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Cited by 315Extracellular vesicles in diseaseGlioma Diagnosis and TreatmentNeuroinflammation and Neurodegeneration Mechanisms

Directly visualized glioblastoma-derived extracellular vesicles transfer RNA to microglia/macrophages in the brain

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van der Vos, Kristan E., Abels, Erik R., Zhang, Xuan, Lai, Charles, Carrizosa, Esteban, Oakley, Derek, Prabhakar, Shilpa, Mardini, Osama +8 more·2016·Neuro-Oncology
DOI 10.1093/neuonc/nov244PMC PMC4677420
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Abstract

BACKGROUND: To understand the ability of gliomas to manipulate their microenvironment, we visualized the transfer of vesicles and the effects of tumor-released extracellular RNA on the phenotype of microglia in culture and in vivo. METHODS: Extracellular vesicles (EVs) released from primary human glioblastoma (GBM) cells were isolated and microRNAs (miRNAs) were analyzed. Primary mouse microglia were exposed to GBM-EVs, and their uptake and effect on proliferation and levels of specific miRNAs, mRNAs, and proteins were analyzed. For in vivo analysis, mouse glioma cells were implanted in the brains of mice, and EV release and uptake by microglia and monocytes/macrophages were monitored by intravital 2-photon microscopy, immunohistochemistry, and fluorescence activated cell sorting analysis, as well as RNA and protein levels. RESULTS: Microglia avidly took up GBM-EVs, leading to increased proliferation and shifting of their cytokine profile toward immune suppression. High levels of miR-451/miR-21 in GBM-EVs were transferred to microglia with a decrease in the miR-451/miR-21 target c-Myc mRNA. In in vivo analysis, we directly visualized release of EVs from glioma cells and their uptake by microglia and monocytes/macrophages in brain. Dissociated microglia and monocytes/macrophages from tumor-bearing brains revealed increased levels of miR-21 and reduced levels of c-Myc mRNA. CONCLUSIONS: Intravital microscopy confirms the release of EVs from gliomas and their uptake into microglia and monocytes/macrophages within the brain. Our studies also support functional effects of GBM-released EVs following uptake into microglia, associated in part with increased miRNA levels, decreased target mRNAs, and encoded proteins, presumably as a means for the tumor to manipulate its environs.

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  • The presence of GFP in microglia indicates tumor-derived EV uptake.

    “The presence of GFP in microglia thus indicates tumor-derived EV uptake (Figure 2C).”

    From Glioblastoma-Associated Microglia Reprogramming Is Mediated by Functional Transfer of Extracellular miR-21 (2019) · cites this paper as van der Vos et al., 2016

    In the in vivo uptake section (Figs. 5–6), GFP labels microglia and monocyte-derived macrophages, while tumor-derived EVs carry a red fluorescent label. The paper identifies red puncta within GFP-positive cells—not GFP in microglia alone—as evidence of EV uptake. (LLM, conf=0.90)

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Authors
van der Vos, K. E., Abels, E. R., Zhang, X., Lai, C., Carrizosa, E., Oakley, D., Prabhakar, S., Mardini, O., Crommentuijn, M. H. W., Skog, J., Krichevsky, A. M., Stemmer-Rachamimov, A., Mempel, T. R., El Khoury, J., Hickman, S. E., & Breakefield, X. O.
Affiliations
Brigham and Women's Hospital (US)
ORCID
Venue
Neuro-Oncology
Publisher
Oxford University Press (OUP)
Published
2015-10-03
Volume
18
Issue
1
Pages
58-69
ISSN
  • 1522-8517 (ISSN-L)
  • 1523-5866
DOI
10.1093/neuonc/nov244
PMC
PMC4677420
OpenAlex
W2175100525
Cited by
315
References
4
Citations by year
2026: 14 · 2025: 16 · 2024: 34 · 2023: 25 · 2022: 34 · 2021: 40 · 2020: 51 · 2019: 34 · 2018: 32 · 2017: 23 · 2016: 11 · 2015: 1
FWCI
9.70
Type
journal article
Language
en
Open access
Locations
  • Neuro-Oncology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
  • Dutch Scientific Organisation (NWO-Rubicon) (U19 CA179563)
  • NIH (P30, NS045776)
  • through the Office of Strategic Coordination/Office
  • NCI (P01 CA069246, R01 CA150975, CA179563)
  • Voices Against Brain Cancer
  • Richard Floor Biorepository Fund
  • Canadian Institute of Health Research
  • NINDS/NIA (R01 NS059005, U24 AI082660)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
glioblastoma, extracellular vesicles, extracellular RNA, microglia, macrophages, microRNA transfer, miR-21, miR-451, c-Myc, tumor microenvironment, intravital microscopy, vesicle uptake, immunosuppression, tumor-associated macrophages
MeSH terms
Extracellular Vesicles, Animals, Brain, Brain Neoplasms, Glioblastoma, Humans, Macrophages, Mice, Inbred C57BL, RNA, Messenger, Tumor Cells, Cultured, Proto-Oncogene Proteins c-myc, Microglia, MicroRNAs, Microscopy, Fluorescence, Multiphoton, Cell Line, Tumor, Mice

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