Tumour-derived CSF2/granulocyte macrophage colony stimulating factor controls myeloid cell accumulation and progression of gliomas
Open Access
- 4 August 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 123 (3), 438-448
- https://doi.org/10.1038/s41416-020-0862-2
Abstract
Background Malignant tumours release factors, which attract myeloid cells and induce their polarisation to pro-invasive, immunosuppressive phenotypes. Brain-resident microglia and peripheral macrophages accumulate in the tumour microenvironment of glioblastoma (GBM) and induce immunosuppression fostering tumour progression. Macrophage colony stimulating factors (CSFs) control the recruitment of myeloid cells during peripheral cancer progression, but it is disputable, which CSFs drive their accumulation in gliomas. Methods The expression of CSF2 (encoding granulocyte-macrophage colony stimulating factor) was determined in TCGA datasets and five human glioma cell lines. Effects of stable CSF2 knockdown in glioma cells or neutralising CSF2 or receptor CSF2R alpha antibodies on glioma invasion were tested in vitro and in vivo. Results CSF2 knockdown or blockade of its signalling reduced microglia-dependent glioma invasion in microglia-glioma co-cultures. CSF2-deficient human glioma cells encapsulated in cell-impermeable hollow fibres and transplanted to mouse brains, failed to attract microglia, but stimulated astrocyte recruitment. CSF2-depleted gliomas were smaller, attracted less microglia and macrophages, and provided survival benefit in tumour-bearing mice. Apoptotic microglia/macrophages were detected in CSF2-depleted tumours. Conclusions CSF2 is overexpressed in a subset of mesenchymal GBMs in association with high immune gene expression. Tumour-derived CSF2 attracts, supports survival and induces pro-tumorigenic polarisation of microglia and macrophages.Funding Information
- Narodowe Centrum Nauki (2011/03/N/NZ1/03156, 2014/15/B/NZ3/04704)
This publication has 52 references indexed in Scilit:
- Defining GM-CSF– and Macrophage-CSF–Dependent Macrophage Responses by In Vitro ModelsThe Journal of Immunology, 2012
- The GM-CSF receptor utilizes β-catenin and Tcf4 to specify macrophage lineage differentiationDifferentiation, 2012
- Characteristics of the Alternative Phenotype of Microglia/Macrophages and its Modulation in Experimental GliomasPLOS ONE, 2011
- GM-CSF Production by Glioblastoma Cells Has a Functional Role in Eosinophil Survival, Activation, and Growth Factor Production for Enhanced Tumor Cell ProliferationThe Journal of Immunology, 2011
- Krüppel-like factor 4 regulates macrophage polarizationJCI Insight, 2011
- Microglia/macrophages promote glioma progressionGlia, 2010
- Macrophage Diversity Enhances Tumor Progression and MetastasisCell, 2010
- Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1Cancer Cell, 2010
- The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in diseaseBlood, 2009
- Gliomas induce and exploit microglial MT1-MMP expression for tumor expansionProceedings of the National Academy of Sciences of the United States of America, 2009