title: Extracellular vesicle-mediated transfer of CLIC1 protein is a novel mechanism for the regulation of glioblastoma growth.
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 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.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Setti
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Osti
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Richichi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ortensi
authors.affiliation: Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Del Bene
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Fornasari
authors.affiliation: Institute of Molecular Oncology (IFOM) of The Italian Foundation for Cancer Research (FIRC), Milan, Italy.
authors.forename: Galina
authors.initials: G
authors.lastname: Beznoussenko
authors.affiliation: Institute of Molecular Oncology (IFOM) of The Italian Foundation for Cancer Research (FIRC), Milan, Italy.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mironov
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Germana
authors.initials: G
authors.lastname: Rappa
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cuomo
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Faretta
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Bonaldi
authors.affiliation: Cancer Research Center, Roseman University of Health Sciences with Roseman University College of Medicine, Las Vegas, NV, USA.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Lorico
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.|Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Pelicci
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D018118:Chloride Channels / Q000378:metabolism*; D055354:Exosomes / Q000378:metabolism / Q000473:pathology*; D000067128:Extracellular Vesicles / Q000378:metabolism / Q000473:pathology*; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C501966:CLIC1 protein, human; D018118:Chloride Channels
keywords: cancer stem cells; cell proliferation; extracellular vesicles; glioblastoma; tumor growth