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Molecular Mechanisms and Pathophysiology of Cerebral Gliomas: Towards Development of New Treatments

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

Deadline for manuscript submissions: 15 June 2024 | Viewed by 6176

Special Issue Editors

Dr. Alessandra Pagano

E-Mail Website
Guest Editor
Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France
Interests: glioblastomas; intracellular signaling pathways; oxidative signaling; apoptosis; cell invasion; therapeutical approaches; tumoral microenvironment; preclinical models
Dr. Chiara Bastiancich

E-Mail Website
Guest Editor
Department of Drug Science and Technology, University of Turin, 10124 Turin, Italy
Interests: glioblastomas; brain drug delivery; nanomedicine; preclinical model; drug repurposing; surgery; tumor microenvironment
Special Issues, Collections and Topics in MDPI journals
Dr. Aurélie Tchoghandjian

E-Mail Website
Guest Editor
Institute of Neurophysiopathology, Aix-Marseille University, CNRS, INP, 13005 Marseille, France
Interests: glioblastomas; cancer stem cells; tumor microenvironment; preclinical models; inhibitor of apoptosis; cell death; immune cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Gliomas are the most frequent brain tumors, and, irrespective of the advances in biological and pharmaceutical knowledge, they still represent an unmet medical need. Low-grade gliomas inexorably evolve to high-grade tumors. Grade IV gliomas, astrocytomas IDH-mutant and glioblastomas IDH-wild type are the most aggressive forms of tumor, which have a poor prognosis and few therapeutic solutions. The discovery of new biomarkers and new molecular mechanisms involved in gliomas pathophysiology is required to develop innovative and more effective treatments.

This Special Issue will include papers investigating the pathological mechanisms of gliomas and new druggable biomarkers. New therapeutic strategies and preclinical (in vitro, in vivo, ex vivo) studies are also welcome.

This Special Issue will gather original research articles and review papers. Potential topics include, but are not limited to, the following:

  1. Molecular mechanisms in gliomagenesis and tumor progression;
  2. Identification of new biomarkers;
  3. Crosstalk between tumor (stem) cells and the brain microenvironment;
  4. New preclinical models (in vitro, in vivo, ex vivo, patient’s derived models);
  5. Innovative therapeutic approaches.

Dr. Alessandra Pagano
Dr. Chiara Bastiancich
Dr. Aurélie Tchoghandjian
Guest Editors

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 pathophysiology
  • biomarkers
  • microenvironment
  • cancer stem cells
  • brain resident cells
  • omics approaches
  • preclinical models
  • targeted treatment
  • brain drug delivery

Published Papers (5 papers)

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Research

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15 pages, 4032 KiB  
Article
Annexin A2 Stabilizes Oncogenic JAG1 Intracellular Domain by Inhibiting Proteasomal Degradation in Glioblastoma Cells
by Seok Won Ham, Jung Yun Kim, Sunyoung Seo, Nayoung Hong, Min Ji Park, Yoonji Kim, Junseok Jang, Sehyeon Park, Silvee Jisoo Lee, Jun-Kyum Kim, Eun-Jung Kim, Sung-Ok Kim, Sung-Chan Kim, Jong-Whi Park and Hyunggee Kim
Int. J. Mol. Sci. 2023, 24(19), 14776; https://doi.org/10.3390/ijms241914776 - 30 Sep 2023
Viewed by 959
Abstract
Glioblastoma (GBM) is the most lethal brain cancer, causing inevitable deaths of patients owing to frequent relapses of cancer stem cells (CSCs). The significance of the NOTCH signaling pathway in CSCs has been well recognized; however, there is no NOTCH-selective treatment applicable to [...] Read more.
Glioblastoma (GBM) is the most lethal brain cancer, causing inevitable deaths of patients owing to frequent relapses of cancer stem cells (CSCs). The significance of the NOTCH signaling pathway in CSCs has been well recognized; however, there is no NOTCH-selective treatment applicable to patients with GBM. We recently reported that Jagged1 (JAG1), a NOTCH ligand, drives a NOTCH receptor-independent signaling pathway via JAG1 intracellular domain (JICD1) as a crucial signal that renders CSC properties. Therefore, mechanisms regulating the JICD1 signaling pathway should be elucidated to further develop a selective therapeutic regimen. Here, we identified annexin A2 (ANXA2) as an essential modulator to stabilize intrinsically disordered JICD1. The binding of ANXA2 to JICD1 prevents the proteasomal degradation of JICD1 by heat shock protein-70/90 and carboxy-terminus of Hsc70 interacting protein E3 ligase. Furthermore, JICD1-driven propagation and tumor aggressiveness were inhibited by ANXA2 knockdown. Taken together, our findings show that ANXA2 maintains the function of the NOTCH receptor-independent JICD1 signaling pathway by stabilizing JICD1, and the targeted suppression of JICD1-driven CSC properties can be achieved by blocking its interaction with ANXA2. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Cerebral Gliomas: Towards Development of New Treatments)
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17 pages, 2524 KiB  
Article
Silencing GMPPB Inhibits the Proliferation and Invasion of GBM via Hippo/MMP3 Pathways
by Zi-Lu Huang, Aalaa Sanad Abdallah, Guang-Xin Shen, Milagros Suarez, Ping Feng, Yan-Jiao Yu, Ying Wang, Shuo-Han Zheng, Yu-Jun Hu, Xiang Xiao, Ya Liu, Song-Ran Liu, Zhong-Ping Chen, Xiao-Nan Li and Yun-Fei Xia
Int. J. Mol. Sci. 2023, 24(19), 14707; https://doi.org/10.3390/ijms241914707 - 28 Sep 2023
Viewed by 1188
Abstract
Glioblastoma multiforme (GBM) is a highly aggressive malignancy and represents the most common brain tumor in adults. To better understand its biology for new and effective therapies, we examined the role of GDP-mannose pyrophosphorylase B (GMPPB), a key unit of the GDP-mannose pyrophosphorylase [...] Read more.
Glioblastoma multiforme (GBM) is a highly aggressive malignancy and represents the most common brain tumor in adults. To better understand its biology for new and effective therapies, we examined the role of GDP-mannose pyrophosphorylase B (GMPPB), a key unit of the GDP-mannose pyrophosphorylase (GDP-MP) that catalyzes the formation of GDP-mannose. Impaired GMPPB function will reduce the amount of GDP-mannose available for O-mannosylation. Abnormal O-mannosylation of alpha dystroglycan (α-DG) has been reported to be involved in cancer metastasis and arenavirus entry. Here, we found that GMPPB is highly expressed in a panel of GBM cell lines and clinical samples and that expression of GMPPB is positively correlated with the WHO grade of gliomas. Additionally, expression of GMPPB was negatively correlated with the prognosis of GBM patients. We demonstrate that silencing GMPPB inhibits the proliferation, migration, and invasion of GBM cells both in vitro and in vivo and that overexpression of GMPPB exhibits the opposite effects. Consequently, targeting GMPPB in GBM cells results in impaired GBM tumor growth and invasion. Finally, we identify that the Hippo/MMP3 axis is essential for GMPPB-promoted GBM aggressiveness. These findings indicate that GMPPB represents a potential novel target for GBM treatment. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Cerebral Gliomas: Towards Development of New Treatments)
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20 pages, 19739 KiB  
Article
Development of Zika Virus E Variants for Pseudotyping Retroviral Vectors Targeting Glioblastoma Cells
by Vivien Grunwald, Hai Dang Ngo, Jan Patrick Formanski, Jana Sue Jonas, Celine Pöhlking, Birco Schwalbe and Michael Schreiber
Int. J. Mol. Sci. 2023, 24(19), 14487; https://doi.org/10.3390/ijms241914487 - 23 Sep 2023
Cited by 2 | Viewed by 1652
Abstract
A fundamental idea for targeting glioblastoma cells is to exploit the neurotropic properties of Zika virus (ZIKV) through its two outer envelope proteins, prM and E. This study aimed to develop envelope glycoproteins for pseudotyping retroviral vectors that can be used for efficient [...] Read more.
A fundamental idea for targeting glioblastoma cells is to exploit the neurotropic properties of Zika virus (ZIKV) through its two outer envelope proteins, prM and E. This study aimed to develop envelope glycoproteins for pseudotyping retroviral vectors that can be used for efficient tumor cell infection. Firstly, the retroviral vector pNLlucAM was packaged using wild-type ZIKV E to generate an E-HIVluc pseudotype. E-HIVluc infection rates for tumor cells were higher than those of normal prME pseudotyped particles and the traditionally used vesicular stomatitis virus G (VSV-G) pseudotypes, indicating that protein E alone was sufficient for the formation of infectious pseudotyped particles. Secondly, two envelope chimeras, E41.1 and E41.2, with the E wild-type transmembrane domain replaced by the gp41 transmembrane and cytoplasmic domains, were constructed; pNLlucAM or pNLgfpAM packaged with E41.1 or E41.2 constructs showed infectivity for tumor cells, with the highest rates observed for E41.2. This envelope construct can be used not only as a tool to further develop oncolytic pseudotyped viruses for therapy, but also as a new research tool to study changes in tumor cells after the transfer of genes that might have therapeutic potential. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Cerebral Gliomas: Towards Development of New Treatments)
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24 pages, 23537 KiB  
Article
Role of Na+/Ca2+ Exchanger (NCX) in Glioblastoma Cell Migration (In Vitro)
by Federico Brandalise, Martino Ramieri, Emanuela Pastorelli, Erica Cecilia Priori, Daniela Ratto, Maria Teresa Venuti, Elisa Roda, Francesca Talpo and Paola Rossi
Int. J. Mol. Sci. 2023, 24(16), 12673; https://doi.org/10.3390/ijms241612673 - 11 Aug 2023
Cited by 3 | Viewed by 1220
Abstract
Glioblastoma (GBM) is the most malignant form of primary brain tumor. It is characterized by the presence of highly invasive cancer cells infiltrating the brain by hijacking neuronal mechanisms and interacting with non-neuronal cell types, such as astrocytes and endothelial cells. To enter [...] Read more.
Glioblastoma (GBM) is the most malignant form of primary brain tumor. It is characterized by the presence of highly invasive cancer cells infiltrating the brain by hijacking neuronal mechanisms and interacting with non-neuronal cell types, such as astrocytes and endothelial cells. To enter the interstitial space of the brain parenchyma, GBM cells significantly shrink their volume and extend the invadopodia and lamellipodia by modulating their membrane conductance repertoire. However, the changes in the compartment-specific ionic dynamics involved in this process are still not fully understood. Here, using noninvasive perforated patch-clamp and live imaging approaches on various GBM cell lines during a wound-healing assay, we demonstrate that the sodium-calcium exchanger (NCX) is highly expressed in the lamellipodia compartment, is functionally active during GBM cell migration, and correlates with the overexpression of large conductance K+ channel (BK) potassium channels. Furthermore, a NCX blockade impairs lamellipodia formation and maintenance, as well as GBM cell migration. In conclusion, the functional expression of the NCX in the lamellipodia of GBM cells at the migrating front is a conditio sine qua non for the invasion strategy of these malignant cells and thus represents a potential target for brain tumor treatment. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Cerebral Gliomas: Towards Development of New Treatments)
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17 pages, 1286 KiB  
Review
Endoplasmic Reticulum Stress in Gliomas: Exploiting a Dual-Effect Dysfunction through Chemical Pharmaceutical Compounds and Natural Derivatives for Therapeutical Uses
by Daniel García-López, Montserrat Zaragoza-Ojeda, Pilar Eguía-Aguilar and Francisco Arenas-Huertero
Int. J. Mol. Sci. 2024, 25(7), 4078; https://doi.org/10.3390/ijms25074078 - 06 Apr 2024
Viewed by 509
Abstract
The endoplasmic reticulum maintains proteostasis, which can be disrupted by oxidative stress, nutrient deprivation, hypoxia, lack of ATP, and toxicity caused by xenobiotic compounds, all of which can result in the accumulation of misfolded proteins. These stressors activate the unfolded protein response (UPR), [...] Read more.
The endoplasmic reticulum maintains proteostasis, which can be disrupted by oxidative stress, nutrient deprivation, hypoxia, lack of ATP, and toxicity caused by xenobiotic compounds, all of which can result in the accumulation of misfolded proteins. These stressors activate the unfolded protein response (UPR), which aims to restore proteostasis and avoid cell death. However, endoplasmic response-associated degradation (ERAD) is sometimes triggered to degrade the misfolded and unassembled proteins instead. If stress persists, cells activate three sensors: PERK, IRE-1, and ATF6. Glioma cells can use these sensors to remain unresponsive to chemotherapeutic treatments. In such cases, the activation of ATF4 via PERK and some proteins via IRE-1 can promote several types of cell death. The search for new antitumor compounds that can successfully and directly induce an endoplasmic reticulum stress response ranges from ligands to oxygen-dependent metabolic pathways in the cell capable of activating cell death pathways. Herein, we discuss the importance of the ER stress mechanism in glioma and likely therapeutic targets within the UPR pathway, as well as chemicals, pharmaceutical compounds, and natural derivatives of potential use against gliomas. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Cerebral Gliomas: Towards Development of New Treatments)
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