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Gliomas: From Molecular Mechanisms to Therapeutic Approaches

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

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 23204

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Prof. Dr. Renzo Boldorini

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1. Department of Health Sciences, Universitá degli Studi del Piemonte Orientale "A. Avogadro", Via Solaroli 17, Novara, Italy
2. Pathology Unit, Maggiore della Carità Hospital, 28100 Novara, Italy
Interests: pathology; molecular pathology; cytopathology; biomarkers of clinical interest in malignant pleural mesothelioma; colorectal carcinoma; lung cancer; malignant melanoma; thyroid tumors; viral carcinogenesis (polyomavirus and papillomavirus)
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Dr. Marta Mellai

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1. Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, Italy
2. Center for Translational Research on Autoimmune and Allergic Disease (CADD), Corso Trieste 15A, 28100 Novara, Italy
Interests: brain tumors; cancer research; molecular genetics; genomics; metagenomics; transcriptomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Gliomas are the most frequent primary brain tumours; despite a multimodal therapeutic approach, based on surgery, radiotherapy and chemotherapy, their prognosis still remains poor. Thus, uncovering the underlying molecular mechanisms of glioma cancerogenesis could provide optional therapeutic strategies, leading to improvements in prognosis.

This Special Issue focuses on the pathogenetic mechanisms involved in the onset and progression of gliomas, in order to refine the existing algorithms in neuropathologic diagnosis and to establish appropriate management in neuro-oncological practice.

Potential topics include, but are not limited to, the following:

Technical advancement in gold standard procedures (including magnetic resonance and positron emission tomography);
Advances in the molecular genetics of gliomas by next-generation techniques with implications for classification and therapy;
The tumour immune microenvironment and tumour heterogeneity in the discovery of new therapeutic biomarkers (i.e., tumour-associated antigens for CART-therapy);
Introductions, in clinics, of novel therapeutic options (proton-therapy or immunotherapy).

This Special Issue is open to original contributions from experimental to clinical studies, including reports on improved experimental models and innovative therapies, describing the current advancement in the diagnosis and treatment of human gliomas.

Prof. Dr. Renzo Boldorini
Dr. Marta Mellai
Guest Editors

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Published Papers (7 papers)

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Research

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22 pages, 8563 KiB

Open AccessArticle

Isolation of Cells from Glioblastoma Multiforme Grade 4 Tumors for Infection with Zika Virus prME and ME Pseudotyped HIV-1

by Celine Pöhlking, Sebastian Beier, Jan Patrick Formanski, Michael Friese, Michael Schreiber and Birco Schwalbe

Int. J. Mol. Sci. 2023, 24(5), 4467; https://doi.org/10.3390/ijms24054467 - 24 Feb 2023

Cited by 4 | Viewed by 3108

Abstract

This study aimed to isolate cells from grade 4 glioblastoma multiforme tumors for infection experiments with Zika virus (ZIKV) prME or ME enveloped HIV-1 pseudotypes. The cells obtained from tumor tissue were successfully cultured in human cerebrospinal fluid (hCSF) or a mixture of hCSF/DMEM in cell culture flasks with polar and hydrophilic surfaces. The isolated tumor cells as well as the U87, U138, and U343 cells tested positive for ZIKV receptors Axl and Integrin αvβ5. Pseudotype entry was detected by the expression of firefly luciferase or green fluorescent protein (gfp). In prME and ME pseudotype infections, luciferase expression in U-cell lines was 2.5 to 3.5 logarithms above the background, but still two logarithms lower than in the VSV-G pseudotype control. Infection of single cells was successfully detected in U-cell lines and isolated tumor cells by gfp detection. Even though prME and ME pseudotypes had low infection rates, pseudotypes with ZIKV envelopes are promising candidates for the treatment of glioblastoma. Full article

(This article belongs to the Special Issue Gliomas: From Molecular Mechanisms to Therapeutic Approaches)

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12 pages, 2472 KiB

Open AccessArticle

Inhibition of MZF1/c-MYC Axis by Cantharidin Impairs Cell Proliferation in Glioblastoma

by Chie-Hong Wang, Hsuan-Cheng Wu, Chen-Wei Hsu, Yun-Wei Chang, Chiung-Yuan Ko, Tsung-I Hsu, Jian-Ying Chuang, Tsui-Hwa Tseng and Shao-Ming Wang

Int. J. Mol. Sci. 2022, 23(23), 14727; https://doi.org/10.3390/ijms232314727 - 25 Nov 2022

Cited by 4 | Viewed by 1935

Abstract

Myeloid zinc finger 1 (MZF1), also known as zinc finger protein 42, is a zinc finger transcription factor, belonging to the Krüppel-like family that has been implicated in several types of malignancies, including glioblastoma multiforme (GBM). MZF1 is reportedly an oncogenic gene that promotes tumor progression. Moreover, higher expression of MZF1 has been associated with a worse overall survival rate among patients with GBM. Thus, MZF1 may be a promising target for therapeutic interventions. Cantharidin (CTD) has been traditionally used in Chinese medicine to induce apoptosis and inhibit cancer cell proliferation; however, the mechanism by which CTD inhibits cell proliferation remains unclear. In this study, we found that the expression of MZF1 was higher in GBM tissues than in adjacent normal tissues and low-grade gliomas. Additionally, the patient-derived GBM cells and GBM cell lines presented higher levels of MZF1 than normal human astrocytes. We demonstrated that CTD had greater anti-proliferative effects on GBM than a derivative of CTD, norcantharidin (NCTD). MZF1 expression was strongly suppressed by CTD treatment. Furthermore, MZF1 enhanced the proliferation of GBM cells and upregulated the expression of c-MYC, whereas these effects were reversed by CTD treatment. The results of our study suggest that CTD may be a promising therapeutic agent for patients with GBM and suggest a promising direction for further investigation. Full article

(This article belongs to the Special Issue Gliomas: From Molecular Mechanisms to Therapeutic Approaches)

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18 pages, 2107 KiB

Open AccessArticle

Antitumor Effects of Ral-GTPases Downregulation in Glioblastoma

by Tània Cemeli, Marta Guasch-Vallés, Marina Ribes-Santolaria, Eva Ibars, Raúl Navaridas, Xavier Dolcet, Neus Pedraza, Neus Colomina, Jordi Torres-Rosell, Francisco Ferrezuelo, Judit Herreros and Eloi Garí

Int. J. Mol. Sci. 2022, 23(15), 8199; https://doi.org/10.3390/ijms23158199 - 25 Jul 2022

Cited by 3 | Viewed by 2024

Abstract

Glioblastoma (GBM) is the most common tumor in the central nervous system in adults. This neoplasia shows a high capacity of growth and spreading to the surrounding brain tissue, hindering its complete surgical resection. Therefore, the finding of new antitumor therapies for GBM treatment is a priority. We have previously described that cyclin D1-CDK4 promotes GBM dissemination through the activation of the small GTPases RalA and RalB. In this paper, we show that RalB GTPase is upregulated in primary GBM cells. We found that the downregulation of Ral GTPases, mainly RalB, prevents the proliferation of primary GBM cells and triggers a senescence-like response. Moreover, downregulation of RalA and RalB reduces the viability of GBM cells growing as tumorspheres, suggesting a possible role of these GTPases in the survival of GBM stem cells. By using mouse subcutaneous xenografts, we have corroborated the role of RalB in GBM growth in vivo. Finally, we have observed that the knockdown of RalB also inhibits cell growth in temozolomide-resistant GBM cells. Overall, our work shows that GBM cells are especially sensitive to Ral-GTPase availability. Therefore, we propose that the inactivation of Ral-GTPases may be a reliable therapeutic approach to prevent GBM progression and recurrence. Full article

(This article belongs to the Special Issue Gliomas: From Molecular Mechanisms to Therapeutic Approaches)

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15 pages, 2214 KiB

Open AccessArticle

Investigating the Potential Use of Chemical Biopsy Devices to Characterize Brain Tumor Lipidomes

by Joanna Bogusiewicz, Bogumiła Kupcewicz, Paulina Zofia Goryńska, Karol Jaroch, Krzysztof Goryński, Marcin Birski, Jacek Furtak, Dariusz Paczkowski, Marek Harat and Barbara Bojko

Int. J. Mol. Sci. 2022, 23(7), 3518; https://doi.org/10.3390/ijms23073518 - 24 Mar 2022

Cited by 8 | Viewed by 2331

Abstract

The development of a fast and accurate intraoperative method that enables the differentiation and stratification of cancerous lesions is still a challenging problem in laboratory medicine. Therefore, it is important to find and optimize a simple and effective analytical method of enabling the selection of distinctive metabolites. This study aims to assess the usefulness of solid-phase microextraction (SPME) probes as a sampling method for the lipidomic analysis of brain tumors. To this end, SPME was applied to sample brain tumors immediately after excision, followed by lipidomic analysis via liquid chromatography-high resolution mass spectrometry (LC-HRMS). The results showed that long fibers were a good option for extracting analytes from an entire lesion to obtain an average lipidomic profile. Moreover, significant differences between tumors of different histological origin were observed. In-depth investigation of the glioma samples revealed that malignancy grade and isocitrate dehydrogenase (IDH) mutation status impact the lipidomic composition of the tumor, whereas 1p/19q co-deletion did not appear to alter the lipid profile. This first on-site lipidomic analysis of intact tumors proved that chemical biopsy with SPME is a promising tool for the simple and fast extraction of lipid markers in neurooncology. Full article

(This article belongs to the Special Issue Gliomas: From Molecular Mechanisms to Therapeutic Approaches)

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20 pages, 7139 KiB

Open AccessArticle

Altered Elemental Distribution in Male Rat Brain Tissue as a Predictor of Glioblastoma Multiforme Growth—Studies Using SR-XRF Microscopy

by Karolina Planeta, Zuzanna Setkowicz, Mateusz Czyzycki, Natalia Janik-Olchawa, Damian Ryszawy, Krzysztof Janeczko, Rolf Simon, Tilo Baumbach and Joanna Chwiej

Int. J. Mol. Sci. 2022, 23(2), 703; https://doi.org/10.3390/ijms23020703 - 9 Jan 2022

Cited by 8 | Viewed by 2369

Abstract

Glioblastoma multiforme (GBM) is a particularly malignant primary brain tumor. Despite enormous advances in the surgical treatment of cancer, radio- and chemotherapy, the average survival of patients suffering from this cancer does not usually exceed several months. For obvious ethical reasons, the search and testing of the new drugs and therapies of GBM cannot be carried out on humans, and for this purpose, animal models of the disease are most often used. However, to assess the efficacy and safety of the therapy basing on these models, a deep knowledge of the pathological changes associated with tumor development in the animal brain is necessary. Therefore, as part of our study, the synchrotron radiation-based X-ray fluorescence microscopy was applied for multi-elemental micro-imaging of the rat brain in which glioblastoma develops. Elemental changes occurring in animals after the implantation of two human glioma cell lines as well as the cells taken directly from a patient suffering from GBM were compared. Both the extent and intensity of elemental changes strongly correlated with the regions of glioma growth. The obtained results showed that the observation of elemental anomalies accompanying tumor development within an animal’s brain might facilitate our understanding of the pathogenesis and progress of GBM and also determine potential biomarkers of its extension. The tumors appearing in a rat’s brain were characterized by an increased accumulation of Fe and Se, whilst the tissue directly surrounding the tumor presented a higher accumulation of Cu. Furthermore, the results of the study allow us to consider Se as a potential elemental marker of GBM progression. Full article

(This article belongs to the Special Issue Gliomas: From Molecular Mechanisms to Therapeutic Approaches)

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18 pages, 5016 KiB

Open AccessArticle

Multiple Irradiation Affects Cellular and Extracellular Components of the Mouse Brain Tissue and Adhesion and Proliferation of Glioblastoma Cells in Experimental System In Vivo

by Maxim O. Politko, Alexandra Y. Tsidulko, Oxana A. Pashkovskaya, Konstantin E. Kuper, Anastasia V. Suhovskih, Galina M. Kazanskaya, Lyubov S. Klyushova, Dmitry K. Sokolov, Alexander M. Volkov, Evgenii E. Kliver, Alexander A. Zheravin, Svetlana V. Aidagulova and Elvira V. Grigorieva

Int. J. Mol. Sci. 2021, 22(24), 13350; https://doi.org/10.3390/ijms222413350 - 12 Dec 2021

Cited by 5 | Viewed by 3497

Abstract

Intensive adjuvant radiotherapy (RT) is a standard treatment for glioblastoma multiforme (GBM) patients; however, its effect on the normal brain tissue remains unclear. Here, we investigated the short-term effects of multiple irradiation on the cellular and extracellular glycosylated components of normal brain tissue and their functional significance. Triple irradiation (7 Gy*3 days) of C57Bl/6 mouse brain inhibited the viability, proliferation and biosynthetic activity of normal glial cells, resulting in a fast brain-zone-dependent deregulation of the expression of proteoglycans (PGs) (decorin, biglycan, versican, brevican and CD44). Complex time-point-specific (24–72 h) changes in decorin and brevican protein and chondroitin sulfate (CS) and heparan sulfate (HS) content suggested deterioration of the PGs glycosylation in irradiated brain tissue, while the transcriptional activity of HS-biosynthetic system remained unchanged. The primary glial cultures and organotypic slices from triple-irradiated brain tissue were more susceptible to GBM U87 cells’ adhesion and proliferation in co-culture systems in vitro and ex vivo. In summary, multiple irradiation affects glycosylated components of normal brain extracellular matrix (ECM) through inhibition of the functional activity of normal glial cells. The changed content and pattern of PGs and GAGs in irradiated brain tissues are accompanied by the increased adhesion and proliferation of GBM cells, suggesting a novel molecular mechanism of negative side-effects of anti-GBM radiotherapy. Full article

(This article belongs to the Special Issue Gliomas: From Molecular Mechanisms to Therapeutic Approaches)

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Review

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20 pages, 1106 KiB

Open AccessReview

Glioma Stem Cells: Novel Data Obtained by Single-Cell Sequencing

by Alisa Gisina, Irina Kholodenko, Yan Kim, Maxim Abakumov, Alexey Lupatov and Konstantin Yarygin

Int. J. Mol. Sci. 2022, 23(22), 14224; https://doi.org/10.3390/ijms232214224 - 17 Nov 2022

Cited by 26 | Viewed by 6723

Abstract

Glioma is the most common type of primary CNS tumor, composed of cells that resemble normal glial cells. Recent genetic studies have provided insight into the inter-tumoral heterogeneity of gliomas, resulting in the updated 2021 WHO classification of gliomas. Thorough understanding of inter-tumoral heterogeneity has already improved the prognosis and treatment outcomes of some types of gliomas. Currently, the challenge for researchers is to study the intratumoral cell heterogeneity of newly defined glioma subtypes. Cancer stem cells (CSCs) present in gliomas and many other tumors are an example of intratumoral heterogeneity of great importance. In this review, we discuss the modern concept of glioma stem cells and recent single-cell sequencing-driven progress in the research of intratumoral glioma cell heterogeneity. The particular emphasis was placed on the recently revealed variations of the cell composition of the subtypes of the adult-type diffuse gliomas, including astrocytoma, oligodendroglioma and glioblastoma. The novel data explain the inconsistencies in earlier glioma stem cell research and also provide insight into the development of more effective targeted therapy and the cell-based immunotherapy of gliomas. Separate sections are devoted to the description of single-cell sequencing approach and its role in the development of cell-based immunotherapies for glioma. Full article

(This article belongs to the Special Issue Gliomas: From Molecular Mechanisms to Therapeutic Approaches)

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