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Exploring the Glioblastoma Complexity: New Perspectives in the Molecular and Imaging Fields

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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: 31 August 2024 | Viewed by 5212

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Special Issue Editors

Prof. Dr. Angela Bentivegna

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Guest Editor

School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
Interests: glioblastoma; cancer stem cells; urothelial carcinoma; developmental disability; human cytogenetics
Special Issues, Collections and Topics in MDPI journals

Dr. Gabriella Nicolini

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Guest Editor

1. Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900 Monza, MB, Italy
2. Milan Center for Neuroscience, University of Milano-Bicocca, 20126 Milan, Italy
Interests: biopsy

Special Issue Information

Dear Colleagues,

Glioblastoma (GBM), despite the advances in surgical resection, chemotherapy (temozolomide) and radiotherapy treatment, remains one of the most fatal tumors. The fight against GBM is made even more difficult by the GBM inter and intra heterogeneity, the presence of the blood–brain barrier and the molecular characteristics of the peritumoral region. Achieving effective outcomes against GBM increasingly requires the integration of imaging and molecular techniques that enable the early diagnosis of GBM and monitoring of GBM response to treatments. In particular, recent advances have been achieved in circRNA, lncRNA, ctDNA and extracellular vesicles characterized by liquid biopsy.

This Special Issue, “Exploring the Glioblastoma Complexity: New Perspectives in the Molecular and Imaging Fields”, will cover a selection of recent research topics and current review articles in the field of imaging and molecular characterization, taking into consideration data obtained both in animal models and in vitro (neurospheres, organoids) and also data on the possible diagnostic biomarkers obtained by liquid biopsy or using innovative imaging techniques.

Prof. Dr. Angela Bentivegna
Dr. Gabriella Nicolini
Guest Editors

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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.

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Keywords

glioblastoma
imaging techniques
molecular techniques
liquid biopsy
in vitro model
in vivo model

Published Papers (5 papers)

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Research

13 pages, 2279 KiB

Open AccessArticle

Diagnostic and Prognostic Value of Circulating DNA Fragments in Glioblastoma Multiforme Patients

by Pawel Jarmuzek, Edyta Wawrzyniak-Gramacka, Barbara Morawin, Anna Tylutka and Agnieszka Zembron-Lacny

Int. J. Mol. Sci. 2024, 25(8), 4221; https://doi.org/10.3390/ijms25084221 - 11 Apr 2024

Viewed by 402

Abstract

Novel blood-circulating molecules, as potential biomarkers for glioblastoma multiforme (GBM) diagnosis and monitoring, are attracting particular attention due to limitations of imaging modalities and invasive tissue biopsy procedures. This study aims to assess the diagnostic and prognostic values of circulating cell-free DNA (cfDNA) in relation to inflammatory status in GBM patients and to determine the concentration and average size of DNA fragments typical of tumour-derived DNA fractions. Preoperative plasma samples from 40 patients (GBM 65.0 ± 11.3 years) and 40 healthy controls (HC 70.4 ± 5.4 years) were compared. The cfDNA concentrations and lengths were measured using the electrophoresis platform, and inflammatory indices (NLR, PLR, LMR, and SII) were calculated from complete blood cell analysis. More fragmented cfDNA and 4-fold higher 50–700 bp cfDNA concentrations were detected in GBM patients than in healthy controls. The average cfDNA size in the GBM group was significantly longer (median 336 bp) than in the HC group (median 271 bp). Optimal threshold values were 1265 pg/μL for 50–700 bp cfDNA (AUC = 0.857) and 290 bp for average cfDNA size (AUC = 0.814). A Kaplan–Meier survival curves analysis also demonstrated a higher mortality risk in the GBM group with a cut-off >303 bp cfDNA. This study is the first to have revealed glioblastoma association with high levels of cfDNA > 1000 pg/μL of 50–700 bp in length, which can be aggravated by immunoinflammatory reactivity. Full article

(This article belongs to the Special Issue Exploring the Glioblastoma Complexity: New Perspectives in the Molecular and Imaging Fields)

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18 pages, 2856 KiB

Open AccessArticle

Gene Expression Patterns Associated with Survival in Glioblastoma

by Christopher Morrison, Eric Weterings, Nicholas Gravbrot, Michael Hammer, Martin Weinand, Abhay Sanan, Ritu Pandey, Daruka Mahadevan and Baldassarre Stea

Int. J. Mol. Sci. 2024, 25(7), 3668; https://doi.org/10.3390/ijms25073668 - 25 Mar 2024

Viewed by 560

Abstract

The aim of this study was to investigate gene expression alterations associated with overall survival (OS) in glioblastoma (GBM). Using the Nanostring nCounter platform, we identified four genes (COL1A2, IGFBP3, NGFR, and WIF1) that achieved statistical significance when comparing GBM with non-neoplastic brain tissue. The four genes were included in a multivariate Cox Proportional Hazard model, along with age, extent of resection, and O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation, to create a unique glioblastoma prognostic index (GPI). The GPI score inversely correlated with survival: patient with a high GPI had a median OS of 7.5 months (18-month OS = 9.7%) whereas patients with a low GPI had a median OS of 20.1 months (18-month OS = 54.5%; log rank p-value = 0.004). The GPI score was then validated in 188 GBM patients from The Cancer Genome Atlas (TCGA) from a national data base; similarly, patients with a high GPI had a median OS of 10.5 months (18-month OS = 12.4%) versus 16.9 months (18-month OS = 41.5%) for low GPI (log rank p-value = 0.0003). We conclude that this novel mRNA-based prognostic index could be useful in classifying GBM patients into risk groups and refine prognosis estimates to better inform treatment decisions or stratification into clinical trials. Full article

(This article belongs to the Special Issue Exploring the Glioblastoma Complexity: New Perspectives in the Molecular and Imaging Fields)

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17 pages, 4824 KiB

Open AccessArticle

Vacuolar Proton-Translocating ATPase May Take Part in the Drug Resistance Phenotype of Glioma Stem Cells

by Martina Giambra, Andrea Di Cristofori, Francesca Raimondo, Roberta Rigolio, Donatella Conconi, Gaia Chiarello, Silvia Maria Tabano, Laura Antolini, Gabriella Nicolini, Miriam Bua, Davide Ferlito, Giorgio Carrabba, Carlo Giorgio Giussani, Marialuisa Lavitrano and Angela Bentivegna

Int. J. Mol. Sci. 2024, 25(5), 2743; https://doi.org/10.3390/ijms25052743 - 27 Feb 2024

Viewed by 674

Abstract

The vacuolar proton-translocating ATPase (V-ATPase) is a transmembrane multi-protein complex fundamental in maintaining a normal intracellular pH. In the tumoral contest, its role is crucial since the metabolism underlying carcinogenesis is mainly based on anaerobic glycolytic reactions. Moreover, neoplastic cells use the V-ATPase to extrude chemotherapy drugs into the extra-cellular compartment as a drug resistance mechanism. In glioblastoma (GBM), the most malignant and incurable primary brain tumor, the expression of this pump is upregulated, making it a new possible therapeutic target. In this work, the bafilomycin A1-induced inhibition of V-ATPase in patient-derived glioma stem cell (GSC) lines was evaluated together with temozolomide, the first-line therapy against GBM. In contrast with previous published data, the proposed treatment did not overcome resistance to the standard therapy. In addition, our data showed that nanomolar dosages of bafilomycin A1 led to the blockage of the autophagy process and cellular necrosis, making the drug unusable in models which are more complex. Nevertheless, the increased expression of V-ATPase following bafilomycin A1 suggests a critical role of the proton pump in GBM stem components, encouraging the search for novel strategies to limit its activity in order to circumvent resistance to conventional therapy. Full article

(This article belongs to the Special Issue Exploring the Glioblastoma Complexity: New Perspectives in the Molecular and Imaging Fields)

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26 pages, 4786 KiB

Open AccessArticle

Correlation of MR-Based Metabolomics and Molecular Profiling in the Tumor Microenvironment of Temozolomide-Treated Orthotopic GL261 Glioblastoma in Mice

by Kai Zhao, Pilar Calero-Pérez, Miriam H. A. Bopp, Vincent Möschl, Axel Pagenstecher, Marta Mulero-Acevedo, Mario Vázquez, Carlos Barcia, Carles Arús, Christopher Nimsky, Tillmann Rusch, Jörg W. Bartsch and Ana Paula Candiota

Int. J. Mol. Sci. 2023, 24(24), 17628; https://doi.org/10.3390/ijms242417628 - 18 Dec 2023

Viewed by 1256

Abstract

The tumor microenvironment in glioblastoma (GB) is considered to be “cold”, i.e., the fraction of cytotoxic T cells, for instance, is low. Instead, macrophages are the major immune cell population in GB, which stem either from tissue response (resident microglia) or recruitment of macrophages from the periphery, thereby undergoing tumor-dependent “imprinting” mechanisms by which macrophages can adapt a tumor-supportive phenotype. In this regard, it is important to describe the nature of macrophages associated with GB, in particular under therapy conditions using the gold standard chemotherapy drug temozolomide (TMZ). Here, we explored the suitability of combining information from in vivo magnetic resonance spectroscopic (MRS) approaches (metabolomics) with in vitro molecular analyses to assess therapy response and characterize macrophage populations in mouse GB using an isogenic GL261 model. For macrophage profiling, expression levels of matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs) were determined, since their gene products affect macrophage–tumor cell communication by extensive cleavage of immunomodulatory membrane proteins, such as PD-L1. In tumor mice with an overall therapy response, expression of genes encoding the proteases ADAM8, ADAM10, and ADAM17 was increased and might contribute to the immunosuppressive phenotype of GB and immune cells. In tumors responding to therapy, expression levels of ADAM8 were upregulated by TMZ, and higher levels of PD-L1 were correlated significantly. Using a CRISPR/Cas9 knockout of ADAM8 in GL261 cells, we demonstrated that soluble PD-L1 (sPD-L1) is only generated in the presence of ADAM8. Moreover, primary macrophages from WT and ADAM8-deficient mice showed ADAM8-dependent release of sPD-L1, independent of the macrophage polarization state. Since ADAM8 expression is induced in responding tumors and PD-L1 shedding is likely to decrease the anti-tumor activities of T-cells, we conclude that immunotherapy resistance is caused, at least in part, by the increased presence of proteases, such as ADAM8. Full article

(This article belongs to the Special Issue Exploring the Glioblastoma Complexity: New Perspectives in the Molecular and Imaging Fields)

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11 pages, 1904 KiB

Open AccessArticle

Innovative Approach to Isolate and Characterize Glioblastoma Circulating Tumor Cells and Correlation with Tumor Mutational Status

by Francesca Lessi, Mariangela Morelli, Sara Franceschi, Paolo Aretini, Michele Menicagli, Andrea Marranci, Francesco Pasqualetti, Carlo Gambacciani, Francesco Pieri, Gianluca Grimod, Vanna Zucchi, Samanta Cupini, Anna Luisa Di Stefano, Orazio Santo Santonocito and Chiara Maria Mazzanti

Int. J. Mol. Sci. 2023, 24(12), 10147; https://doi.org/10.3390/ijms241210147 - 14 Jun 2023

Cited by 1 | Viewed by 1310

Abstract

Circulating tumor cells (CTCs) are one of the most important causes of tumor recurrence and distant metastases. Glioblastoma (GBM) has been considered restricted to the brain for many years. Nevertheless, in the past years, several pieces of evidence indicate that hematogenous dissemination is a reality, and this is also in the caseof GBM. Our aim was to optimize CTCs’ detection in GBM and define the genetic background of single CTCs compared to the primary GBM tumor and its recurrence to demonstrate that CTCs are indeed derived from the parental tumor. We collected blood samples from a recurrent IDH wt GBM patient. We genotyped the parental recurrent tumor tissue and the respective primary GBM tissue. CTCs were analyzed using the DEPArray system. CTCs Copy Number Alterations (CNAs) and sequencing analyses were performed to compare CTCs’ genetic background with the same patient’s primary and recurrent GBM tissues. We identified 210 common mutations in the primary and recurrent tumors. Among these, three somatic high-frequency mutations (in PRKCB, TBX1, and COG5 genes) were selected to investigate their presence in CTCs. Almost all sorted CTCs (9/13) had at least one of the mutations tested. The presence of TERT promoter mutations was also investigated and C228T variation was found in parental tumors and CTCs (C228T heterozygous and homozygous, respectively). We were able to isolate and genotype CTCs from a patient with GBM. We found common mutations but also exclusive molecular characteristics. Full article

(This article belongs to the Special Issue Exploring the Glioblastoma Complexity: New Perspectives in the Molecular and Imaging Fields)

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