Extracellular vesicle-mediated transfer of CLIC1 protein is a novel mechanism for the regulation of glioblastoma growth
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Matteo Setti1,*, Daniela Osti1,*, Cristina Richichi1, Barbara Ortensi1, Massimiliano Del Bene2, Lorenzo Fornasari1, Galina Beznoussenko3, Alexandre Mironov3, Germana Rappa1, Alessandro Cuomo1, Mario Faretta1, Tiziana Bonaldi1, Aurelio Lorico4, Giuliana Pelicci1,5
1Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
2Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
3Institute of Molecular Oncology (IFOM) of the Italian Foundation for Cancer Research (FIRC), Milan, Italy
4Cancer Research Center, Roseman University of Health Sciences with Roseman University College of Medicine, Las Vegas, NV, USA
5Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
*These authors have contributed equally to this work
Giuliana Pelicci, e-mail: firstname.lastname@example.org
Keywords: glioblastoma, cancer stem cells, extracellular vesicles, cell proliferation, tumor growth
Received: April 28, 2015 Accepted: September 18, 2015 Published: September 30, 2015
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 GBM-derived 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.
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