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Special Issue "Advances of Molecular Biology and Translational Aspects in CNS Tumors"

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

Deadline for manuscript submissions: closed (31 December 2019).

Special Issue Editors

Prof. Dr. Christel Herold-Mende
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Guest Editor
Head of Experimental Neurosurgery, Department of Neurosurgery, Division of Experimental Neurosurgery, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
Interests: Brain tumors; HNSCC; immunobiology; drug testing; cell models; biomarkers
Prof. Dr. Katrin Lamszus
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Guest Editor
Laboratory for Brain Tumor Biology, Department of Neurosurgery, University of Hamburg, 20146 Hamburg, Germany
Interests: Brain tumors; invasion; angiogenesis; metabolism; immunobiology; liquid biopsy; cell and animal models; drug testing
Prof. Dr. Rainer Glass
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Guest Editor
Department of Neurosurgery, Munich University Hospital (LMU), Marchioninistr. 15, D-81377 Munich, Germany
Interests: Neuroscience; primary brain tumours; brain macrophages; neurovascular unit

Special Issue Information

Dear Colleagues,

About 30.9 % of all primary CNS tumors in the US are malignant. The most commonly occurring malignant tumor is glioblastoma (14.7% of all and 47.7% of malignant tumors), and the most common nonmalignant tumor is meningioma (37.1% of all and 53.1% of nonmalignant tumors), with an overall incidence of 23.03 per 100,000 (CBTRUS 2018). The occurrence of secondary, metastatic tumors is about four times more common (NCI). Current therapy includes varying combinations of surgery, radio-, and chemotherapy. The five-year survival rate following diagnosis of a malignant CNS tumor is 35% and 90.7% for nonmalignant CNS tumors (CTRUS), indicating an urgent need for more effective therapies for different types of CNS tumors even if they are benign, as well as a better understanding of the molecular determinants of therapy response and tumor biology.

This Special Issue shall cover results of studies using animal or cell culture models to investigate the molecular underpinnings and treatment approaches of different CNS tumor types, applying molecular biological methods. This issue will also publish reports on tissue samples of patient tumors, providing novel mechanistic insights into new aspects that may impact on the development of novel biomarkers and clinical therapy of CNS tumors. In addition, reviews about the current status of new therapy options in different CNS cancer types and prognostic and predictive biomarkers will be published.

Prof. Dr. Christel Herold-Mende
Prof. Dr. Katrin Lamszus
Prof. Dr. Rainer Glass
Guest Editors

Manuscript Submission Information

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 papers will be 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.

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.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • molecular determinants of CNS tumors
  • novel biomarkers
  • novel therapeutics and mechanistic insights in mode of action
  • drug screens
  • immunotherapy
  • immunobiology
  • transcriptional profiles

Published Papers (6 papers)

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Research

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Open AccessArticle
Replication Protein A (RPA) Mediates Radio-Resistance of Glioblastoma Cancer Stem-Like Cells
Int. J. Mol. Sci. 2020, 21(5), 1588; https://doi.org/10.3390/ijms21051588 - 26 Feb 2020
Abstract
Glioblastoma (GBM) is among the deadliest of solid tumors with median survival rates of approximately 12–15 months despite maximal therapeutic intervention. A rare population of self-renewing cells referred to as GBM cancer stem-like cells (GSCs) are believed to be the source of inevitable [...] Read more.
Glioblastoma (GBM) is among the deadliest of solid tumors with median survival rates of approximately 12–15 months despite maximal therapeutic intervention. A rare population of self-renewing cells referred to as GBM cancer stem-like cells (GSCs) are believed to be the source of inevitable recurrence in GBM. GSCs exhibit preferential activation of the DNA damage response pathway (DDR) and evade ionizing radiation (IR) therapy by superior execution of DNA repair compared to their differentiated counterparts, differentiated GBM cells (DGCs). Replication Protein A (RPA) plays a central role in most of the DNA metabolic processes essential for genomic stability, including DNA repair. Here, we show that RPA is preferentially expressed by GSCs and high RPA expression informs poor glioma patient survival. RPA loss either by shRNA-mediated silencing or chemical inhibition impairs GSCs’ survival and self-renewal and most importantly, sensitizes these cells to IR. This newly uncovered role of RPA in GSCs supports its potential clinical significance as a druggable biomarker in GBM. Full article
(This article belongs to the Special Issue Advances of Molecular Biology and Translational Aspects in CNS Tumors)
Open AccessArticle
A Rapid Robust Method for Subgrouping Non-NF2 Meningiomas According to Genotype and Detection of Lower Levels of M2 Macrophages in AKT1 E17K Mutated Tumours
Int. J. Mol. Sci. 2020, 21(4), 1273; https://doi.org/10.3390/ijms21041273 - 13 Feb 2020
Abstract
The majority of meningiomas are grade I, but some grade I tumours are clinically more aggressive. Recent advances in the genetic study of meningiomas has allowed investigation into the influence of genetics on the tumour microenvironment, which is important for tumorigenesis. We have [...] Read more.
The majority of meningiomas are grade I, but some grade I tumours are clinically more aggressive. Recent advances in the genetic study of meningiomas has allowed investigation into the influence of genetics on the tumour microenvironment, which is important for tumorigenesis. We have established that the endpoint genotyping method Kompetitive Allele Specific PCR (KASP™) is a fast, reliable method for the screening of meningioma samples into different non-NF2 mutational groups using a standard real-time PCR instrument. This genotyping method and four-colour flow cytometry has enabled us to assess the variability in the largest immune cell infiltrate population, M2 macrophages (CD45+HLA-DR+CD14+CD163+) in 42 meningioma samples, and to suggest that underlying genetics is relevant. Further immunohistochemistry analysis comparing AKT1 E17K mutants to WHO grade I NF2-negative samples showed significantly lower levels of CD163-positive activated M2 macrophages in meningiomas with mutated AKT1 E17K, signifying a more immunosuppressive tumour microenvironment in NF2 meningiomas. Our data suggested that underlying tumour genetics play a part in the development of the immune composition of the tumour microenvironment. Stratifying meningiomas by mutational status and correlating this with their cellular composition will aid in the development of new immunotherapies for patients. Full article
(This article belongs to the Special Issue Advances of Molecular Biology and Translational Aspects in CNS Tumors)
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Open AccessArticle
Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells
Int. J. Mol. Sci. 2020, 21(2), 612; https://doi.org/10.3390/ijms21020612 - 17 Jan 2020
Abstract
Molecular imaging is essential for diagnosis and treatment planning for glioblastoma patients. Positron emission tomography (PET) with tracers for the detection of the solute carrier family 7 member 5 (SLC7A5; also known as the amino acid transporter light chain L system, [...] Read more.
Molecular imaging is essential for diagnosis and treatment planning for glioblastoma patients. Positron emission tomography (PET) with tracers for the detection of the solute carrier family 7 member 5 (SLC7A5; also known as the amino acid transporter light chain L system, LAT1) and for the mitochondrial translocator protein (TSPO) is successfully used to provide additional information on tumor volume and prognosis. The current approaches for TSPO-PET and the visualization of tracer ([18F] Fluoroethyltyrosine, FET) uptake by LAT1 (FET-PET) do not yet exploit the full diagnostic potential of these molecular imaging techniques. Therefore, we investigated the expression of TSPO and LAT1 in patient glioblastoma (GBM) samples, as well as in various GBM mouse models representing patient GBMs of different genetic subtypes. By immunohistochemistry, we found that TSPO and LAT1 are upregulated in human GBM samples compared to normal brain tissue. Next, we orthotopically implanted patient-derived GBM cells, as well as genetically engineered murine GBM cells, representing different genetic subtypes of the disease. To determine TSPO and LAT1 expression, we performed immunofluorescence staining. We found that both TSPO and LAT1 expression was increased in tumor regions of the implanted human or murine GBM cells when compared to the neighboring mouse brain tissue. While LAT1 was largely restricted to tumor cells, we found that TSPO was also expressed by microglia, tumor-associated macrophages, endothelial cells, and pericytes. The Cancer Genome Atlas (TCGA)-data analysis corroborates the upregulation of TSPO in a bigger cohort of GBM patient samples compared to tumor-free brain tissue. In addition, AIF1 (the gene encoding for the myeloid cell marker Iba1) was also upregulated in GBM compared to the control. Interestingly, TSPO, as well as AIF1, showed significantly different expression levels depending on the GBM genetic subtype, with the highest expression being exhibited in the mesenchymal subtype. High TSPO and AIF1 expression also correlated with a significant decrease in patient survival compared to low expression. In line with this finding, the expression levels for TSPO and AIF1 were also significantly higher in (isocitrate-dehydrogenase wild-type) IDHWT compared to IDH mutant (IDHMUT) GBM. LAT1 expression, on the other hand, was not different among the individual GBM subtypes. Therefore, we could conclude that FET- and TSPO-PET confer different information on pathological features based on different genetic GBM subtypes and may thus help in planning individualized strategies for brain tumor therapy in the future. A combination of TSPO-PET and FET-PET could be a promising way to visualize tumor-associated myeloid cells and select patients for treatment strategies targeting the myeloid compartment. Full article
(This article belongs to the Special Issue Advances of Molecular Biology and Translational Aspects in CNS Tumors)
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Open AccessArticle
Pre-Clinical Drug Testing in 2D and 3D Human In Vitro Models of Glioblastoma Incorporating Non-Neoplastic Astrocytes: Tunneling Nano Tubules and Mitochondrial Transfer Modulates Cell Behavior and Therapeutic Respons
Int. J. Mol. Sci. 2019, 20(23), 6017; https://doi.org/10.3390/ijms20236017 - 29 Nov 2019
Abstract
The role of astrocytes in the glioblastoma (GBM) microenvironment is poorly understood; particularly with regard to cell invasion and drug resistance. To assess this role of astrocytes in GBMs we established an all human 2D co-culture model and a 3D hyaluronic acid-gelatin based [...] Read more.
The role of astrocytes in the glioblastoma (GBM) microenvironment is poorly understood; particularly with regard to cell invasion and drug resistance. To assess this role of astrocytes in GBMs we established an all human 2D co-culture model and a 3D hyaluronic acid-gelatin based hydrogel model (HyStem™-HP) with different ratios of GBM cells to astrocytes. A contact co-culture of fluorescently labelled GBM cells and astrocytes showed that the latter promotes tumour growth and migration of GBM cells. Notably, the presence of non-neoplastic astrocytes in direct contact, even in low amounts in co-culture, elicited drug resistance in GBM. Recent studies showed that non-neoplastic cells can transfer mitochondria along tunneling nanotubes (TNT) and rescue damaged target cancer cells. In these studies, we explored TNT formation and mitochondrial transfer using 2D and 3D in vitro co-culture models of GBM and astrocytes. TNT formation occurs in glial fibrillary acidic protein (GFAP) positive “reactive” astrocytes after 48 h co-culture and the increase of TNT formations was greater in 3D hyaluronic acid-gelatin based hydrogel models. This study shows that human astrocytes in the tumour microenvironment, both in 2D and 3D in vitro co-culture models, could form TNT connections with GBM cells. We postulate that the association on TNT delivery non-neoplastic mitochondria via a TNT connection may be related to GBM drug response as well as proliferation and migration. Full article
(This article belongs to the Special Issue Advances of Molecular Biology and Translational Aspects in CNS Tumors)
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Review

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Open AccessReview
Integrin Signaling in Glioma Pathogenesis: From Biology to Therapy
Int. J. Mol. Sci. 2020, 21(3), 888; https://doi.org/10.3390/ijms21030888 - 30 Jan 2020
Abstract
Integrins are a large family of transmembrane adhesion receptors, which play a key role in interactions of a cell with the surrounding stroma. Integrins are comprised of non-covalently linked α and β chains, which form heterodimeric receptor complexes. The signals from integrin receptors [...] Read more.
Integrins are a large family of transmembrane adhesion receptors, which play a key role in interactions of a cell with the surrounding stroma. Integrins are comprised of non-covalently linked α and β chains, which form heterodimeric receptor complexes. The signals from integrin receptors are combined with those originating from growth factor receptors and participate in orchestrating morphological changes of cells, organization of the cytoskeleton, stimulation of cell proliferation and rescuing cells from programmed cell death induced by extracellular matrix (ECM) detachment. Upon binding to specific ligands or ECM components, integrin dimers activate downstream signaling pathways, including focal adhesion kinase, phosphoinositide-3-kinase (PI3K) and AKT kinases, which regulate migration, invasion, proliferation and survival. Expression of specific integrins is upregulated in both tumor cells and stromal cells in a tumor microenvironment. Therefore, integrins became an attractive therapeutic target for many cancers, including the most common primary brain tumors—gliomas. In this review we provide an overview of the involvement of integrin signaling in glioma pathogenesis, formation of the tumor niche and brain tissue infiltration. We will summarize up-to-date therapeutic strategies for gliomas focused on interference with integrin ligand-receptor signaling. Full article
(This article belongs to the Special Issue Advances of Molecular Biology and Translational Aspects in CNS Tumors)
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Open AccessReview
Revealing and Harnessing Tumour-Associated Microglia/Macrophage Heterogeneity in Glioblastoma
Int. J. Mol. Sci. 2020, 21(3), 689; https://doi.org/10.3390/ijms21030689 - 21 Jan 2020
Abstract
Cancer heterogeneity and progression are subject to complex interactions between neoplastic cells and their microenvironment, including the immune system. Although glioblastomas (GBMs) are classified as ‘cold tumours’ with very little lymphocyte infiltration, they can contain up to 30–40% of tumour-associated macrophages, reported to [...] Read more.
Cancer heterogeneity and progression are subject to complex interactions between neoplastic cells and their microenvironment, including the immune system. Although glioblastomas (GBMs) are classified as ‘cold tumours’ with very little lymphocyte infiltration, they can contain up to 30–40% of tumour-associated macrophages, reported to contribute to a supportive microenvironment that facilitates tumour proliferation, survival and migration. In GBM, tumour-associated macrophages comprise either resident parenchymal microglia, perivascular macrophages or peripheral monocyte-derived cells. They are recruited by GBMs and in turn release growth factors and cytokines that affect the tumour. Notably, tumour-associated microglia/macrophages (TAMs) acquire different expression programs, which shape the tumour microenvironment and contribute to GBM molecular subtyping. Further, emerging evidence highlights that TAM programs may adapt to specific tumour features and landscapes. Here, we review key evidence describing TAM transcriptional and functional heterogeneity in GBM. We propose that unravelling the intricate complexity and diversity of the myeloid compartment as well as understanding how different TAM subsets may affect tumour progression will possibly pave the way to new immune therapeutic avenues for GBM patients. Full article
(This article belongs to the Special Issue Advances of Molecular Biology and Translational Aspects in CNS Tumors)
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