New Insights into Signaling, Genetics and Therapeutic Targeting 2.0)

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11 pages, 567 KiB

Open AccessReview

EHMT2/G9a as an Epigenetic Target in Pediatric and Adult Brain Tumors

by Barbara Kunzler Souza, Natalia Hogetop Freire, Mariane Jaeger, Caroline Brunetto de Farias, Algemir L. Brunetto, André T. Brunetto and Rafael Roesler

Int. J. Mol. Sci. 2021, 22(20), 11292; https://doi.org/10.3390/ijms222011292 - 19 Oct 2021

Cited by 8 | Viewed by 3195

Abstract

Epigenetic mechanisms, including post-translational modifications of DNA and histones that influence chromatin structure, regulate gene expression during normal development and are also involved in carcinogenesis and cancer progression. The histone methyltransferase G9a (euchromatic histone lysine methyltransferase 2, EHMT2), which mostly mediates mono- and dimethylation by histone H3 lysine 9 (H3K9), influences gene expression involved in embryonic development and tissue differentiation. Overexpression of G9a has been observed in several cancer types, and different classes of G9a inhibitors have been developed as potential anticancer agents. Here, we review the emerging evidence suggesting the involvement of changes in G9a activity in brain tumors, namely glioblastoma (GBM), the main type of primary malignant brain cancer in adults, and medulloblastoma (MB), the most common type of malignant brain cancer in children. We also discuss the role of G9a in neuroblastoma (NB) and the drug development of G9a inhibitors. Full article

(This article belongs to the Special Issue Tumors of the Nervous System: New Insights into Signaling, Genetics and Therapeutic Targeting 2.0)

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16 pages, 320 KiB

Open AccessReview

Targeted Therapies in Rare Brain Tumours

by Francesco Bruno, Alessia Pellerino, Luca Bertero, Riccardo Soffietti and Roberta Rudà

Int. J. Mol. Sci. 2021, 22(15), 7949; https://doi.org/10.3390/ijms22157949 - 26 Jul 2021

Cited by 4 | Viewed by 2487

Abstract

Rare central nervous system (CNS) tumours represent a unique challenge. Given the difficulty of conducting dedicated clinical trials, there is a lack of therapies for these tumours supported by high quality evidence, and knowledge regarding the impact of standard treatments (i.e., surgery, radiotherapy or chemotherapy) is commonly based on retrospective studies. Recently, new molecular techniques have led to the discovery of actionable molecular alterations. The aim of this article is to review recent progress in the molecular understanding of and therapeutic options for rare brain tumours, both in children and adults. We will discuss options such as targeting the mechanistic target of rapamycin (mTOR) pathway in subependymal giant cells astrocytomas (SEGAs) of tuberous sclerosis and BRAF V600E mutation in rare glial (pleomorphic xanthoastrocytomas) or glioneuronal (gangliogliomas) tumours, which are a model of how specific molecular treatments can also favourably impact neurological symptoms (such as seizures) and quality of life. Moreover, we will discuss initial experiences in targeting new molecular alterations in gliomas, such as isocitrate dehydrogenase (IDH) mutations and neurotrophic tyrosine receptor kinase (NTRK) fusions, and in medulloblastomas such as the sonic hedgehog (SHH) pathway. Full article

(This article belongs to the Special Issue Tumors of the Nervous System: New Insights into Signaling, Genetics and Therapeutic Targeting 2.0)

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