Extracellular Vesicles Modulate the Glioblastoma Microenvironment via a Tumor Suppression Signaling Network Directed by miR-1

Abstract

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.

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

“…These particles can move freely through the extracellular medium and interact with different cell types by as yet undetermined mechanisms [199]. MVs carry and may shuttle specific proteins and noncoding nucleic acids such as microRNAs [200]. In fact, some miRNA may be found in MVs at higher concentrations than in cells [201].…”

miR-663 Suppresses Oncogenic Function of CXCR4 in Glioblastoma

“…Recent studies emphasized that manipulation of miRNAs and their oligonucleotide antagonists, including miRNA-based nanodrugs, miRNA mimics, miRNA sponge and miR-mask, represents an attractive approach for antitumor therapy (12,13). In the GBM model, miRNAs could modulate pivotal protein expressions in the signaling cascades, thus, regulate tumor malignant behaviors (14)(15)(16). We propose that by overlapping the datasets of predictive miRNAs targeting CXCR4 and the miRNA profiling between GBM tissues and adjacent normal tissues, we could identify the tumor-specific miRNAs regulating CXCR4 expression in GBMs and offer new miRNA candidates for anti-GBM strategies.…”

Multiplexed Nanomedicine for Brain Tumors: Nanosized Hercules to Tame Our Lernaean Hydra inside?

“…The formulation of nano vehicles for RNAi is critical for the clinical success. Early efforts focused on dendrimer inspired nano constructs and solid nanoparticles (NPs), followed by the biomimetic development of tumor derived exosome-based experimental therapeutics for brain delivery [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. The engineering potential of cell type selectivity for these vehicles is limited.…”