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13 pages, 1520 KiB

Open AccessArticle

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://doi.org/10.3390/ijms21207801 - 21 Oct 2020

Cited by 7 | Viewed by 3215

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

Open AccessArticle

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://doi.org/10.3390/ijms21114179 - 11 Jun 2020

Cited by 22 | Viewed by 3620

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

Open AccessArticle

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://doi.org/10.3390/ijms21082959 - 22 Apr 2020

Cited by 15 | Viewed by 3266

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

Open AccessArticle

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://doi.org/10.3390/ijms21061931 - 12 Mar 2020

Cited by 20 | Viewed by 3178

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

Open AccessArticle

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://doi.org/10.3390/ijms21051588 - 26 Feb 2020

Cited by 23 | Viewed by 3915

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

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

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://doi.org/10.3390/ijms21041273 - 13 Feb 2020

Cited by 12 | Viewed by 3124

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

Open AccessArticle

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://doi.org/10.3390/ijms21020612 - 17 Jan 2020

Cited by 27 | Viewed by 3940

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) IDH^WT compared to IDH mutant (IDH^MUT) 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

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 Response

by Prospero Civita, Diana M. Leite and Geoffrey J. Pilkington

Int. J. Mol. Sci. 2019, 20(23), 6017; https://doi.org/10.3390/ijms20236017 - 29 Nov 2019

Cited by 40 | Viewed by 6492

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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35 pages, 3987 KiB

Open AccessReview

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://doi.org/10.3390/ijms22020924 - 18 Jan 2021

Cited by 29 | Viewed by 6783

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

Open AccessReview

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://doi.org/10.3390/ijms21061954 - 13 Mar 2020

Cited by 57 | Viewed by 4699

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

Open AccessReview

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://doi.org/10.3390/ijms21061932 - 12 Mar 2020

Cited by 147 | Viewed by 12657

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

Open AccessReview

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://doi.org/10.3390/ijms21030888 - 30 Jan 2020

Cited by 79 | Viewed by 6131

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

Open AccessReview

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://doi.org/10.3390/ijms21030689 - 21 Jan 2020

Cited by 46 | Viewed by 6371

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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