Extracellular vesicle-mediated transfer of CLIC1 protein is a novel mechanism for the regulation of glioblastoma growth

Matteo Setti, Daniela Osti, Cristina Richichi, Barbara Ortensi, Massimiliano Del Bene, Lorenzo Fornasari, Galina Beznoussenko, Alexandre Mironov, Germana Rappa, Alessandro Cuomo, Mario Faretta, Tiziana Bonaldi, Aurelio Lorico, Giuliana Pelicci

Research output: Contribution to journalArticle

Abstract

Little progresses have been made in the treatment of glioblastoma (GBM), the most aggressive and lethal among brain tumors. Recently we have demonstrated that Chloride Intracellular Channel-1 (CLIC1) is overexpressed in GBM compared to normal tissues, with highest expression in patients with poor prognosis. Moreover, CLIC1- silencing in cancer stem cells (CSCs) isolated from human GBM patients negatively influences proliferative capacity and self-renewal properties in vitro and impairs the in vivo tumorigenic potential. Here we show that CLIC1 exists also as a circulating protein, secreted via extracellular vesicles (EVs) released by either cell lines or GBMderived CSCs. Extracellular vesicles (EVs), comprising exosomes and microvesicles based on their composition and biophysical properties, have been shown to sustain tumor growth in a variety of model systems, including GBM. Interestingly, treatment of GBM cells with CLIC1-containing EVs stimulates cell growth both in vitro and in vivo in a CLIC1-dose dependent manner. EVs derived from CLIC1-overexpressing GBM cells are strong inducers of proliferation in vitro and tumor engraftment in vivo. These stimulations are significantly attenuated by treatment of GBM cells with EVs derived from CLIC1-silenced cells. However, CLIC1 modulation appears to have no direct role in EV structure, biogenesis and secretion. These findings reveal that, apart from the function of CLIC1 cellular reservoir, CLIC1 contained in EVs is a novel regulator of GBM growth.

Original languageEnglish
Pages (from-to)31413-31427
Number of pages15
JournalOncotarget
Volume6
Issue number31
DOIs
Publication statusPublished - 2015

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Keywords

  • Cancer stem cells
  • Cell proliferation
  • Extracellular vesicles
  • Glioblastoma
  • Tumor growth

ASJC Scopus subject areas

  • Oncology

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