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Molecular Biology and Translational Aspects in CNS Tumors 2.0
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Molecular Biology and Translational Aspects in CNS Tumors 2.0

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 (30 April 2022) | Viewed by 19010

Special Issue Editors

Prof. Dr. Christel Herold-Mende

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Guest Editor
Division of Experimental Neurosurgery, Department of Neurosurgery, Universityof Heidelberg, 69120 Heidelberg, Germany
Interests: characterization and treatment of tumor stem cells as well as on the development of immuntherapies for brain tumors
Special Issues, Collections and Topics in MDPI journals
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
Special Issues, Collections and Topics in MDPI journals
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 Issues, Collections and Topics in MDPI journals

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 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.

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

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Published Papers (19 papers)

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Research

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15 pages, 2089 KiB  
Article
Chromosomal Instability Characterizes Pediatric Medulloblastoma but Is Not Tolerated in the Developing Cerebellum
by Irena Bočkaj, Tosca E. I. Martini, Marlinde J. Smit, Inna Armandari, Bjorn Bakker, René Wardenaar, Tiny G. J. Meeuwsen-de Boer, Petra L. Bakker, Diana C. J. Spierings, Eelco W. Hoving, Victor Guryev, Floris Foijer and Sophia W. M. Bruggeman
Int. J. Mol. Sci. 2022, 23(17), 9852; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179852 - 30 Aug 2022
Cited by 1 | Viewed by 1443
Abstract
Medulloblastoma is a pediatric brain malignancy that consists of four transcriptional subgroups. Structural and numerical aneuploidy are common in all subgroups, although they are particularly profound in Group 3 and Group 4 medulloblastoma and in a subtype of SHH medulloblastoma termed SHHα. This [...] Read more.
Medulloblastoma is a pediatric brain malignancy that consists of four transcriptional subgroups. Structural and numerical aneuploidy are common in all subgroups, although they are particularly profound in Group 3 and Group 4 medulloblastoma and in a subtype of SHH medulloblastoma termed SHHα. This suggests that chromosomal instability (CIN), the process leading to aneuploidy, is an important player in medulloblastoma pathophysiology. However, it is not known if there is ongoing CIN in medulloblastoma or if CIN affects the developing cerebellum and promotes tumor formation. To investigate this, we performed karyotyping of single medulloblastoma cells and demonstrated the presence of distinct tumor cell clones harboring unique copy number alterations, which is suggestive of ongoing CIN. We also found enrichment for processes related to DNA replication, repair, and mitosis in both SHH medulloblastoma and in the highly proliferative compartment of the presumed tumor cell lineage-of-origin, the latter also being sensitive to genotoxic stress. However, when challenging these tumor cells-of-origin with genetic lesions inducing CIN using transgenic mouse modeling, we found no evidence for large chromosomal aberrations in the cerebellum or for medulloblastoma formation. We therefore conclude that without a background of specific genetic mutations, CIN is not tolerated in the developing cerebellum in vivo and, thus, by itself is not sufficient to initiate medulloblastoma. Full article
(This article belongs to the Special Issue Molecular Biology and Translational Aspects in CNS Tumors 2.0)
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16 pages, 3191 KiB  
Article
BCOR Internal Tandem Duplication Expression in Neural Stem Cells Promotes Growth, Invasion, and Expression of PRC2 Targets
by Satoshi Nakata, Ming Yuan, Jeffrey A. Rubens, Ulf D. Kahlert, Jarek Maciaczyk, Eric H. Raabe and Charles G. Eberhart
Int. J. Mol. Sci. 2021, 22(8), 3913; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083913 - 10 Apr 2021
Cited by 1 | Viewed by 2694
Abstract
Central nervous system tumor with BCL6-corepressor internal tandem duplication (CNS-BCOR ITD) is a malignant entity characterized by recurrent alterations in exon 15 encoding the essential binding domain for the polycomb repressive complex (PRC). In contrast to deletion or truncating mutations seen in other [...] Read more.
Central nervous system tumor with BCL6-corepressor internal tandem duplication (CNS-BCOR ITD) is a malignant entity characterized by recurrent alterations in exon 15 encoding the essential binding domain for the polycomb repressive complex (PRC). In contrast to deletion or truncating mutations seen in other tumors, BCOR expression is upregulated in CNS-BCOR ITD, and a distinct oncogenic mechanism has been suggested. However, the effects of this change on the biology of neuroepithelial cells is poorly understood. In this study, we introduced either wildtype BCOR or BCOR-ITD into human and murine neural stem cells and analyzed them with quantitative RT-PCR and RNA-sequencing, as well as growth, clonogenicity, and invasion assays. In human cells, BCOR-ITD promoted derepression of PRC2-target genes compared to wildtype BCOR. A similar effect was found in clinical specimens from previous studies. However, no growth advantage was seen in the human neural stem cells expressing BCOR-ITD, and long-term models could not be established. In the murine cells, both wildtype BCOR and BCOR-ITD overexpression affected cellular differentiation and histone methylation, but only BCOR-ITD increased cellular growth, invasion, and migration. BCOR-ITD overexpression drives transcriptional changes, possibly due to altered PRC function, and contributes to the oncogenic transformation of neural precursors. Full article
(This article belongs to the Special Issue Molecular Biology and Translational Aspects in CNS Tumors 2.0)
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18 pages, 3385 KiB  
Article
Prognostic Value of microRNA-221/2 and 17-92 Families in Primary Glioblastoma Patients Treated with Postoperative Radiotherapy
by Elena Schnabel, Maximilian Knoll, Christian Schwager, Rolf Warta, Andreas Mock, Benito Campos, Laila König, Christine Jungk, Wolfgang Wick, Andreas Unterberg, Jürgen Debus, Christel Herold-Mende and Amir Abdollahi
Int. J. Mol. Sci. 2021, 22(6), 2960; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062960 - 15 Mar 2021
Cited by 5 | Viewed by 2106
Abstract
MicroRNAs (miRs) are non-coding master regulators of transcriptome that could act as tumor suppressors (TSs) or oncogenes (oncomiRs). We aimed to systematically investigate the relevance of miRs as prognostic biomarkers in primary glioblastoma multiforme (GBM) treated with postoperative radio(chemo)therapy (PORT). For hypothesis generation, [...] Read more.
MicroRNAs (miRs) are non-coding master regulators of transcriptome that could act as tumor suppressors (TSs) or oncogenes (oncomiRs). We aimed to systematically investigate the relevance of miRs as prognostic biomarkers in primary glioblastoma multiforme (GBM) treated with postoperative radio(chemo)therapy (PORT). For hypothesis generation, tumor miR expression by Agilent 8x15K human microRNA microarrays and survival data from 482 GBM patients of The Cancer Genome Atlas (TCGA cohort) were analyzed using Cox-PH models. Expression of candidate miRs with prognostic relevance (miR-221/222; miR-17-5p, miR-18a, miR-19b) was validated by qRT-PCR using Taqman technology on an independent validation cohort of GBM patients (n = 109) treated at Heidelberg University Hospital (HD cohort). In TCGA, 50 miRs showed significant association with survival. Among the top ranked prognostic miRs were members of the two miR families miR-221/222 and miR-17-92. Loss of miR-221/222 was correlated with improved prognosis in both cohorts (TCGA, HD) and was an independent prognostic marker in a multivariate analysis considering demographic characteristics (age, sex, Karnofsky performance index (KPI)), molecular markers (O-6-methylguanine-DNA methyltransferase (MGMT) methylation, IDH mutation status) and PORT as co-variables. The prognostic value of miR-17-92 family members was ambiguous and in part contradictory by direct comparison of the two cohorts, thus warranting further validation in larger prospective trials. Full article
(This article belongs to the Special Issue Molecular Biology and Translational Aspects in CNS Tumors 2.0)
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14 pages, 2417 KiB  
Article
mRNA and miRNA Expression Analyses of the MYC/E2F/miR-17-92 Network in the Most Common Pediatric Brain Tumors
by Renata Gruszka, Krzysztof Zakrzewski, Paweł Piotr Liberski and Magdalena Zakrzewska
Int. J. Mol. Sci. 2021, 22(2), 543; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020543 - 07 Jan 2021
Cited by 12 | Viewed by 2635
Abstract
Numerous molecular factors disrupt the correctness of the cell cycle process leading to the development of cancer due to increased cell proliferation. Among known causative factors of such process is abnormal gene expression. Nowadays in the light of current knowledge such alterations are [...] Read more.
Numerous molecular factors disrupt the correctness of the cell cycle process leading to the development of cancer due to increased cell proliferation. Among known causative factors of such process is abnormal gene expression. Nowadays in the light of current knowledge such alterations are frequently considered in the context of mRNA–miRNA correlation. One of the molecular factors with potential value in tumorigenesis is the feedback loop between MYC and E2F genes in which miR-17-5p and miR-20a from the miR-17-92 cluster are involved. The current literature shows that overexpression of the members of the OncomiR-1 are involved in the development of many solid tumors. In the present work, we investigated the expression of components of the MYC/E2F/miR-17-92 network and their closely related elements including members of MYC and E2F families and miRNAs from two paralogs of miR-17-92: miR-106b-25 and miR-106a-363, in the most common brain tumors of childhood, pilocytic astrocytoma (PA), WHO grade 1; ependymoma (EP), WHO grade 2; and medulloblastoma (MB), WHO grade 4. We showed that the highest gene expression was observed in the MYC family for MYCN and in the E2F family for E2F2. Positive correlation was observed between the gene expression and tumor grade and type, with the highest expression being noted for medulloblastomas, followed by ependymomas, and the lowest for pilocytic astrocytomas. Most members of miR-17-92, miR-106a-363 and miR-106b-25 clusters were upregulated and the highest expression was noted for miR-18a and miR-18b. The rest of the miRNAs, including miR-19a, miR-92a, miR-106a, miR-93, or miR-25 also showed high values. miR-17-5p, miR-20a obtained a high level of expression in medulloblastomas and ependymomas, while close to the control in the pilocytic astrocytoma samples. miRNA expression also depended on tumor grade and histology. Full article
(This article belongs to the Special Issue Molecular Biology and Translational Aspects in CNS Tumors 2.0)
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13 pages, 1520 KiB  
Article
Increased Radiation-Associated T-Cell Infiltration in Recurrent IDH-Mutant Glioma
by Anastasia Makarevic, Carmen Rapp, Steffen Dettling, David Reuss, Christine Jungk, Amir Abdollahi, Andreas von Deimling, Andreas Unterberg, Christel Herold-Mende and Rolf Warta
Int. J. Mol. Sci. 2020, 21(20), 7801; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207801 - 21 Oct 2020
Cited by 7 | Viewed by 3177
Abstract
Most gliomas are associated with a fatal prognosis and remain incurable because of their infiltrative growth. Consequently, the addition of immunotherapy to conventional therapy may improve patient outcomes. Here, we analyzed T-cell infiltration and, therefore, a major prerequisite for successful immunotherapy in a [...] Read more.
Most gliomas are associated with a fatal prognosis and remain incurable because of their infiltrative growth. Consequently, the addition of immunotherapy to conventional therapy may improve patient outcomes. Here, we analyzed T-cell infiltration and, therefore, a major prerequisite for successful immunotherapy in a series of primary (n = 78) and recurrent (n = 66) isocitrate dehydrogenase (IDH)-mutant glioma and their changes following treatment with radio- and/or chemotherapy. After multicolor immunofluorescence staining, T cells were counted in entire tumor sections using a software-based setup. Newly diagnosed diffuse IDH-mutant gliomas displayed a median T-cell infiltration of 0.99 T cells/mm2 (range: 0–48.97 CD3+ T cells/mm2), which was about two-fold increased for CD3+, helper, and cytotoxic T cells in recurrent glioma. Furthermore, T-cell infiltration of recurrent tumors was associated with the type of adjuvant treatment of the primary tumor. Interestingly, only glioma patients solely receiving radiotherapy presented consistently with increased T-cell infiltration in their recurrent tumors. This was confirmed in a subset of 27 matched pairs. In conclusion, differences in the T-cell infiltration of primary and recurrent gliomas were demonstrated, and evidence was provided for a beneficial long-term effect on T-cell infiltration upon treatment with radiotherapy. Full article
(This article belongs to the Special Issue Advances of Molecular Biology and Translational Aspects in CNS Tumors)
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19 pages, 2972 KiB  
Article
Apelin Controls Angiogenesis-Dependent Glioblastoma Growth
by Anne Frisch, Stefanie Kälin, Raymond Monk, Josefine Radke, Frank L. Heppner and Roland E. Kälin
Int. J. Mol. Sci. 2020, 21(11), 4179; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21114179 - 11 Jun 2020
Cited by 22 | Viewed by 3571
Abstract
Glioblastoma (GBM) present with an abundant and aberrant tumor neo-vasculature. While rapid growth of solid tumors depends on the initiation of tumor angiogenesis, GBM also progress by infiltrative growth and vascular co-option. The angiogenic factor apelin (APLN) and its receptor ( [...] Read more.
Glioblastoma (GBM) present with an abundant and aberrant tumor neo-vasculature. While rapid growth of solid tumors depends on the initiation of tumor angiogenesis, GBM also progress by infiltrative growth and vascular co-option. The angiogenic factor apelin (APLN) and its receptor (APLNR) are upregulated in GBM patient samples as compared to normal brain tissue. Here, we studied the role of apelin/APLNR signaling in GBM angiogenesis and growth. By functional analysis of apelin in orthotopic GBM mouse models, we found that apelin/APLNR signaling is required for in vivo tumor angiogenesis. Knockdown of tumor cell-derived APLN massively reduced the tumor vasculature. Additional loss of the apelin signal in endothelial tip cells using the APLN-knockout (KO) mouse led to a further reduction of GBM angiogenesis. Direct infusion of the bioactive peptide apelin-13 rescued the vascular loss-of-function phenotype specifically. In addition, APLN depletion massively reduced angiogenesis-dependent tumor growth. Consequently, survival of GBM-bearing mice was significantly increased when APLN expression was missing in the brain tumor microenvironment. Thus, we suggest that targeting vascular apelin may serve as an alternative strategy for anti-angiogenesis in GBM. Full article
(This article belongs to the Special Issue Advances of Molecular Biology and Translational Aspects in CNS Tumors)
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13 pages, 2060 KiB  
Article
O-Vanillin Attenuates the TLR2 Mediated Tumor-Promoting Phenotype of Microglia
by Paul Triller, Julia Bachorz, Michael Synowitz, Helmut Kettenmann and Darko Markovic
Int. J. Mol. Sci. 2020, 21(8), 2959; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082959 - 22 Apr 2020
Cited by 15 | Viewed by 3241
Abstract
Malignant gliomas are primary brain tumors with poor prognoses. These tumors are infiltrated by brain intrinsic microglia and peripheral monocytes which promote glioma cell invasion. In our previous studies, we discovered that the activation of Toll-like receptor 2 (TLR2) on microglia/brain macrophages converts [...] Read more.
Malignant gliomas are primary brain tumors with poor prognoses. These tumors are infiltrated by brain intrinsic microglia and peripheral monocytes which promote glioma cell invasion. In our previous studies, we discovered that the activation of Toll-like receptor 2 (TLR2) on microglia/brain macrophages converts them into a protumorigenic phenotype through the induction of matrix metalloproteinases (MMP) 9 and 14. In the present study, we used in vitro and in situ microglia-glioma interaction experimental models to test the impact of a novel inhibitor of TLR 2, ortho vanillin (O-Vanillin) to block TLR2 mediated microglia protumorigenic phenotype. We demonstrate that O-Vanillin inhibits the TLR2 mediated upregulation of MMP 9, MMP 14, IL 6 and iNOS expression. Similarly, the glioma supernatant induced MMP 9 and MMP 14 expression in murine and human microglia is abrogated by O-Vanillin treatment. O-Vanillin is not toxic for microglia, astrocytes or oligodendrocytes. Glioma growth in murine brain slice cultures is significantly reduced after treatment with O-Vanillin, and this reduced glioma growth depends on the presence of microglia. In addition, we also found that O-Vanillin inhibited the glioma induced proliferation of murine primary microglia. In summary, O-Vanillin attenuates the pro-tumorigenic phenotype of microglia/brain macrophages and thus qualifies as a candidate for glioma therapy. Full article
(This article belongs to the Special Issue Advances of Molecular Biology and Translational Aspects in CNS Tumors)
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12 pages, 2851 KiB  
Article
FASN Is a Biomarker Enriched in Malignant Glioma-Derived Extracellular Vesicles
by Franz L. Ricklefs, Cecile L. Maire, Jakob Matschke, Lasse Dührsen, Thomas Sauvigny, Mareike Holz, Katharina Kolbe, Sven Peine, Christel Herold-Mende, Bob Carter, E. Antonio Chiocca, Sean E. Lawler, Manfred Westphal and Katrin Lamszus
Int. J. Mol. Sci. 2020, 21(6), 1931; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21061931 - 12 Mar 2020
Cited by 20 | Viewed by 3150
Abstract
Extracellular vesicles (EVs) are known for their important role in cancer progression and hold considerable potential as a source for tumor biomarkers. However, purification of tumor-specific EVs from patient plasma is still an urgent unmet need due to contamination by normal host cell-derived [...] Read more.
Extracellular vesicles (EVs) are known for their important role in cancer progression and hold considerable potential as a source for tumor biomarkers. However, purification of tumor-specific EVs from patient plasma is still an urgent unmet need due to contamination by normal host cell-derived EVs, that results in compromised analytical sensitivity. Here we identified fatty acid synthase (FASN), a key lipogenic enzyme which is highly expressed in malignant glioma cells, to be elevated in CD63- and CD81-positive EVs in glioma patient plasma samples, opening vital opportunities to sort brain tumor-specific EVs. Full article
(This article belongs to the Special Issue Advances of Molecular Biology and Translational Aspects in CNS Tumors)
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13 pages, 3967 KiB  
Article
Replication Protein A (RPA) Mediates Radio-Resistance of Glioblastoma Cancer Stem-Like Cells
by Henriette Pedersen, Elisabeth Anne Adanma Obara, Kirstine Juul Elbæk, Kristoffer Vitting-Serup and Petra Hamerlik
Int. J. Mol. Sci. 2020, 21(5), 1588; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21051588 - 26 Feb 2020
Cited by 23 | Viewed by 3881
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)
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16 pages, 2137 KiB  
Article
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
by Claire L. Adams, Emanuela Ercolano, Sara Ferluga, Agbolahan Sofela, Foram Dave, Caterina Negroni, Kathreena M. Kurian, David A. Hilton and C. Oliver Hanemann
Int. J. Mol. Sci. 2020, 21(4), 1273; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041273 - 13 Feb 2020
Cited by 12 | Viewed by 3096
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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17 pages, 3536 KiB  
Article
Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells
by Linzhi Cai, Sabrina V. Kirchleitner, Dongxu Zhao, Min Li, Jörg-Christian Tonn, Rainer Glass and Roland E. Kälin
Int. J. Mol. Sci. 2020, 21(2), 612; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020612 - 17 Jan 2020
Cited by 27 | Viewed by 3890
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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24 pages, 4651 KiB  
Article
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 Response
by Prospero Civita, Diana M. Leite and Geoffrey J. Pilkington
Int. J. Mol. Sci. 2019, 20(23), 6017; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20236017 - 29 Nov 2019
Cited by 40 | Viewed by 6327
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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18 pages, 910 KiB  
Review
Blood–Brain Barrier in Brain Tumors: Biology and Clinical Relevance
by Francesca Mo, Alessia Pellerino, Riccardo Soffietti and Roberta Rudà
Int. J. Mol. Sci. 2021, 22(23), 12654; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312654 - 23 Nov 2021
Cited by 61 | Viewed by 5027
Abstract
The presence of barriers, such as the blood–brain barrier (BBB) and brain–tumor barrier (BTB), limits the penetration of antineoplastic drugs into the brain, resulting in poor response to treatments. Many techniques have been developed to overcome the presence of these barriers, including direct [...] Read more.
The presence of barriers, such as the blood–brain barrier (BBB) and brain–tumor barrier (BTB), limits the penetration of antineoplastic drugs into the brain, resulting in poor response to treatments. Many techniques have been developed to overcome the presence of these barriers, including direct injections of substances by intranasal or intrathecal routes, chemical modification of drugs or constituents of BBB, inhibition of efflux pumps, physical disruption of BBB by radiofrequency electromagnetic radiation (EMP), laser-induced thermal therapy (LITT), focused ultrasounds (FUS) combined with microbubbles and convection enhanced delivery (CED). However, most of these strategies have been tested only in preclinical models or in phase 1–2 trials, and none of them have been approved for treatment of brain tumors yet. Concerning the treatment of brain metastases, many molecules have been developed in the last years with a better penetration across BBB (new generation tyrosine kinase inhibitors like osimertinib for non-small-cell lung carcinoma and neratinib/tucatinib for breast cancer), resulting in better progression-free survival and overall survival compared to older molecules. Promising studies concerning neural stem cells, CAR-T (chimeric antigen receptors) strategies and immunotherapy with checkpoint inhibitors are ongoing. Full article
(This article belongs to the Special Issue Molecular Biology and Translational Aspects in CNS Tumors 2.0)
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19 pages, 654 KiB  
Review
Liquid Biomarkers for Improved Diagnosis and Classification of CNS Tumors
by Severa Bunda, Jeffrey A. Zuccato, Mathew R. Voisin, Justin Z. Wang, Farshad Nassiri, Vikas Patil, Sheila Mansouri and Gelareh Zadeh
Int. J. Mol. Sci. 2021, 22(9), 4548; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094548 - 27 Apr 2021
Cited by 21 | Viewed by 4068
Abstract
Liquid biopsy, as a non-invasive technique for cancer diagnosis, has emerged as a major step forward in conquering tumors. Current practice in diagnosis of central nervous system (CNS) tumors involves invasive acquisition of tumor biopsy upon detection of tumor on neuroimaging. Liquid biopsy [...] Read more.
Liquid biopsy, as a non-invasive technique for cancer diagnosis, has emerged as a major step forward in conquering tumors. Current practice in diagnosis of central nervous system (CNS) tumors involves invasive acquisition of tumor biopsy upon detection of tumor on neuroimaging. Liquid biopsy enables non-invasive, rapid, precise and, in particular, real-time cancer detection, prognosis and treatment monitoring, especially for CNS tumors. This approach can also uncover the heterogeneity of these tumors and will likely replace tissue biopsy in the future. Key components of liquid biopsy mainly include circulating tumor cells (CTC), circulating tumor nucleic acids (ctDNA, miRNA) and exosomes and samples can be obtained from the cerebrospinal fluid, plasma and serum of patients with CNS malignancies. This review covers current progress in application of liquid biopsies for diagnosis and monitoring of CNS malignancies. Full article
(This article belongs to the Special Issue Molecular Biology and Translational Aspects in CNS Tumors 2.0)
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35 pages, 3987 KiB  
Review
Advances in Research of Adult Gliomas
by Alina Finch, Georgios Solomou, Victoria Wykes, Ute Pohl, Chiara Bardella and Colin Watts
Int. J. Mol. Sci. 2021, 22(2), 924; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020924 - 18 Jan 2021
Cited by 29 | Viewed by 6700
Abstract
Diffuse gliomas are the most frequent brain tumours, representing 75% of all primary malignant brain tumours in adults. Because of their locally aggressive behaviour and the fact that they cannot be cured by current therapies, they represent one of the most devastating cancers. [...] Read more.
Diffuse gliomas are the most frequent brain tumours, representing 75% of all primary malignant brain tumours in adults. Because of their locally aggressive behaviour and the fact that they cannot be cured by current therapies, they represent one of the most devastating cancers. The present review summarises recent advances in our understanding of glioma development and progression by use of various in vitro and in vivo models, as well as more complex techniques including cultures of 3D organoids and organotypic slices. We discuss the progress that has been made in understanding glioma heterogeneity, alteration in gene expression and DNA methylation, as well as advances in various in silico models. Lastly current treatment options and future clinical trials, which aim to improve early diagnosis and disease monitoring, are also discussed. Full article
(This article belongs to the Special Issue Advances of Molecular Biology and Translational Aspects in CNS Tumors)
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18 pages, 499 KiB  
Review
Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance
by Sabbir Khan, Sandeep Mittal, Kain McGee, Kristin D. Alfaro-Munoz, Nazanin Majd, Veerakumar Balasubramaniyan and John F. de Groot
Int. J. Mol. Sci. 2020, 21(6), 1954; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21061954 - 13 Mar 2020
Cited by 57 | Viewed by 4528
Abstract
Recent efforts in brain tumor research have been directed towards the modulation of the immune system for therapeutic interventions. Several human cancers, including gliomas, are infiltrated with immune cell types—including neutrophils and myeloid-derived suppressor cells—that contribute to tumor progression, invasiveness, and treatment resistance. [...] Read more.
Recent efforts in brain tumor research have been directed towards the modulation of the immune system for therapeutic interventions. Several human cancers, including gliomas, are infiltrated with immune cell types—including neutrophils and myeloid-derived suppressor cells—that contribute to tumor progression, invasiveness, and treatment resistance. The role of tumor-associated neutrophils and myeloid-derived suppressor cells in cancer biology remains elusive, as these cells can exert a multitude of pro-tumor and antitumor effects. In this review, we provide the current understanding and novel insights on the role of neutrophils and myeloid-derived suppressor cells in glioma progression and treatment resistance, as well as the mechanisms of pleiotropic behaviors in these cells during disease progression, with an emphasis on possible strategies to reprogram these cells towards their antitumor actions. Full article
(This article belongs to the Special Issue Advances of Molecular Biology and Translational Aspects in CNS Tumors)
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21 pages, 1057 KiB  
Review
Tumor Cell Invasion in Glioblastoma
by Arabel Vollmann-Zwerenz, Verena Leidgens, Giancarlo Feliciello, Christoph A. Klein and Peter Hau
Int. J. Mol. Sci. 2020, 21(6), 1932; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21061932 - 12 Mar 2020
Cited by 147 | Viewed by 12563
Abstract
Glioblastoma (GBM) is a particularly devastating tumor with a median survival of about 16 months. Recent research has revealed novel insights into the outstanding heterogeneity of this type of brain cancer. However, all GBM subtypes share the hallmark feature of aggressive invasion into [...] Read more.
Glioblastoma (GBM) is a particularly devastating tumor with a median survival of about 16 months. Recent research has revealed novel insights into the outstanding heterogeneity of this type of brain cancer. However, all GBM subtypes share the hallmark feature of aggressive invasion into the surrounding tissue. Invasive glioblastoma cells escape surgery and focal therapies and thus represent a major obstacle for curative therapy. This review aims to provide a comprehensive understanding of glioma invasion mechanisms with respect to tumor-cell-intrinsic properties as well as cues provided by the microenvironment. We discuss genetic programs that may influence the dissemination and plasticity of GBM cells as well as their different invasion patterns. We also review how tumor cells shape their microenvironment and how, vice versa, components of the extracellular matrix and factors from non-neoplastic cells influence tumor cell motility. We further discuss different research platforms for modeling invasion. Finally, we highlight the importance of accounting for the complex interplay between tumor cell invasion and treatment resistance in glioblastoma when considering new therapeutic approaches. Full article
(This article belongs to the Special Issue Advances of Molecular Biology and Translational Aspects in CNS Tumors)
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18 pages, 1557 KiB  
Review
Integrin Signaling in Glioma Pathogenesis: From Biology to Therapy
by Aleksandra Ellert-Miklaszewska, Katarzyna Poleszak, Maria Pasierbinska and Bozena Kaminska
Int. J. Mol. Sci. 2020, 21(3), 888; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030888 - 30 Jan 2020
Cited by 79 | Viewed by 6076
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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13 pages, 983 KiB  
Review
Revealing and Harnessing Tumour-Associated Microglia/Macrophage Heterogeneity in Glioblastoma
by Yolanda Pires-Afonso, Simone P. Niclou and Alessandro Michelucci
Int. J. Mol. Sci. 2020, 21(3), 689; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030689 - 21 Jan 2020
Cited by 46 | Viewed by 6327
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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