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

Cancer Research

PubMedID: 24310399

Bronisz A, Wang Y, Nowicki MO, Peruzzi P, Ansari KI, Ogawa D, Balaj L, De Rienzo G, Mineo M, Nakano I, Ostrowski MC, Hochberg F, Weissleder R, Lawler SE, Chiocca EA, Godlewski J. Extracellular vesicles modulate the glioblastoma microenvironment via a tumor suppression signaling network directed by miR-1. Cancer Res. 2014;74(3):738-50.
Extracellular vesicles (EVs) 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 (GBM) that identifies miR-1 as an orchestrator of EV function and GBM growth and invasion. Ectopic expression of miR-1 in GBM 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 EVs released by cancer stem-like GBM cells. An EV-dependent phenotype defined by GBM invasion, neurosphere growth and endothelial tube formation was mitigated by loading miR-1 into GBM-derived EVs. Protein cargo in EVs was characterized to learn how miR-1 directed EV function. The mRNA encoding Annexin A2 (ANXA2), one of the most abundant proteins in GBM-derived EVs, was found to be a direct target of miR-1 control. In addition, EV-derived miR-1 along with other ANXA2 EV networking partners targeted multiple pro-oncogenic signals in cells within the GBM microenvironment. Together, our results showed how EV signalling promotes the malignant character of GBM and how ectopic expression of miR-1 can mitigate this character, with possible implications for how to develop a unique miRNA-based therapy for GBM management.