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

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 14569

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Dr. Ander Matheu

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Cellular Oncology Group, Biodonostia Health Research Institute, E-20014 San Sebastian, Spain
Interests: stem cell biology; oncology; aging; frailty; neuroscience
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite recent advances in the treatment of solid tumors, malignant brain tumors, i.e., primary brain tumors and brain metastasis, remain challenging and often fatal diseases. Irrespective of their heterogeneous nature, the brain with its specific brain microenvironment (e.g., with distinct cell types such as astrocytes) and anatomy (e.g., the blood–brain barrier) makes brain tumors unique diseases in many aspects. There is an unmet need for novel therapeutic approaches that take into account events in tumor development, primary and adaptive molecular tumor cell characteristics, cellular heterogeneity, as well as interactions between tumor cells and the brain microenvironment (e.g., immune cells, blood vessels, and neurons). Furthermore, molecular biomarkers could help to predict therapy efficacy, to tailor personalized treatment regimens, and to monitor therapy response. As damage to the healthy brain tissue severely impacts patients’ quality of life, more insights into specific tumor cell vulnerabilities and molecular mechanisms of normal tissue toxicity are urgently needed.

This Special Issue, “Neuro-Oncology: From Molecular Basis to Therapy”, will cover a selection of original and review articles on the molecular biology of brain tumors and novel therapeutic approaches.

Dr. Ander Matheu
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

neuro-oncology
brain tumor
glioblastoma
glioma
brain metastasis
medulloblastoma
cancer neuroscience
molecular cancer biology

Published Papers (6 papers)

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Research

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17 pages, 4547 KiB

Open AccessArticle

Pro- vs. Anti-Inflammatory Features of Monocyte Subsets in Glioma Patients

by Natalia Lehman, Wioleta Kowalska, Michał Zarobkiewicz, Marek Mazurek, Karolina Mrozowska, Agnieszka Bojarska-Junak and Radosław Rola

Int. J. Mol. Sci. 2023, 24(3), 1879; https://doi.org/10.3390/ijms24031879 - 18 Jan 2023

Cited by 2 | Viewed by 2026

Abstract

Monocytes constitute a heterogenous group of antigen-presenting cells that can be subdivided based on CD14, CD16 and SLAN expression. This division reflects the functional diversity of cells that may play different roles in a variety of pathologies including gliomas. In the current study, the three monocyte subpopulations: classical (CD14⁺ CD16⁺ SLAN⁻), intermediate (CD14^dim CD16⁺ SLAN⁻) and non-classical (CD14^low/− CD16⁺ SLAN⁺) in glioma patients’ peripheral blood were analysed with flow cytometry. The immune checkpoint molecule (PD-1, PD-L1, SIRPalpha, TIM-3) expression along with pro- and anti-inflammatory cytokines (TNF, IL-12, TGF-beta, IL-10) were assessed. The significant overproduction of anti-inflammatory cytokines by intermediate monocytes was observed. Additionally, SLAN-positive cells overexpressed IL-12 and TNF when compared to the other two groups of monocytes. In conclusion, these results show the presence of different profiles of glioma patient monocytes depending on CD14, CD16 and SLAN expression. The bifold function of monocyte subpopulations might be an additional obstacle to the effectiveness of possible immunotherapies. Full article

(This article belongs to the Special Issue Neuro-Oncology: From Molecular Basis to Therapy)

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15 pages, 2584 KiB

Open AccessArticle

MT1-MMP Expression Levels and Catalytic Functions Dictate LDL Receptor-Related Protein-1 Ligand Internalization Capacity in U87 Glioblastoma Cells

by Jonathan Pratt, Khadidja Haidara and Borhane Annabi

Int. J. Mol. Sci. 2022, 23(22), 14214; https://doi.org/10.3390/ijms232214214 - 17 Nov 2022

Cited by 1 | Viewed by 1362

Abstract

Modulations in cell surface receptor ectodomain proteolytic shedding impact on receptor function and cancer biomarker expression. As such, heavily pursued therapeutic avenues have exploited LDL receptor-related protein-1 (LRP-1)-mediated capacity in internalizing Angiopep-2 (An2), a brain-penetrating peptide that allows An2–drug conjugates to cross the blood–brain tumor barrier (BBTB). Given that LRP-1 is proteolytically shed from the cell surface through matrix metalloproteinase (MMP) activity, the balance between MMP expression/function and LRP-1-mediated An2 internalization is unknown. In this study, we found that membrane type-1 (MT1)-MMP expression increased from grade 1 to 4 brain tumors, while that of LRP-1 decreased inversely. MMP pharmacological inhibitors such as Ilomastat, Doxycycline and Actinonin increased in vitro An2 internalization by up to 2.5 fold within a human grade IV-derived U87 glioblastoma cell model. Transient siRNA-mediated MT1-MMP gene silencing resulted in increased basal An2 cell surface binding and intracellular uptake, while recombinant MT1-MMP overexpression reduced both cell surface LRP-1 expression as well as An2 internalization. The addition of Ilomastat to cells overexpressing recombinant MT1-MMP restored LRP-1 expression at the cell surface and An2 uptake to levels comparable to those observed in control cells. Collectively, our data suggest that MT1-MMP expression status dictates An2-mediated internalization processes in part by regulating cell surface LRP-1 functions. Such evidence prompts preclinical evaluations of combined MMP inhibitors/An2–drug conjugate administration to potentially increase the treatment of high-MT1-MMP-expressing brain tumors. Full article

(This article belongs to the Special Issue Neuro-Oncology: From Molecular Basis to Therapy)

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20 pages, 2562 KiB

Open AccessArticle

High SOX9 Maintains Glioma Stem Cell Activity through a Regulatory Loop Involving STAT3 and PML

by Paula Aldaz, Natalia Martín-Martín, Ander Saenz-Antoñanzas, Estefania Carrasco-Garcia, María Álvarez-Satta, Alejandro Elúa-Pinin, Steven M. Pollard, Charles H. Lawrie, Manuel Moreno-Valladares, Nicolás Samprón, Jürgen Hench, Robin Lovell-Badge, Arkaitz Carracedo and Ander Matheu

Int. J. Mol. Sci. 2022, 23(9), 4511; https://doi.org/10.3390/ijms23094511 - 19 Apr 2022

Cited by 2 | Viewed by 2637

Abstract

Glioma stem cells (GSCs) are critical targets for glioma therapy. SOX9 is a transcription factor with critical roles during neurodevelopment, particularly within neural stem cells. Previous studies showed that high levels of SOX9 are associated with poor glioma patient survival. SOX9 knockdown impairs GSCs proliferation, confirming its potential as a target for glioma therapy. In this study, we characterized the function of SOX9 directly in patient-derived glioma stem cells. Notably, transcriptome analysis of GSCs with SOX9 knockdown revealed STAT3 and PML as downstream targets. Functional studies demonstrated that SOX9, STAT3, and PML form a regulatory loop that is key for GSC activity and self-renewal. Analysis of glioma clinical biopsies confirmed a positive correlation between SOX9/STAT3/PML and poor patient survival among the cases with the highest SOX9 expression levels. Importantly, direct STAT3 or PML inhibitors reduced the expression of SOX9, STAT3, and PML proteins, which significantly reduced GSCs tumorigenicity. In summary, our study reveals a novel role for SOX9 upstream of STAT3, as a GSC pathway regulator, and presents pharmacological inhibitors of the signaling cascade. Full article

(This article belongs to the Special Issue Neuro-Oncology: From Molecular Basis to Therapy)

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28 pages, 6250 KiB

Open AccessArticle

Enhanced Survival of High-Risk Medulloblastoma-Bearing Mice after Multimodal Treatment with Radiotherapy, Decitabine, and Abacavir

by Marieke Gringmuth, Jenny Walther, Sebastian Greiser, Magali Toussaint, Benjamin Schwalm, Marcel Kool, Rolf-Dieter Kortmann, Annegret Glasow and Ina Patties

Int. J. Mol. Sci. 2022, 23(7), 3815; https://doi.org/10.3390/ijms23073815 - 30 Mar 2022

Cited by 1 | Viewed by 2434

Abstract

Children with high-risk SHH/TP53-mut and Group 3 medulloblastoma (MB) have a 5-year overall survival of only 40%. Innovative approaches to enhance survival while preventing adverse effects are urgently needed. We investigated an innovative therapy approach combining irradiation (RT), decitabine (DEC), and abacavir (ABC) in a patient-derived orthotopic SHH/TP53-mut and Group 3 MB mouse model. MB-bearing mice were treated with DEC, ABC and RT. Mouse survival, tumor growth (BLI, MRT) tumor histology (H/E), proliferation (Ki-67), and endothelial (CD31) staining were analyzed. Gene expression was examined by microarray and RT-PCR (Ki-67, VEGF, CD31, CD15, CD133, nestin, CD68, IBA). The RT/DEC/ABC therapy inhibited tumor growth and enhanced mouse survival. Ki-67 decreased in SHH/TP53-mut MBs after RT, DEC, RT/ABC, and RT/DEC/ABC therapy. CD31 was higher in SHH/TP53-mut compared to Group 3 MBs and decreased after RT/DEC/ABC. Microarray analyses showed a therapy-induced downregulation of cell cycle genes. By RT-PCR, no therapy-induced effect on stem cell fraction or immune cell invasion/activation could be shown. We showed for the first time that RT/DEC/ABC therapy improves survival of orthotopic SHH/TP53-mut and Group 3 MB-bearing mice without inducing adverse effects suggesting the potential for an adjuvant application of this multimodal therapy approach in the human clinic. Full article

(This article belongs to the Special Issue Neuro-Oncology: From Molecular Basis to Therapy)

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Review

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23 pages, 2354 KiB

Open AccessReview

Crosstalk between SOX Genes and Long Non-Coding RNAs in Glioblastoma

by Milena Stevanovic, Natasa Kovacevic-Grujicic, Isidora Petrovic, Danijela Drakulic, Milena Milivojevic and Marija Mojsin

Int. J. Mol. Sci. 2023, 24(7), 6392; https://doi.org/10.3390/ijms24076392 - 28 Mar 2023

Cited by 1 | Viewed by 2425

Abstract

Glioblastoma (GBM) continues to be the most devastating primary brain malignancy. Despite significant advancements in understanding basic GBM biology and enormous efforts in developing new therapeutic approaches, the prognosis for most GBM patients remains poor with a median survival time of 15 months. Recently, the interplay between the SOX (SRY-related HMG-box) genes and lncRNAs (long non-coding RNAs) has become the focus of GBM research. Both classes of molecules have an aberrant expression in GBM and play essential roles in tumor initiation, progression, therapy resistance, and recurrence. In GBM, SOX and lncRNAs crosstalk through numerous functional axes, some of which are part of the complex transcriptional and epigenetic regulatory mechanisms. This review provides a systematic summary of current literature data on the complex interplay between SOX genes and lncRNAs and represents an effort to underscore the effects of SOX/lncRNA crosstalk on the malignant properties of GBM cells. Furthermore, we highlight the significance of this crosstalk in searching for new biomarkers and therapeutic approaches in GBM treatment. Full article

(This article belongs to the Special Issue Neuro-Oncology: From Molecular Basis to Therapy)

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13 pages, 1202 KiB

Open AccessReview

Chaperone-Mediated Autophagy in Pericytes: A Key Target for the Development of New Treatments against Glioblastoma Progression

by María Dolores Salinas and Rut Valdor

Int. J. Mol. Sci. 2022, 23(16), 8886; https://doi.org/10.3390/ijms23168886 - 10 Aug 2022

Cited by 5 | Viewed by 2414

Abstract

Glioblastoma (GB) cells physically interact with peritumoral pericytes (PCs) present in the brain microvasculature. These interactions facilitate tumor cells to aberrantly increase and benefit from chaperone-mediated autophagy (CMA) in the PC. GB-induced CMA leads to major changes in PC immunomodulatory phenotypes, which, in turn, support cancer progression. In this review, we focus on the consequences of the GB-induced up-regulation of CMA activity in PCs and evaluate how manipulation of this process could offer new strategies to fight glioblastoma, increasing the availability of treatments for this cancer that escapes conventional therapies. We finally discuss the use of modified PCs unable to increase CMA in response to GB as a cell therapy alternative to minimize undesired off-target effects associated with a generalized CMA inhibition. Full article

(This article belongs to the Special Issue Neuro-Oncology: From Molecular Basis to Therapy)

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