title: Glioblastoma-derived extracellular vesicles modify the phenotype of monocytic cells.
abstract: Glioblastoma multiforme (GBM) is the most common primary brain tumor and is without exception lethal. GBMs modify the immune system, which contributes to the aggressive nature of the disease. Particularly, cells of the monocytic lineage, including monocytes, macrophages and microglia, are affected. We investigated the influence of GBM-derived extracellular vesicles (EVs) on the phenotype of monocytic cells. Proteomic profiling showed GBM EVs to be enriched with proteins functioning in extracellular matrix interaction and leukocyte migration. GBM EVs appeared to skew the differentiation of peripheral blood-derived monocytes to alternatively activated/M2-type macrophages. This was observed for EVs from an established cell line, as well as for EVs from primary cultures of GBM stem-like cells (GSCs). Unlike EVs of non-GBM origin, GBM EVs induced modified expression of cell surface proteins, modified cytokine secretion (e.g., an increase in vascular endothelial growth factor and IL-6) and increased phagocytic capacity of the macrophages. Most pronounced effects were observed upon incubation with EVs from mesenchymal GSCs. GSC EVs also affected primary human microglia, resulting in increased expression of Membrane type 1-matrix metalloproteinase, a marker for GBM microglia and functioning as tumor-supportive factor. In conclusion, GBM-derived EVs can modify cells of the monocytic lineage, which acquire characteristics that resemble the tumor-supportive phenotypes observed in patients.
authors: Department of Neurosurgery, Brain Center Rudolf Magnus Institute of Neurosciences, University Medical Center, Utrecht, The Netherlands.
authors: Jeroen
authors: J
authors: de Vrij
authors: Department of Neurosurgery, Brain Center Rudolf Magnus Institute of Neurosciences, University Medical Center, Utrecht, The Netherlands.
authors: S L Niek
authors: SL
authors: Maas
authors: Department of Pediatrics, Leiden University Medical Center, The Netherlands.
authors: Kitty M C
authors: KM
authors: Kwappenberg
authors: Department of Neurosurgery, Brain Center Rudolf Magnus Institute of Neurosciences, University Medical Center, Utrecht, The Netherlands.
authors: Rosalie
authors: R
authors: Schnoor
authors: Department of Neurosurgery, Brain Tumor Center, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Anne
authors: A
authors: Kleijn
authors: Department of Neurology, Brain Tumor Center, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Lennard
authors: L
authors: Dekker
authors: Department of Neurology, Brain Tumor Center, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Theo M
authors: TM
authors: Luider
authors: Department of Translational Neuroscience, Brain Center Rudolf Magnus Institute of Neurosciences, University Medical Center, Utrecht, The Netherlands.|Department of Psychiatry, University Medical Center, Utrecht, The Netherlands.
authors: Lot D
authors: LD
authors: de Witte
authors: Department of Translational Neuroscience, Brain Center Rudolf Magnus Institute of Neurosciences, University Medical Center, Utrecht, The Netherlands.
authors: Manja
authors: M
authors: Litjens
authors: Department of Translational Neuroscience, Brain Center Rudolf Magnus Institute of Neurosciences, University Medical Center, Utrecht, The Netherlands.
authors: Miriam E
authors: ME
authors: van Strien
authors: Department of Translational Neuroscience, Brain Center Rudolf Magnus Institute of Neurosciences, University Medical Center, Utrecht, The Netherlands.|Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands.|Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, The Netherlands.
authors: Elly M
authors: EM
authors: Hol
authors: Department of Neurosurgery, Brain Center Rudolf Magnus Institute of Neurosciences, University Medical Center, Utrecht, The Netherlands.
authors: Jerome
authors: J
authors: Kroonen
authors: Department of Neurosurgery, Brain Center Rudolf Magnus Institute of Neurosciences, University Medical Center, Utrecht, The Netherlands.
authors: Pierre A
authors: PA
authors: Robe
authors: Department of Neurosurgery, Brain Tumor Center, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Martine L
authors: ML
authors: Lamfers
authors: Department of Pediatrics, Leiden University Medical Center, The Netherlands.
authors: Marco W
authors: MW
authors: Schilham
authors: Department of Neurosurgery, Brain Center Rudolf Magnus Institute of Neurosciences, University Medical Center, Utrecht, The Netherlands.
authors: Marike L D
authors: ML
authors: Broekman
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D055354:Exosomes / Q000378:metabolism / Q000473:pathology; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D010641:Phenotype
keywords: exosome; extracellular vesicle; glioblastoma; macrophage; microglia; microvesicle; monocyte