Glioblastoma Cell: From Cellular and Molecular Mechanisms to Innovative Therapy

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: 10 June 2024 | Viewed by 5091

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I.R.C.C.S Neuromed, Via Atinense, 18, 86077 Pozzilli, IS, Italy
Interests: cancer biology; glioma; cell biology; cell adhesion; pharmacology; neuro-oncology; natural adjuvant therapy; astrocytoma
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Special Issue Information

Dear Colleagues,

Gliomas are the most malignant and aggressive form of brain tumors and account for the majority of brain-cancer-related deaths. Malignant gliomas are treated with chemo- (temozolomide) and radiotherapy, with survival times only experiencing slight increases. Numerous advances have been made in understanding the biology of gliomas, including the discovery that cancer stem cells, called glioma stem cells (GSCs), are likely responsible for tumor recurrence. Several molecular markers have been proposed as predictors for the prognosis of patients with glioblastoma: some of the best-known molecular markers (IDH, EGFR, p53, PI3K, Rb and RAF), have considerable clinical relevance. In the context of the molecular characterization of brain tumors, the diagnosis of the methylation of the MGMT gene is of particular clinical interest. The new WHO classification 2016 supplemented the morphological classification with molecular changes (IDH1 mutations, 1p/19q loss, and MGMT methylation). This Special Issue will cover all aspects of glioblastoma cell growth, including the study of the mechanisms underlying growth inhibition: apoptosis, autophagy, and necrosis. Studies on new adjuvant substances for the treatment of glioblastomas, advanced personalized molecular diagnosis and responses to novel molecular-targeted therapies will be promising. Along with original research articles of in vitro and in vivo models of glioblastoma, comprehensive and up-to-date reviews of these topics are encouraged to summarize and understand the current state and future directions of glioblastoma cell biology and therapy.

A previous Special Issue, entitled "Glioblastoma Cell: From Molecular Target to Innovative Therapy”, was very successful, and comprises 11 papers and reviews concerning various aspects of glioblastomas. However, mechanisms related to glioblastomas are complicated and dynamic, making them difficult to cover in one Special Issue. Therefore, we aim to work towards creating an additional Special Issue on this topic.

The purpose of this Special Issue is to highlight the recent findings related to cellular and molecular mechanisms and therapies for glioblastomas. We welcome the submission of both original research articles and reviews. All scientists working in these fields are cordially invited to submit their manuscripts.

All papers will be published on an ongoing basis as fully open access. We look forward to receiving your contributions.

Dr. Antonella Arcella
Guest Editor

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Keywords

  • glioblastoma cell line
  • adjuvant substance
  • target therapy
  • molecular pathways
  • molecular markers
  • GSCs

Published Papers (3 papers)

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Research

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22 pages, 8231 KiB  
Article
Association between MGMT Enhancer Methylation and MGMT Promoter Methylation, MGMT Protein Expression, and Overall Survival in Glioblastoma
by Katja Zappe, Katharina Pühringer, Simon Pflug, Daniel Berger, Andreas Böhm, Sabine Spiegl-Kreinecker and Margit Cichna-Markl
Cells 2023, 12(12), 1639; https://doi.org/10.3390/cells12121639 - 15 Jun 2023
Cited by 5 | Viewed by 1419
Abstract
The repair protein O6-methylguanine-DNA methyltransferase (MGMT) is regulated epigenetically, mainly by the methylation of the MGMT promoter. MGMT promoter methylation status has emerged as a prognostic and predictive biomarker for patients with newly diagnosed glioblastoma (GBM). However, a strong negative correlation between MGMT [...] Read more.
The repair protein O6-methylguanine-DNA methyltransferase (MGMT) is regulated epigenetically, mainly by the methylation of the MGMT promoter. MGMT promoter methylation status has emerged as a prognostic and predictive biomarker for patients with newly diagnosed glioblastoma (GBM). However, a strong negative correlation between MGMT promoter methylation and MGMT protein expression cannot be applied as a rule for all GBM patients. In order to investigate if the DNA methylation status of MGMT enhancers is associated with MGMT promoter methylation, MGMT expression, and the overall survival (OS) of GBM patients, we established assays based on high-resolution melting analysis and pyrosequencing for one intragenic and three intergenic MGMT enhancers. For CpGs in an enhancer located 560 kb upstream of the MGMT promoter, we found a significant negative correlation between the methylation status and MGMT protein levels of GBM samples expressing MGMT. The methylation status of CpGs in the intragenic enhancer (hs696) was strongly negatively correlated with MGMT promoter methylation and was significantly higher in MGMT-expressing GBM samples than in MGMT-non-expressing GBM samples. Moreover, low methylation of CpGs 01–03 and CpGs 09–13 was associated with the longer OS of the GBM patients. Our findings indicate an association between MGMT enhancer methylation and MGMT promoter methylation, MGMT protein expression, and/or OS. Full article
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27 pages, 20314 KiB  
Article
Interaction of a Novel Alternatively Spliced Variant of HSD11B1L with Parkin Enhances the Carcinogenesis Potential of Glioblastoma: Peiminine Interferes with This Interaction
by Ru-Huei Fu, Syuan-Yu Hong, Chia-Wen Tsai, Shih-Ping Liu, Shao-Chih Chiu, Meng-Zhen Wu, Woei-Cherng Shyu and Shinn-Zong Lin
Cells 2023, 12(6), 894; https://doi.org/10.3390/cells12060894 - 14 Mar 2023
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Abstract
Glioblastoma (GBM) is a primary brain tumor of unknown etiology. It is extremely aggressive, incurable and has a short average survival time for patients. Therefore, understanding the precise molecular mechanisms of this diseases is essential to establish effective treatments. In this study, we [...] Read more.
Glioblastoma (GBM) is a primary brain tumor of unknown etiology. It is extremely aggressive, incurable and has a short average survival time for patients. Therefore, understanding the precise molecular mechanisms of this diseases is essential to establish effective treatments. In this study, we cloned and sequenced a splice variant of the hydroxysteroid 11-β dehydrogenase 1 like gene (HSD11B1L) and named it HSD11B1L-181. HSD11 B1L-181 was specifically expressed only in GBM cells. Overexpression of this variant can significantly promote the proliferation, migration and invasion of GBM cells. Knockdown of HSD11B1L-181 expression inhibited the oncogenic potential of GBM cells. Furthermore, we identified the direct interaction of parkin with HSD11B1L-181 by screening the GBM cDNA expression library via yeast two-hybrid. Parkin is an RBR E3 ubiquitin ligase whose mutations are associated with tumorigenesis. Small interfering RNA treatment of parkin enhanced the proliferative, migratory and invasive abilities of GBM. Finally, we found that the alkaloid peiminine from the bulbs of Fritillaria thunbergii Miq blocks the interaction between HSD11B1L-181 and parkin, thereby lessening carcinogenesis of GBM. We further confirmed the potential of peiminine to prevent GBM in cellular, ectopic and orthotopic xenograft mouse models. Taken together, these findings not only provide insight into GBM, but also present an opportunity for future GBM treatment. Full article
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Review

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17 pages, 1133 KiB  
Review
Signaling Pathways of AXL Receptor Tyrosine Kinase Contribute to the Pathogenetic Mechanisms of Glioblastoma
by Alberto Repici, Alessio Ardizzone, Fabiola De Luca, Lorenzo Colarossi, Angela Prestifilippo, Gabriele Pizzino, Irene Paterniti, Emanuela Esposito and Anna Paola Capra
Cells 2024, 13(4), 361; https://doi.org/10.3390/cells13040361 - 19 Feb 2024
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Abstract
Brain tumors are a diverse collection of neoplasms affecting the brain with a high prevalence rate in people of all ages around the globe. In this pathological context, glioblastoma, a form of glioma that belongs to the IV-grade astrocytoma group, is the most [...] Read more.
Brain tumors are a diverse collection of neoplasms affecting the brain with a high prevalence rate in people of all ages around the globe. In this pathological context, glioblastoma, a form of glioma that belongs to the IV-grade astrocytoma group, is the most common and most aggressive form of the primary brain tumors. Indeed, despite the best treatments available including surgery, radiotherapy or a pharmacological approach with Temozolomide, glioblastoma patients’ mortality is still high, within a few months of diagnosis. Therefore, to increase the chances of these patients surviving, it is critical to keep finding novel treatment opportunities. In the past, efforts to treat glioblastoma have mostly concentrated on customized treatment plans that target specific mutations such as epidermal growth factor receptor (EGFR) mutations, Neurotrophic Tyrosine Receptor Kinase (NTRK) fusions, or multiple receptors using multi-kinase inhibitors like Sunitinib and Regorafenib, with varying degrees of success. Here, we focused on the receptor tyrosine kinase AXL that has been identified as a mediator for tumor progression and therapy resistance in various cancer types, including squamous cell tumors, small cell lung cancer, and breast cancer. Activated AXL leads to a significant increase in tumor proliferation, tumor cell migration, and angiogenesis in different in vitro and in vivo models of cancer since this receptor regulates interplay with apoptotic, angiogenic and inflammatory pathways. Based on these premises, in this review we mainly focused on the role of AXL in the course of glioblastoma, considering its primary biological mechanisms and as a possible target for the application of the most recent treatments. Full article
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