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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: closed (20 October 2023) | Viewed by 30139

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Prof. Dr. Giuseppe Lombardi

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Department of Oncology, Oncology 1, Veneto Institute of Oncology-IRCCS, 35128 Padua, Italy
Interests: neuro-oncology; glioblastoma; gliomas; targeted therapy; brain tumors; immunotherapy; quality of life
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Dear Colleagues,

Glioblastoma is the most common and aggressive primary malignant brain tumor in adult patients. Despite multimodal treatment with maximal safe surgical resection followed by concurrent radio–chemotherapy and adjuvant chemotherapy with temozolomide, prognosis remains poor with a median survival of 1 year. Because glioblastoma treatment remains a highly unmet clinical need, deeper mechanistic insight into the molecular changes present in these tumors is required.

In recent years, a multitude of novel therapies have shown promising signs of efficacy in glioblastoma patients. Precision medicine such as the combination of dabrafenib and trametinib in BRAF-V600E-mutated gliomas, or other tyrosine kinase inhibitors such as regorafenib or NTRK inhibitors, may be used in certain patients. However, in the longer term an enhanced understanding of the underlying molecular characteristics and genetic landscape of glioblastoma is required to identify novel therapies such as targeted therapies and combination regimens.

This Special Issue will cover all molecular aspects of glioblastoma, including original research on current and experimental treatment options with molecular research and translational work on the molecular characteristics of glioblastoma. Full reviews and novel communications on these topics are also welcome.

Prof. Dr. Giuseppe Lombardi
Guest Editor

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Keywords

glioblastoma
glioma
brain tumors
targeted therapy

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New Insights into Glioblastoma: Cellular and Molecular (2nd Edition) in International Journal of Molecular Sciences (3 articles)

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Editorial

Jump to: Research, Review

3 pages, 170 KiB

Open AccessEditorial

New Insights into Glioblastoma

by Eugenia Cella, Alberto Bosio and Giuseppe Lombardi

Int. J. Mol. Sci. 2024, 25(7), 4090; https://doi.org/10.3390/ijms25074090 - 7 Apr 2024

Viewed by 963

Abstract

Glioblastoma (GBM) is the most aggressive malignant primary central nervous system (CNS) tumor and, despite decades of research, it remains a lethal disease with a median overall survival of less than two years [...] Full article

(This article belongs to the Special Issue New Insights into Glioblastoma: Cellular and Molecular)

Research

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20 pages, 3007 KiB

Open AccessArticle

Repurposed Drugs Celecoxib and Fmoc-L-Leucine Alone and in Combination as Temozolomide-Resistant Antiglioma Agents—Comparative Studies on Normal and Immortalized Cell Lines, and on C. elegans

by Łukasz Uram, Natalia Pieńkowska, Maria Misiorek, Żaneta Szymaszek, Magdalena Twardowska, Michał Siorek and Stanisław Wołowiec

Int. J. Mol. Sci. 2024, 25(6), 3226; https://doi.org/10.3390/ijms25063226 - 12 Mar 2024

Viewed by 1259

Abstract

Glioblastoma multiforme therapy remains a significant challenge since there is a lack of effective treatment for this cancer. As most of the examined gliomas express or overexpress cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptors γ (PPARγ), we decided to use these proteins as therapeutic targets. Toxicity, antiproliferative, proapoptotic, and antimigratory activity of COX-2 inhibitor (celecoxib—CXB) and/or PPARγ agonist (Fmoc-L-Leucine—FL) was examined in vitro on temozolomide resistant U-118 MG glioma cell line and comparatively on BJ normal fibroblasts and immortalized HaCaT keratinocytes. The in vivo activity of both agents was studied on C. elegans nematode. Both drugs effectively destroyed U-118 MG glioma cells via antiproliferative, pro-apoptotic, and anti-migratory effects in a concentration range 50–100 µM. The mechanism of action of CXB and FL against glioma was COX-2 and PPARγ dependent and resulted in up-regulation of these factors. Unlike reports by other authors, we did not observe the expected synergistic or additive effect of both drugs. Comparative studies on normal BJ fibroblast cells and immortalized HaCaT keratinocytes showed that the tested drugs did not have a selective effect on glioma cells and their mechanism of action differs significantly from that observed in the case of glioma. HaCaTs did not react with concomitant changes in the expression of COX-2 and PPARγ and were resistant to FL. Safety tests of repurposing drugs used in cancer therapy tested on C. elegans nematode indicated that CXB, FL, or their mixture at a concentration of up to 100 µM had no significant effect on the entire nematode organism up to 4th day of incubation. After a 7-day treatment, CXB significantly shortened the lifespan of C. elegans at 25–400 µM concentration and body length at 50–400 µM concentration. Full article

(This article belongs to the Special Issue New Insights into Glioblastoma: Cellular and Molecular)

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19 pages, 9108 KiB

Open AccessArticle

Role of Luteolin as Potential New Therapeutic Option for Patients with Glioblastoma through Regulation of Sphingolipid Rheostat

by Stefania Elena Navone, Laura Guarnaccia, Massimiliano D. Rizzaro, Laura Begani, Emanuela Barilla, Giovanni Alotta, Emanuele Garzia, Manuela Caroli, Antonella Ampollini, Aniello Violetti, Noreen Gervasi, Rolando Campanella, Laura Riboni, Marco Locatelli and Giovanni Marfia

Int. J. Mol. Sci. 2024, 25(1), 130; https://doi.org/10.3390/ijms25010130 - 21 Dec 2023

Cited by 2 | Viewed by 1654

Abstract

Glioblastoma (GBM) is the most aggressive brain tumor, still considered incurable. In this study, conducted on primary GBM stem cells (GSCs), specifically selected as the most therapy-resistant, we examined the efficacy of luteolin, a natural flavonoid, as an anti-tumoral compound. Luteolin is known to impact the sphingolipid rheostat, a pathway regulated by the proliferative sphingosine-1-phosphate (S1P) and the proapoptotic ceramide (Cer), and implicated in numerous oncopromoter biological processes. Here, we report that luteolin is able to inhibit the expression of SphK1/2, the two kinases implicated in S1P formation, and to increase the expression of both SGPL1, the lyase responsible for S1P degradation, and CERS1, the ceramide synthase 1, thus shifting the balance toward the production of ceramide. In addition, luteolin proved to decrease the expression of protumoral signaling as MAPK, RAS/MEK/ERK and PI3K/AKT/mTOR and cyclins involved in cell cycle progression. In parallel, luteolin succeeded in upregulation of proapoptotic mediators as caspases and Bcl-2 family and cell cycle controllers as p53 and p27. Furthermore, luteolin determined the shutdown of autophagy contributing to cell survival. Overall, our data support the use of luteolin as add-on therapy, having demonstrated a good ability in impairing GSC viability and survival and increasing cell sensitivity to TMZ. Full article

(This article belongs to the Special Issue New Insights into Glioblastoma: Cellular and Molecular)

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17 pages, 1366 KiB

Open AccessArticle

Cytokine Profile in Development of Glioblastoma in Relation to Healthy Individuals

by Pawel Jarmuzek, Piotr Defort, Marcin Kot, Edyta Wawrzyniak-Gramacka, Barbara Morawin and Agnieszka Zembron-Lacny

Int. J. Mol. Sci. 2023, 24(22), 16206; https://doi.org/10.3390/ijms242216206 - 11 Nov 2023

Cited by 3 | Viewed by 1521

Abstract

Cytokines play an essential role in the control of tumor cell development and multiplication. However, the available literature provides ambiguous data on the involvement of these proteins in the formation and progression of glioblastoma (GBM). This study was designed to evaluate the inflammatory profile and to investigate its potential for the identification of molecular signatures specific to GBM. Fifty patients aged 66.0 ± 10.56 years with newly diagnosed high-grade gliomas and 40 healthy individuals aged 71.7 ± 4.9 years were included in the study. White blood cells were found to fall within the referential ranges and were significantly higher in GBM than in healthy controls. Among immune cells, neutrophils showed the greatest changes, resulting in elevated neutrophil-to-lymphocyte ratio (NLR). The neutrophil count inversely correlated with survival time expressed by Spearman’s coefficient r_s = −0.359 (p = 0.010). The optimal threshold values corresponded to 2.630 × 103/µL for NLR (the area under the ROC curve AUC = 0.831, specificity 90%, sensitivity 76%, the relative risk RR = 7.875, the confidence intervals 95%CI 3.333–20.148). The most considerable changes were recorded in pro-inflammatory cytokines interleukin IL-1β, IL-6, and IL-8, which were approx. 1.5–2-fold higher, whereas tumor necrosis factor α (TNFα) and high mobility group B1 (HMGB1) were lower in GBM than healthy control (p < 0.001). The results of the ROC, AUC, and RR analysis of IL-1β, IL-6, IL-8, and IL-10 indicate their high diagnostics potential for clinical prognosis. The highest average RR was observed for IL-6 (RR = 2.923) and IL-8 (RR = 3.151), which means there is an approx. three-fold higher probability of GBM development after exceeding the cut-off values of 19.83 pg/mL for IL-6 and 10.86 pg/mL for IL-8. The high values of AUC obtained for the models NLR + IL-1β (AUC = 0.907), NLR + IL-6 (AUC = 0.908), NLR + IL-8 (AUC = 0.896), and NLR + IL-10 (AUC = 0.887) prove excellent discrimination of GBM patients from healthy individuals and may represent GBM-specific molecular signatures. Full article

(This article belongs to the Special Issue New Insights into Glioblastoma: Cellular and Molecular)

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23 pages, 6215 KiB

Open AccessArticle

The Antitumor Effect of the DNA Polymerase Alpha Inhibitor ST1926 in Glioblastoma: A Proteomics Approach

by Chirine El-Baba, Zeinab Ayache, Mona Goli, Berthe Hayar, Zeinab Kawtharani, Claudio Pisano, Firas Kobeissy, Yehia Mechref and Nadine Darwiche

Int. J. Mol. Sci. 2023, 24(18), 14069; https://doi.org/10.3390/ijms241814069 - 14 Sep 2023

Cited by 3 | Viewed by 1606

Abstract

Glioblastoma Multiforme (GBM) is the most aggressive form of malignant brain tumor. The median survival rate does not exceed two years, indicating an imminent need to develop novel therapies. The atypical adamantyl retinoid ST1926 induces apoptosis and growth inhibition in different cancer types. We have shown that ST1926 is an inhibitor of the catalytic subunit of DNA polymerase alpha (POLA1), which is involved in initiating DNA synthesis in eukaryotic cells. POLA1 levels are elevated in GBM versus normal brain tissues. Therefore, we studied the antitumor effects of ST1926 in several human GBM cell lines. We further explored the global protein expression profiles in GBM cell lines using liquid chromatography coupled with tandem mass spectrometry to identify new targets of ST1926. Low sub-micromolar concentrations of ST1926 potently decreased cell viability, induced cell damage and apoptosis, and reduced POLA1 protein levels in GBM cells. The proteomics profiles revealed 197 proteins significantly differentially altered upon ST1926 treatment of GBM cells involved in various cellular processes. We explored the differential gene and protein expression of significantly altered proteins in GBM compared to normal brain tissues. Full article

(This article belongs to the Special Issue New Insights into Glioblastoma: Cellular and Molecular)

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25 pages, 11709 KiB

Open AccessArticle

Transcranial Photosensitizer-Free Laser Treatment of Glioblastoma in Rat Brain

by Oxana Semyachkina-Glushkovskaya, Sergey Sokolovski, Ivan Fedosov, Alexander Shirokov, Nikita Navolokin, Alla Bucharskaya, Inna Blokhina, Andrey Terskov, Alexander Dubrovski, Valeria Telnova, Anna Tzven, Maria Tzoy, Arina Evsukova, Daria Zhlatogosrkaya, Viktoria Adushkina, Alexander Dmitrenko, Maria Manzhaeva, Valeria Krupnova, Alessio Noghero, Denis Bragin, Olga Bragina, Ekaterina Borisova, Jürgen Kurths and Edik Rafailov Show full author list Hide full author list

Int. J. Mol. Sci. 2023, 24(18), 13696; https://doi.org/10.3390/ijms241813696 - 5 Sep 2023

Cited by 4 | Viewed by 1651

Abstract

Over sixty years, laser technologies have undergone a technological revolution and become one of the main tools in biomedicine, particularly in neuroscience, neurodegenerative diseases and brain tumors. Glioblastoma is the most lethal form of brain cancer, with very limited treatment options and a poor prognosis. In this study on rats, we demonstrate that glioblastoma (GBM) growth can be suppressed by photosensitizer-free laser treatment (PS-free-LT) using a quantum-dot-based 1267 nm laser diode. This wavelength, highly absorbed by oxygen, is capable of turning triplet oxygen to singlet form. Applying 1267 nm laser irradiation for a 4 week course with a total dose of 12.7 kJ/cm² firmly suppresses GBM growth and increases survival rate from 34% to 64%, presumably via LT-activated apoptosis, inhibition of the proliferation of tumor cells, a reduction in intracranial pressure and stimulation of the lymphatic drainage and clearing functions. PS-free-LT is a promising breakthrough technology in non- or minimally invasive therapy for superficial GBMs in infants as well as in adult patients with high photosensitivity or an allergic reaction to PSs. Full article

(This article belongs to the Special Issue New Insights into Glioblastoma: Cellular and Molecular)

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13 pages, 4703 KiB

Open AccessArticle

Metabolomics Approach Reveals Important Glioblastoma Plasma Biomarkers for Tumor Biology

by Adriana C. Ferrasi, Ricardo Puttini, Aline F. Galvani, Pedro T. Hamamoto Filho, Jeany Delafiori, Victoria D. Argente, Arthur N. de Oliveira, Flávia L. Dias-Audibert, Rodrigo R. Catharino, Octavio C. Silva, Marco A. Zanini, Gabriel A. Kurokawa and Estela O. Lima

Int. J. Mol. Sci. 2023, 24(10), 8813; https://doi.org/10.3390/ijms24108813 - 16 May 2023

Cited by 3 | Viewed by 1940

Abstract

Glioblastoma (GB) is the most aggressive and frequent primary malignant tumor of the central nervous system and is associated with poor overall survival even after treatment. To better understand tumor biochemical alterations and broaden the potential targets of GB, this study aimed to evaluate differential plasma biomarkers between GB patients and healthy individuals using metabolomics analysis. Plasma samples from both groups were analyzed via untargeted metabolomics using direct injection with an electrospray ionization source and an LTQ mass spectrometer. GB biomarkers were selected via Partial Least Squares Discriminant and Fold-Change analyses and were identified using tandem mass spectrometry with in silico fragmentation, consultation of metabolomics databases, and a literature search. Seven GB biomarkers were identified, some of which were unprecedented biomarkers for GB, including arginylproline (m/z 294), 5-hydroxymethyluracil (m/z 143), and N-acylphosphatidylethanolamine (m/z 982). Notably, four other metabolites were identified. The roles of all seven metabolites in epigenetic modulation, energy metabolism, protein catabolism or folding processes, and signaling pathways that activate cell proliferation and invasion were elucidated. Overall, the findings of this study highlight new molecular targets to guide future investigations on GB. These molecular targets can also be further evaluated to derive their potential as biomedical analytical tools for peripheral blood samples. Full article

(This article belongs to the Special Issue New Insights into Glioblastoma: Cellular and Molecular)

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21 pages, 4327 KiB

Open AccessArticle

GSK343, an Inhibitor of Enhancer of Zeste Homolog 2, Reduces Glioblastoma Progression through Inflammatory Process Modulation: Focus on Canonical and Non-Canonical NF-κB/IκBα Pathways

by Sarah Adriana Scuderi, Alessia Filippone, Rossella Basilotta, Deborah Mannino, Giovanna Casili, Anna Paola Capra, Giulia Chisari, Lorenzo Colarossi, Serena Sava, Michela Campolo, Emanuela Esposito and Irene Paterniti

Int. J. Mol. Sci. 2022, 23(22), 13915; https://doi.org/10.3390/ijms232213915 - 11 Nov 2022

Cited by 11 | Viewed by 1937

Abstract

Glioblastoma (GB) is a tumor of the central nervous system characterized by high proliferation and invasiveness. The standard treatment for GB includes radiotherapy and chemotherapy; however, new therapies are needed. Particular attention was given to the role of histone methyltransferase enhancer of zeste-homolog-2 (EZH2) in GB. Recently, several EZH2-inhibitors have been developed, particularly GSK343 is well-known to regulate apoptosis and autophagy processes; however, its abilities to modulate canonical/non-canonical NF-κB/IκBα pathways or an immune response in GB have not yet been investigated. Therefore, this study investigated for the first time the effect of GSK343 on canonical/non-canonical NF-κB/IκBα pathways and the immune response, by an in vitro, in vivo and ex vivo model of GB. In vitro results demonstrated that GSK343 treatments 1, 10 and 25 μM significantly reduced GB cell viability, showing the modulation of canonical/non-canonical NF-κB/IκBα pathway activation. In vivo GSK343 reduced subcutaneous tumor mass, regulating canonical/non-canonical NF-κB/IκBα pathway activation and the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). Ex vivo results confirmed the anti-proliferative effect of GSK343 and also demonstrated its ability to regulate immune response through CXCL9, CXCL10 and CXCL11 expression in GB. Thus, GSK343 could represent a therapeutic strategy to counteract GB progression, thanks to its ability to modulate canonical/non-canonical NF-κB/IκBα pathways and immune response. Full article

(This article belongs to the Special Issue New Insights into Glioblastoma: Cellular and Molecular)

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Review

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24 pages, 2407 KiB

Open AccessReview

Understanding Glioblastoma Signaling, Heterogeneity, Invasiveness, and Drug Delivery Barriers

by Nadin Rabah, Fatima-Ezzahra Ait Mohand and Nataly Kravchenko-Balasha

Int. J. Mol. Sci. 2023, 24(18), 14256; https://doi.org/10.3390/ijms241814256 - 19 Sep 2023

Cited by 6 | Viewed by 2155

Abstract

The most prevalent and aggressive type of brain cancer, namely, glioblastoma (GBM), is characterized by intra- and inter-tumor heterogeneity and strong spreading capacity, which makes treatment ineffective. A true therapeutic answer is still in its infancy despite various studies that have made significant progress toward understanding the mechanisms behind GBM recurrence and its resistance. The primary causes of GBM recurrence are attributed to the heterogeneity and diffusive nature; therefore, monitoring the tumor’s heterogeneity and spreading may offer a set of therapeutic targets that could improve the clinical management of GBM and prevent tumor relapse. Additionally, the blood–brain barrier (BBB)-related poor drug delivery that prevents effective drug concentrations within the tumor is discussed. With a primary emphasis on signaling heterogeneity, tumor infiltration, and computational modeling of GBM, this review covers typical therapeutic difficulties and factors contributing to drug resistance development and discusses potential therapeutic approaches. Full article

(This article belongs to the Special Issue New Insights into Glioblastoma: Cellular and Molecular)

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34 pages, 1255 KiB

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Preclinical and Clinical Applications of Metabolomics and Proteomics in Glioblastoma Research

by Munazza Ahmed, Ahlam M. Semreen, Waseem El-Huneidi, Yasser Bustanji, Eman Abu-Gharbieh, Mohammad A. Y. Alqudah, Ahmed Alhusban, Mohd Shara, Ahmad Y. Abuhelwa, Nelson C. Soares, Mohammad H. Semreen and Karem H. Alzoubi

Int. J. Mol. Sci. 2023, 24(1), 348; https://doi.org/10.3390/ijms24010348 - 25 Dec 2022

Cited by 8 | Viewed by 3408

Abstract

Glioblastoma (GB) is a primary malignancy of the central nervous system that is classified by the WHO as a grade IV astrocytoma. Despite decades of research, several aspects about the biology of GB are still unclear. Its pathogenesis and resistance mechanisms are poorly understood, and methods to optimize patient diagnosis and prognosis remain a bottle neck owing to the heterogeneity of the malignancy. The field of omics has recently gained traction, as it can aid in understanding the dynamic spatiotemporal regulatory network of enzymes and metabolites that allows cancer cells to adjust to their surroundings to promote tumor development. In combination with other omics techniques, proteomic and metabolomic investigations, which are a potent means for examining a variety of metabolic enzymes as well as intermediate metabolites, might offer crucial information in this area. Therefore, this review intends to stress the major contribution these tools have made in GB clinical and preclinical research and highlights the crucial impacts made by the integrative “omics” approach in reducing some of the therapeutic challenges associated with GB research and treatment. Thus, our study can purvey the use of these powerful tools in research by serving as a hub that particularly summarizes studies employing metabolomics and proteomics in the realm of GB diagnosis, treatment, and prognosis. Full article

(This article belongs to the Special Issue New Insights into Glioblastoma: Cellular and Molecular)

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21 pages, 1267 KiB

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Ferroptosis Modulation: Potential Therapeutic Target for Glioblastoma Treatment

by Izadora de Souza, Maria Carolina Clares Ramalho, Camila Banca Guedes, Isabeli Yumi Araújo Osawa, Linda Karolynne Seregni Monteiro, Luciana Rodrigues Gomes and Clarissa Ribeiro Reily Rocha

Int. J. Mol. Sci. 2022, 23(13), 6879; https://doi.org/10.3390/ijms23136879 - 21 Jun 2022

Cited by 15 | Viewed by 4959

Abstract

Glioblastoma multiforme is a lethal disease and represents the most common and severe type of glioma. Drug resistance and the evasion of cell death are the main characteristics of its malignancy, leading to a high percentage of disease recurrence and the patients’ low survival rate. Exploiting the modulation of cell death mechanisms could be an important strategy to prevent tumor development and reverse the high mortality and morbidity rates in glioblastoma patients. Ferroptosis is a recently described type of cell death, which is characterized by iron accumulation, high levels of polyunsaturated fatty acid (PUFA)-containing phospholipids, and deficiency in lipid peroxidation repair. Several studies have demonstrated that ferroptosis has a potential role in cancer treatment and could be a promising approach for glioblastoma patients. Thus, here, we present an overview of the mechanisms of the iron-dependent cell death and summarize the current findings of ferroptosis modulation on glioblastoma including its non-canonical pathway. Moreover, we focused on new ferroptosis-inducing compounds for glioma treatment, and we highlight the key ferroptosis-related genes to glioma prognosis, which could be further explored. Thereby, understanding how to trigger ferroptosis in glioblastoma may provide promising pharmacological targets and indicate new therapeutic approaches to increase the survival of glioblastoma patients. Full article

(This article belongs to the Special Issue New Insights into Glioblastoma: Cellular and Molecular)

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22 pages, 1527 KiB

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The Primary Microglial Leukodystrophies: A Review

by Isidro Ferrer

Int. J. Mol. Sci. 2022, 23(11), 6341; https://doi.org/10.3390/ijms23116341 - 6 Jun 2022

Cited by 13 | Viewed by 5677

Abstract

Primary microglial leukodystrophy or leukoencephalopathy are disorders in which a genetic defect linked to microglia causes cerebral white matter damage. Pigmented orthochromatic leukodystrophy, adult-onset orthochromatic leukodystrophy associated with pigmented macrophages, hereditary diffuse leukoencephalopathy with (axonal) spheroids, and adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) are different terms apparently used to designate the same disease. However, ALSP linked to dominantly inherited mutations in CSF1R (colony stimulating factor receptor 1) cause CSF-1R-related leukoencephalopathy (CRP). Yet, recessive ALSP with ovarian failure linked to AARS2 (alanyl-transfer (t)RNA synthase 2) mutations (LKENP) is a mitochondrial disease and not a primary microglial leukoencephalopathy. Polycystic membranous lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; Nasu–Hakola disease: NHD) is a systemic disease affecting bones, cerebral white matter, selected grey nuclei, and adipose tissue The disease is caused by mutations of one of the two genes TYROBP or TREM2, identified as PLOSL1 and PLOSL2, respectively. TYROBP associates with receptors expressed in NK cells, B and T lymphocytes, dendritic cells, monocytes, macrophages, and microglia. TREM2 encodes the protein TREM2 (triggering receptor expressed on myeloid cells 2), which forms a receptor signalling complex with TYROBP in macrophages and dendritic cells. Rather than pure microglial leukoencephalopathy, NHD can be considered a multisystemic “immunological” disease. Full article

(This article belongs to the Special Issue New Insights into Glioblastoma: Cellular and Molecular)

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