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Cancer Res. 2014 Feb 1;74(3):738-750. doi: 10.1158/0008-5472.CAN-13-2650. Epub 2013 Dec 5.

Extracellular vesicles modulate the glioblastoma microenvironment via a tumor suppression signaling network directed by miR-1.

Author information

1
Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
2
Department of Molecular and Cellular Biochemistry, the Ohio State University Medical Center, Columbus, OH 43210, USA.
3
Department of Neurological Surgery, the Ohio State University Medical Center, Columbus, OH 43210, USA.
4
Neuroscience Center at Massachusetts General Hospital, Charlestown, MA 02129.
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Contributed equally

Abstract

Extracellular vesicles have emerged as important mediators of intercellular communication in cancer, including by conveying tumor-promoting microRNAs between cells, but their regulation is poorly understood. In this study, we report the findings of a comparative microRNA profiling and functional analysis in human glioblastoma that identifies miR-1 as an orchestrator of extracellular vesicle function and glioblastoma growth and invasion. Ectopic expression of miR-1 in glioblastoma cells blocked in vivo growth, neovascularization, and invasiveness. These effects were associated with a role for miR-1 in intercellular communication in the microenvironment mediated by extracellular vesicles released by cancer stem-like glioblastoma cells. An extracellular vesicle-dependent phenotype defined by glioblastoma invasion, neurosphere growth, and endothelial tube formation was mitigated by loading miR-1 into glioblastoma-derived extracellular vesicles. Protein cargo in extracellular vesicles was characterized to learn how miR-1 directed extracellular vesicle function. The mRNA encoding Annexin A2 (ANXA2), one of the most abundant proteins in glioblastoma-derived extracellular vesicles, was found to be a direct target of miR-1 control. In addition, extracellular vesicle-derived miR-1 along with other ANXA2 extracellular vesicle networking partners targeted multiple pro-oncogenic signals in cells within the glioblastoma microenvironment. Together, our results showed how extracellular vesicle signaling promotes the malignant character of glioblastoma and how ectopic expression of miR-1 can mitigate this character, with possible implications for how to develop a unique miRNA-based therapy for glioblastoma management.

PMID:
24310399
PMCID:
PMC3928601
DOI:
10.1158/0008-5472.CAN-13-2650
[Indexed for MEDLINE]
Free PMC Article

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