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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 July 2024) | Viewed by 33146

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Dr. Lorenzo Corsi

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Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
Interests: pharmacology; cancer; toxicology, neuroscience; phytotherapy; cell biology; molecular pharmacology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite the significant amount of research on glioma published in the last decade, further studies are needed to design new therapeutic and diagnostic targets. Thus, identifying and understanding the key element(s) of new molecular mechanisms involving glioma growth and progression in the microenvironment are critical. In this Special Issue, particular attention will be paid to glioblastoma multiforme (GBM). GBM is one of the deadliest common primary brain tumors. This highly malignant tumor represents 50% of all types of primary gliomas in the central nervous system. Considering that in the last decades the mechanical properties of the cell environment together with the variable “stiffness” of cancer cells have emerged as a major determinant of cell behavior in terms of migration, proliferation and differentiation, these aspects are also of interest. Particular attention will be devoted to papers describing new molecular pathways involved in GBM growth and progression and its biomechanical features. Moreover, studies on new molecules able to interfere with GBM growth and recurrence to yield new potential diagnostic and therapeutic targets are welcome.

Dr. Lorenzo Corsi
Guest Editor

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Keywords

GBM
molecular pathways
biomechanics
oncogene
cancer
microenvironment
drug targeting
diagnostic
immunotherapy

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Published Papers (11 papers)

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Research

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14 pages, 2561 KiB

Open AccessArticle

BMP4 and Temozolomide Synergize in the Majority of Patient-Derived Glioblastoma Cultures

by Iris S. C. Verploegh, Andrea Conidi, Hoesna El Hassnaoui, Floor A. M. Verhoeven, Anne L. Korporaal, Ioannis Ntafoulis, Mirjam C. G. N. van den Hout, Rutger W. W. Brouwer, Martine L. M. Lamfers, Wilfred F. J. van IJcken, Danny Huylebroeck and Sieger Leenstra

Int. J. Mol. Sci. 2024, 25(18), 10176; https://doi.org/10.3390/ijms251810176 - 22 Sep 2024

Viewed by 745

Abstract

One of the main causes of poor prognoses in patient with glioblastoma (GBM) is drug resistance to current standard treatment, which includes chemoradiation and adjuvant temozolomide (TMZ). In addition, the concept of cancer stem cells provides new insights into therapy resistance and management also in GBM and glioblastoma stem cell-like cells (GSCs), which might contribute to therapy resistance. Bone morphogenetic protein-4 (BMP4) stimulates astroglial differentiation of GSCs and thereby reduces their self-renewal capacity. Exposure of GSCs to BMP4 may also sensitize these cells to TMZ. A recent phase I trial has shown that local delivery of BMP4 is safe, but a large variation in survival is seen in these treated patients and in features of their cultured tumors. We wanted to combine TMZ and BMP4 (TMZ + BMP4) therapy and assess the inter-tumoral variability in response to TMZ + BMP4 in patient-derived GBM cultures. A phase II trial could then benefit a larger group of patients than those treated with BMP4 only. We first show that simultaneous treatment with TMZ + BMP4 is more effective than sequential treatment. Second, when applying our optimized treatment protocol, 70% of a total of 20 GBM cultures displayed TMZ + BMP4 synergy. This combination induces cellular apoptosis and does not inhibit cell proliferation. Comparative bulk RNA-sequencing indicates that treatment with TMZ + BMP4 eventually results in decreased MAPK signaling, in line with previous evidence that increased MAPK signaling is associated with resistance to TMZ. Based on these results, we advocate further clinical trial research to test patient benefit and validate pathophysiological hypothesis. Full article

(This article belongs to the Special Issue Biomechanics and Molecular Research on Glioblastoma)

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19 pages, 4733 KiB

Open AccessArticle

Discovery of a Therapeutic Agent for Glioblastoma Using a Systems Biology-Based Drug Repositioning Approach

by Ali Kaynar, Mehmet Ozcan, Xiangyu Li, Hasan Turkez, Cheng Zhang, Mathias Uhlén, Saeed Shoaie and Adil Mardinoglu

Int. J. Mol. Sci. 2024, 25(14), 7868; https://doi.org/10.3390/ijms25147868 - 18 Jul 2024

Cited by 1 | Viewed by 941

Abstract

Glioblastoma (GBM), a highly malignant tumour of the central nervous system, presents with a dire prognosis and low survival rates. The heterogeneous and recurrent nature of GBM renders current treatments relatively ineffective. In our study, we utilized an integrative systems biology approach to uncover the molecular mechanisms driving GBM progression and identify viable therapeutic drug targets for developing more effective GBM treatment strategies. Our integrative analysis revealed an elevated expression of CHST2 in GBM tumours, designating it as an unfavourable prognostic gene in GBM, as supported by data from two independent GBM cohorts. Further, we pinpointed WZ-4002 as a potential drug candidate to modulate CHST2 through computational drug repositioning. WZ-4002 directly targeted EGFR (ERBB1) and ERBB2, affecting their dimerization and influencing the activity of adjacent genes, including CHST2. We validated our findings by treating U-138 MG cells with WZ-4002, observing a decrease in CHST2 protein levels and a reduction in cell viability. In summary, our research suggests that the WZ-4002 drug candidate may effectively modulate CHST2 and adjacent genes, offering a promising avenue for developing efficient treatment strategies for GBM patients. Full article

(This article belongs to the Special Issue Biomechanics and Molecular Research on Glioblastoma)

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14 pages, 2343 KiB

Open AccessArticle

Establishment and Comprehensive Molecular Characterization of an Immortalized Glioblastoma Cell Line from a Brazilian Patient

by Fernanda F. da Silva, Fernanda C. S. Lupinacci, Bruno D. S. Elias, Adriano O. Beserra, Paulo Sanematsu, Martin Roffe, Leslie D. Kulikowski, Felipe D’almeida Costa, Tiago G. Santos and Glaucia N. M. Hajj

Int. J. Mol. Sci. 2023, 24(21), 15861; https://doi.org/10.3390/ijms242115861 - 1 Nov 2023

Viewed by 1937

Abstract

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with few effective treatment strategies. The research on the development of new treatments is often constrained by the limitations of preclinical models, which fail to accurately replicate the disease’s essential characteristics. Herein, we describe the obtention, molecular, and functional characterization of the GBM33 cell line. This cell line belongs to the GBM class according to the World Health Organization 2021 Classification of Central Nervous System Tumors, identified by methylation profiling. GBM33 expresses the astrocytic marker GFAP, as well as markers of neuronal origin commonly expressed in GBM cells, such as βIII-tubulin and neurofilament. Functional assays demonstrated an increased growth rate when compared to the U87 commercial cell line and a similar sensitivity to temozolamide. GBM33 cells retained response to serum starvation, with reduced growth and diminished activation of the Akt signaling pathway. Unlike LN-18 and LN-229 commercial cell lines, GBM33 is able to produce primary cilia upon serum starvation. In summary, the successful establishment and comprehensive characterization of this GBM cell line provide researchers with invaluable tools for studying GBM biology, identifying novel therapeutic targets, and evaluating the efficacy of potential treatments. Full article

(This article belongs to the Special Issue Biomechanics and Molecular Research on Glioblastoma)

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15 pages, 30072 KiB

Open AccessArticle

Nuclear Translocation of LDHA Promotes the Catabolism of BCAAs to Sustain GBM Cell Proliferation through the TxN Antioxidant Pathway

by Zhujun Li, Zhiyan Gu, Lan Wang, Yun Guan, Yingying Lyu, Jialong Zhang, Yin Wang, Xin Wang, Ji Xiong and Ying Liu

Int. J. Mol. Sci. 2023, 24(11), 9365; https://doi.org/10.3390/ijms24119365 - 27 May 2023

Cited by 3 | Viewed by 2076

Abstract

Glutamate is excitotoxic to neurons. The entry of glutamine or glutamate from the blood into the brain is limited. To overcome this, branched-chain amino acids (BCAAs) catabolism replenishes the glutamate in brain cells. Branched-chain amino acid transaminase 1 (BCAT1) activity is silenced by epigenetic methylation in IDH mutant gliomas. However, glioblastomas (GBMs) express wild type IDH. Here, we investigated how oxidative stress promotes BCAAs’ metabolism to maintain intracellular redox balance and, consequently, the rapid progression of GBMs. We found that reactive oxygen species (ROS) accumulation promoted the nuclear translocation of lactate dehydrogenase A (LDHA), which triggered DOT1L (disruptor of telomeric silencing 1-like)-mediated histone H3K79 hypermethylation and enhanced BCAA catabolism in GBM cells. Glutamate derived from BCAAs catabolism participates in antioxidant thioredoxin (TxN) production. The inhibition of BCAT1 decreased the tumorigenicity of GBM cells in orthotopically transplanted nude mice, and prolonged their survival time. In GBM samples, BCAT1 expression was negatively correlated with the overall survival time (OS) of patients. These findings highlight the role of the non-canonical enzyme activity of LDHA on BCAT1 expression, which links the two major metabolic pathways in GBMs. Glutamate produced by the catabolism of BCAAs was involved in complementary antioxidant TxN synthesis to balance the redox state in tumor cells and promote the progression of GBMs. Full article

(This article belongs to the Special Issue Biomechanics and Molecular Research on Glioblastoma)

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16 pages, 22770 KiB

Open AccessArticle

Nanomechanical Signatures in Glioma Cells Depend on CD44 Distribution in IDH1 Wild-Type but Not in IDH1R132H Mutant Early-Passage Cultures

by Mikhail E. Shmelev, Vladislav M. Farniev, Nikita A. Shved and Vadim V. Kumeiko

Int. J. Mol. Sci. 2023, 24(4), 4056; https://doi.org/10.3390/ijms24044056 - 17 Feb 2023

Cited by 1 | Viewed by 2158

Abstract

Atomic force microscopy (AFM) recently burst into biomedicine, providing morphological and functional characteristics of cancer cells and their microenvironment responsible for tumor invasion and progression, although the novelty of this assay needs to coordinate the malignant profiles of patients’ specimens to diagnostically valuable criteria. Applying high-resolution semi-contact AFM mapping on an extended number of cells, we analyzed the nanomechanical properties of glioma early-passage cell cultures with a different IDH1 R132H mutation status. Each cell culture was additionally clustered on CD44+/− cells to find possible nanomechanical signatures that differentiate cell phenotypes varying in proliferative activity and the characteristic surface marker. IDH1 R132H mutant cells compared to IDH1 wild-type ones (IDH1wt) characterized by two-fold increased stiffness and 1.5-fold elasticity modulus. CD44+/IDH1wt cells were two-fold more rigid and much stiffer than CD44-/IDH1wt ones. In contrast to IDH1 wild-type cells, CD44+/IDH1 R132H and CD44-/IDH1 R132H did not exhibit nanomechanical signatures providing statistically valuable differentiation of these subpopulations. The median stiffness depends on glioma cell types and decreases according to the following manner: IDH1 R132H mt (4.7 mN/m), CD44+/IDH1wt (3.7 mN/m), CD44-/IDH1wt (2.5 mN/m). This indicates that the quantitative nanomechanical mapping would be a promising assay for the quick cell population analysis suitable for detailed diagnostics and personalized treatment of glioma forms. Full article

(This article belongs to the Special Issue Biomechanics and Molecular Research on Glioblastoma)

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18 pages, 2279 KiB

Open AccessArticle

Hierarchical Voting-Based Feature Selection and Ensemble Learning Model Scheme for Glioma Grading with Clinical and Molecular Characteristics

by Erdal Tasci, Ying Zhuge, Harpreet Kaur, Kevin Camphausen and Andra Valentina Krauze

Int. J. Mol. Sci. 2022, 23(22), 14155; https://doi.org/10.3390/ijms232214155 - 16 Nov 2022

Cited by 19 | Viewed by 4284

Abstract

Determining the aggressiveness of gliomas, termed grading, is a critical step toward treatment optimization to increase the survival rate and decrease treatment toxicity for patients. Streamlined grading using molecular information has the potential to facilitate decision making in the clinic and aid in treatment planning. In recent years, molecular markers have increasingly gained importance in the classification of tumors. In this study, we propose a novel hierarchical voting-based methodology for improving the performance results of the feature selection stage and machine learning models for glioma grading with clinical and molecular predictors. To identify the best scheme for the given soft-voting-based ensemble learning model selections, we utilized publicly available TCGA and CGGA datasets and employed four dimensionality reduction methods to carry out a voting-based ensemble feature selection and five supervised models, with a total of sixteen combination sets. We also compared our proposed feature selection method with the LASSO feature selection method in isolation. The computational results indicate that the proposed method achieves 87.606% and 79.668% accuracy rates on TCGA and CGGA datasets, respectively, outperforming the LASSO feature selection method. Full article

(This article belongs to the Special Issue Biomechanics and Molecular Research on Glioblastoma)

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Review

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19 pages, 374 KiB

Open AccessReview

Potential Diagnostic and Clinical Significance of Selected Genetic Alterations in Glioblastoma

by Silvia Tomoszková, Jozef Škarda and Radim Lipina

Int. J. Mol. Sci. 2024, 25(8), 4438; https://doi.org/10.3390/ijms25084438 - 18 Apr 2024

Cited by 3 | Viewed by 1306

Abstract

Glioblastoma is currently considered the most common and, unfortunately, also the most aggressive primary brain tumor, with the highest morbidity and mortality rates. The average survival of patients diagnosed with glioblastoma is 14 months, and only 2% of patients survive 3 years after surgery. Based on our clinical experience and knowledge from extensive clinical studies, survival is mainly related to the molecular biological properties of glioblastoma, which are of interest to the general medical community. Our study examined a total of 71 retrospective studies published from 2016 through 2022 and available on PubMed that deal with mutations of selected genes in the pathophysiology of GBM. In conclusion, we can find other mutations within a given gene group that have different effects on the prognosis and quality of survival of a patient with glioblastoma. These mutations, together with the associated mutations of other genes, as well as intratumoral heterogeneity itself, offer enormous potential for further clinical research and possible application in therapeutic practice. Full article

(This article belongs to the Special Issue Biomechanics and Molecular Research on Glioblastoma)

14 pages, 991 KiB

Open AccessReview

Glioblastoma: An Update in Pathology, Molecular Mechanisms and Biomarkers

by Zhong Lan, Xin Li and Xiaoqin Zhang

Int. J. Mol. Sci. 2024, 25(5), 3040; https://doi.org/10.3390/ijms25053040 - 6 Mar 2024

Cited by 4 | Viewed by 6106

Abstract

Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor in adults. Despite important advances in understanding the molecular pathogenesis and biology of this tumor in the past decade, the prognosis for GBM patients remains poor. GBM is characterized by aggressive biological behavior and high degrees of inter-tumor and intra-tumor heterogeneity. Increased understanding of the molecular and cellular heterogeneity of GBM may not only help more accurately define specific subgroups for precise diagnosis but also lay the groundwork for the successful implementation of targeted therapy. Herein, we systematically review the key achievements in the understanding of GBM molecular pathogenesis, mechanisms, and biomarkers in the past decade. We discuss the advances in the molecular pathology of GBM, including genetics, epigenetics, transcriptomics, and signaling pathways. We also review the molecular biomarkers that have potential clinical roles. Finally, new strategies, current challenges, and future directions for discovering new biomarkers and therapeutic targets for GBM will be discussed. Full article

(This article belongs to the Special Issue Biomechanics and Molecular Research on Glioblastoma)

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19 pages, 737 KiB

Open AccessReview

Comparative Insight into Microglia/Macrophages-Associated Pathways in Glioblastoma and Alzheimer’s Disease

by Jian Shi and Shiwei Huang

Int. J. Mol. Sci. 2024, 25(1), 16; https://doi.org/10.3390/ijms25010016 - 19 Dec 2023

Cited by 6 | Viewed by 2517

Abstract

Microglia and macrophages are pivotal to the brain’s innate immune response and have garnered considerable attention in the context of glioblastoma (GBM) and Alzheimer’s disease (AD) research. This review delineates the complex roles of these cells within the neuropathological landscape, focusing on a range of signaling pathways—namely, NF-κB, microRNAs (miRNAs), and TREM2—that regulate the behavior of tumor-associated macrophages (TAMs) in GBM and disease-associated microglia (DAMs) in AD. These pathways are critical to the processes of neuroinflammation, angiogenesis, and apoptosis, which are hallmarks of GBM and AD. We concentrate on the multifaceted regulation of TAMs by NF-κB signaling in GBM, the influence of TREM2 on DAMs’ responses to amyloid-beta deposition, and the modulation of both TAMs and DAMs by GBM- and AD-related miRNAs. Incorporating recent advancements in molecular biology, immunology, and AI techniques, through a detailed exploration of these molecular mechanisms, we aim to shed light on their distinct and overlapping regulatory functions in GBM and AD. The review culminates with a discussion on how insights into NF-κB, miRNAs, and TREM2 signaling may inform novel therapeutic approaches targeting microglia and macrophages in these neurodegenerative and neoplastic conditions. This comparative analysis underscores the potential for new, targeted treatments, offering a roadmap for future research aimed at mitigating the progression of these complex diseases. Full article

(This article belongs to the Special Issue Biomechanics and Molecular Research on Glioblastoma)

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12 pages, 281 KiB

Open AccessReview

Neuromodulation for Brain Tumors: Myth or Reality? A Narrative Review

by Quintino Giorgio D’Alessandris, Grazia Menna, Alessandro Izzo, Manuela D’Ercole, Giuseppe Maria Della Pepa, Liverana Lauretti, Roberto Pallini, Alessandro Olivi and Nicola Montano

Int. J. Mol. Sci. 2023, 24(14), 11738; https://doi.org/10.3390/ijms241411738 - 21 Jul 2023

Viewed by 1711

Abstract

In recent years, research on brain cancers has turned towards the study of the interplay between the tumor and its host, the normal brain. Starting from the establishment of a parallelism between neurogenesis and gliomagenesis, the influence of neuronal activity on the development of brain tumors, particularly gliomas, has been partially unveiled. Notably, direct electrochemical synapses between neurons and glioma cells have been identified, paving the way for new approaches for the cure of brain cancers. Since this novel field of study has been defined “cancer neuroscience”, anticancer therapeutic approaches exploiting these discoveries can be referred to as “cancer neuromodulation”. In the present review, we provide an up-to-date description of the novel findings and of the therapeutic neuromodulation perspectives in cancer neuroscience. We focus both on more traditional oncologic approaches, aimed at modulating the major pathways involved in cancer neuroscience through drugs or genetic engineering techniques, and on electric stimulation proposals; the latter is at the cutting-edge of neuro-oncology. Full article

(This article belongs to the Special Issue Biomechanics and Molecular Research on Glioblastoma)

28 pages, 1607 KiB

Open AccessReview

Fluoride in the Central Nervous System and Its Potential Influence on the Development and Invasiveness of Brain Tumours—A Research Hypothesis

by Wojciech Żwierełło, Agnieszka Maruszewska, Marta Skórka-Majewicz and Izabela Gutowska

Int. J. Mol. Sci. 2023, 24(2), 1558; https://doi.org/10.3390/ijms24021558 - 13 Jan 2023

Cited by 9 | Viewed by 7815

Abstract

The purpose of this review is to attempt to outline the potential role of fluoride in the pathogenesis of brain tumours, including glioblastoma (GBM). In this paper, we show for the first time that fluoride can potentially affect the generally accepted signalling pathways implicated in the formation and clinical course of GBM. Fluorine compounds easily cross the blood–brain barrier. Enhanced oxidative stress, disruption of multiple cellular pathways, and microglial activation are just a few examples of recent reports on the role of fluoride in the central nervous system (CNS). We sought to present the key mechanisms underlying the development and invasiveness of GBM, as well as evidence on the current state of knowledge about the pleiotropic, direct, or indirect involvement of fluoride in the regulation of these mechanisms in various tissues, including neural and tumour tissue. The effects of fluoride on the human body are still a matter of controversy. However, given the growing incidence of brain tumours, especially in children, and numerous reports on the effects of fluoride on the CNS, it is worth taking a closer look at these mechanisms in the context of brain tumours, including gliomas. Full article

(This article belongs to the Special Issue Biomechanics and Molecular Research on Glioblastoma)

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