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Biomedicines
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Molecular Research of Glioblastoma
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Molecular Research of Glioblastoma

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 16336

Special Issue Editors

Dr. Esperanza R. Matarredona

E-Mail Website
Guest Editor
Departamento de Fisiología, Facultad de Biología, Universidad de Sevilla, Seville, Spain
Interests: neural stem cells; glioblastoma; extracellular vesicles; glial cells; brain damage
Dr. Ricardo Gargini

E-Mail Website
Co-Guest Editor
Neurooncology Unit, Instituto de Salud Carlos III-UFIEC, 28220 Madrid, Spain
Interests: glioblastoma; blood vessels; brain damage; EGFR; IDH; genomics

Special Issue Information

Dear Colleagues,

The molecular biology of human glioblastoma, the most aggressive primary brain tumor, is a fast-progressing field in which basic research needs to meet clinical expectations in terms of anti-tumor efficacy. Therefore, a deeper knowledge of the connection between the bio-molecular and clinical features of this disease is needed in order to develop new treatments. These include signal transduction pathways involved in glioma formation and progression, energy metabolism requirements, interactions between glioma cells and their microenvironment (immune cells, blood vessels, or neurons/glial cells), as well as signaling mechanisms involved in these interactions.

This Special Issue aims to present a collection of original research and review articles dealing with different aspects of the molecular biology and clinical features of glioblastoma, with the hope of shedding some light on the pathological mechanisms of this devastating tumor that may help to improve treatment strategies for patients with this disease.

Dr. Esperanza R. Matarredona
Dr. Ricardo Gargini
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. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

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

  • glioma stem cell
  • tumor microenvironment
  • molecular heterogeneity
  • IDH-mutant glioblastoma
  • IDH-wild type glioblastoma
  • targeted therapies
  • EGFR mutations

Published Papers (5 papers)

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Research

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19 pages, 4557 KiB  
Article
Eltanexor Effectively Reduces Viability of Glioblastoma and Glioblastoma Stem-Like Cells at Nano-Molar Concentrations and Sensitizes to Radiotherapy and Temozolomide
by Katharina Otte, Kai Zhao, Madita Braun, Andreas Neubauer, Hartmann Raifer, Frederik Helmprobst, Felipe Ovalle Barrera, Christopher Nimsky, Jörg W. Bartsch and Tillmann Rusch
Biomedicines 2022, 10(9), 2145; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10092145 - 31 Aug 2022
Cited by 3 | Viewed by 2259
Abstract
Current standard adjuvant therapy of glioblastoma multiforme (GBM) using temozolomide (TMZ) frequently fails due to therapy resistance. Thus, novel therapeutic approaches are highly demanded. We tested the therapeutic efficacy of the second-generation XPO1 inhibitor Eltanexor using assays for cell viability and apoptosis in [...] Read more.
Current standard adjuvant therapy of glioblastoma multiforme (GBM) using temozolomide (TMZ) frequently fails due to therapy resistance. Thus, novel therapeutic approaches are highly demanded. We tested the therapeutic efficacy of the second-generation XPO1 inhibitor Eltanexor using assays for cell viability and apoptosis in GBM cell lines and GBM stem-like cells. For most GBM-derived cells, IC50 concentrations for Eltanexor were below 100 nM. In correlation with reduced cell viability, apoptosis rates were significantly increased. GBM stem-like cells presented a combinatorial effect of Eltanexor with TMZ on cell viability. Furthermore, pretreatment of GBM cell lines with Eltanexor significantly enhanced radiosensitivity in vitro. To explore the mechanism of apoptosis induction by Eltanexor, TP53-dependent genes were analyzed at the mRNA and protein level. Eltanexor caused induction of TP53-related genes, TP53i3, PUMA, CDKN1A, and PML on both mRNA and protein level. Immunofluorescence of GBM cell lines treated with Eltanexor revealed a strong accumulation of CDKN1A, and, to a lesser extent, of p53 and Tp53i3 in cell nuclei as a plausible mechanism for Eltanexor-induced apoptosis. From these data, we conclude that monotherapy with Eltanexor effectively induces apoptosis in GBM cells and can be combined with current adjuvant therapies to provide a more effective therapy of GBM. Full article
(This article belongs to the Special Issue Molecular Research of Glioblastoma)
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20 pages, 7387 KiB  
Article
Ubiquitin-Specific Protease 6 n-Terminal-like Protein (USP6NL) and the Epidermal Growth Factor Receptor (EGFR) Signaling Axis Regulates Ubiquitin-Mediated DNA Repair and Temozolomide-Resistance in Glioblastoma
by I-Chang Su, Yu-Kai Su, Hao-Yu Chuang, Vijesh Kumar Yadav, Syahru Agung Setiawan, Iat-Hang Fong, Chi-Tai Yeh, Hui-Chuan Huang and Chien-Min Lin
Biomedicines 2022, 10(7), 1531; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10071531 - 28 Jun 2022
Cited by 4 | Viewed by 2378
Abstract
Glioblastoma multiforme (GBM) is the most malignant glioma, with a 30–60% epidermal growth factor receptor (EGFR) mutation. This mutation is associated with unrestricted cell growth and increases the possibility of cancer invasion. Patients with EGFR-mutated GBM often develop resistance to the available treatment [...] Read more.
Glioblastoma multiforme (GBM) is the most malignant glioma, with a 30–60% epidermal growth factor receptor (EGFR) mutation. This mutation is associated with unrestricted cell growth and increases the possibility of cancer invasion. Patients with EGFR-mutated GBM often develop resistance to the available treatment modalities and higher recurrence rates. The drug resistance observed is associated with multiple genetic or epigenetic factors. The ubiquitin-specific protease 6 N-terminal-like protein (USP6NL) is a GTPase-activating protein that functions as a deubiquitinating enzyme and regulates endocytosis and signal transduction. It is highly expressed in many cancer types and may promote the growth and proliferation of cancer cells. We hypothesized that USP6NL affects GBM chemoresistance and tumorigenesis, and that its inhibition may be a novel therapeutic strategy for GBM treatment. The USP6NL level, together with EGFR expression in human GBM tissue samples and cell lines associated with therapy resistance, tumor growth, and cancer invasion, were investigated. Its pivotal roles and potential mechanism in modulating tumor growth, and the key mechanism associated with therapy resistance of GBM cells, were studied, both in vitro and in vivo. Herein, we found that deubiquitinase USP6NL and growth factor receptor EGFR were strongly associated with the oncogenicity and resistance of GBM, both in vitro and in vivo, toward temozolomide, as evidenced by enhanced migration, invasion, and acquisition of a highly invasive and drug-resistant phenotype by the GBM cells. Furthermore, abrogation of USP6NL reversed the properties of GBM cells and resensitized them toward temozolomide by enhancing autophagy and reducing the DNA damage repair response. Our results provide novel insights into the probable mechanism through which USP6NL/EGFR signaling might suppress the anticancer therapeutic response, induce cancer invasiveness, and facilitate reduced sensitivity to temozolomide treatment in GBM in an autolysosome-dependent manner. Therefore, controlling the USP6NL may offer an alternative, but efficient, therapeutic strategy for targeting and eradicating otherwise resistant and recurrent phenotypes of aggressive GBM cells. Full article
(This article belongs to the Special Issue Molecular Research of Glioblastoma)
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Review

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23 pages, 845 KiB  
Review
Recurrent Glioblastoma Treatment: State of the Art and Future Perspectives in the Precision Medicine Era
by Augusto Leone, Antonio Colamaria, Nicola Pio Fochi, Matteo Sacco, Matteo Landriscina, Giovanni Parbonetti, Matteo de Notaris, Giulia Coppola, Elena De Santis, Guido Giordano and Francesco Carbone
Biomedicines 2022, 10(8), 1927; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10081927 - 9 Aug 2022
Cited by 17 | Viewed by 3601
Abstract
Current treatment guidelines for the management of recurrent glioblastoma (rGBM) are far from definitive, and the prognosis remains dismal. Despite recent advancements in the pharmacological and surgical fields, numerous doubts persist concerning the optimal strategy that clinicians should adopt for patients who fail [...] Read more.
Current treatment guidelines for the management of recurrent glioblastoma (rGBM) are far from definitive, and the prognosis remains dismal. Despite recent advancements in the pharmacological and surgical fields, numerous doubts persist concerning the optimal strategy that clinicians should adopt for patients who fail the first lines of treatment and present signs of progressive disease. With most recurrences being located within the margins of the previously resected lesion, a comprehensive molecular and genetic profiling of rGBM revealed substantial differences compared with newly diagnosed disease. In the present comprehensive review, we sought to examine the current treatment guidelines and the new perspectives that polarize the field of neuro-oncology, strictly focusing on progressive disease. For this purpose, updated PRISMA guidelines were followed to search for pivotal studies and clinical trials published in the last five years. A total of 125 articles discussing locoregional management, radiotherapy, chemotherapy, and immunotherapy strategies were included in our analysis, and salient findings were critically summarized. In addition, an in-depth description of the molecular profile of rGBM and its distinctive characteristics is provided. Finally, we integrate the above-mentioned evidence with the current guidelines published by international societies, including AANS/CNS, EANO, AIOM, and NCCN. Full article
(This article belongs to the Special Issue Molecular Research of Glioblastoma)
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20 pages, 1943 KiB  
Review
The Vascular Microenvironment in Glioblastoma: A Comprehensive Review
by Alejandra Mosteiro, Leire Pedrosa, Abel Ferrés, Diouldé Diao, Àngels Sierra and José Juan González
Biomedicines 2022, 10(6), 1285; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061285 - 31 May 2022
Cited by 15 | Viewed by 4686
Abstract
Glioblastoma multiforme, the deadliest primary brain tumor, is characterized by an excessive and aberrant neovascularization. The initial expectations raised by anti-angiogenic drugs were soon tempered due to their limited efficacy in improving the overall survival. Intrinsic resistance and escape mechanisms against anti-VEGF therapies [...] Read more.
Glioblastoma multiforme, the deadliest primary brain tumor, is characterized by an excessive and aberrant neovascularization. The initial expectations raised by anti-angiogenic drugs were soon tempered due to their limited efficacy in improving the overall survival. Intrinsic resistance and escape mechanisms against anti-VEGF therapies evidenced that tumor angiogenesis is an intricate multifaceted phenomenon and that vessels not only support the tumor but exert indispensable interactions for resistance and spreading. This holistic review covers the essentials of the vascular microenvironment of glioblastoma, including the perivascular niche components, the vascular generation patterns and the implicated signaling pathways, the endothelial–tumor interrelation, and the interconnection between vessel aberrancies and immune disarrangement. The revised concepts provide novel insights into the preclinical models and the potential explanations for the failure of conventional anti-angiogenic therapies, leading to an era of new and combined anti-angiogenic-based approaches. Full article
(This article belongs to the Special Issue Molecular Research of Glioblastoma)
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13 pages, 878 KiB  
Review
Signaling Pathways Regulating the Expression of the Glioblastoma Invasion Factor TENM1
by María Carcelen, Carlos Velasquez, Verónica Vidal, Olga Gutiérrez and José L. Fernández-Luna
Biomedicines 2022, 10(5), 1104; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10051104 - 10 May 2022
Cited by 1 | Viewed by 2149
Abstract
Glioblastoma (GBM) is one of the most aggressive cancers, with dismal prognosis despite continuous efforts to improve treatment. Poor prognosis is mostly due to the invasive nature of GBM. Thus, most research has focused on studying the molecular players involved in GBM cell [...] Read more.
Glioblastoma (GBM) is one of the most aggressive cancers, with dismal prognosis despite continuous efforts to improve treatment. Poor prognosis is mostly due to the invasive nature of GBM. Thus, most research has focused on studying the molecular players involved in GBM cell migration and invasion of the surrounding parenchyma, trying to identify effective therapeutic targets against this lethal cancer. Our laboratory discovered the implication of TENM1, also known as ODZ1, in GBM cell migration in vitro and in tumor invasion using different in vivo models. Moreover, we investigated the microenvironmental stimuli that promote the expression of TENM1 in GBM cells and found that macrophage-secreted IL-6 and the extracellular matrix component fibronectin upregulated TENM1 through activation of Stat3. We also described that hypoxia, a common feature of GBM tumors, was able to induce TENM1 by both an epigenetic mechanism and a HIF2α-mediated transcriptional pathway. The fact that TENM1 is a convergence point for various cancer-related signaling pathways might give us a new therapeutic opportunity for GBM treatment. Here, we briefly review the findings described so far about the mechanisms that control the expression of the GBM invasion factor TENM1. Full article
(This article belongs to the Special Issue Molecular Research of Glioblastoma)
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