Extracellular vesicle-mediated transfer of CLIC1 protein is a novel mechanism for the regulation of glioblastoma growth
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// Matteo Setti 1, * , Daniela Osti 1, * , Cristina Richichi 1 , Barbara Ortensi 1 , Massimiliano Del Bene 2 , Lorenzo Fornasari 1 , Galina Beznoussenko 3 , Alexandre Mironov 3 , Germana Rappa 1 , Alessandro Cuomo 1 , Mario Faretta 1 , Tiziana Bonaldi 1 , Aurelio Lorico 4 , Giuliana Pelicci 1, 5 1 Department of Experimental Oncology, European Institute of Oncology, Milan, Italy 2 Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy 3 Institute of Molecular Oncology (IFOM) of the Italian Foundation for Cancer Research (FIRC), Milan, Italy 4 Cancer Research Center, Roseman University of Health Sciences with Roseman University College of Medicine, Las Vegas, NV, USA 5 Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy * These authors have contributed equally to this work Correspondence to: Giuliana Pelicci, e-mail: giuliana.pelicci@ieo.eu Keywords: glioblastoma, cancer stem cells, extracellular vesicles, cell proliferation, tumor growth Received: April 28, 2015 Accepted: September 18, 2015 Published: September 30, 2015 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.
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In GBM, communication between tumor cells and the microenvironment has a big impact on tumor progression.
“In GBM, similar to other cancer types, the communication between tumor cells and its microenvironment has a big impact on tumor progression; and hence it provided a new approach for cancer treatment (3, 4).”
From Potential Therapeutic Effects of Exosomes Packed With a miR-21-Sponge Construct in a Rat Model of Glioblastoma (2019) · cites this paper as [4]
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- Authors
- Setti, M., Osti, D., Richichi, C., Ortensi, B., Del Bene, M., Fornasari, L., Beznoussenko, G., Mironov, A., Rappa, G., Cuomo, A., Faretta, M., Bonaldi, T., Lorico, A., & Pelicci, G.
- Affiliations
- European Institute of Oncology (IT)
- Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- IFOM (IT)
- Roseman University of Health Sciences (US)
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- Corresponding author
- Setti, Matteo
- Osti, Daniela
- ORCID
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2015-09-30
- Volume
- 6
- Issue
- 31
- Pages
- 31413-31427
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC4741615
- OpenAlex
- W2213440919
- Cited by
- 93
- References
- 58
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 4 · 2023: 6 · 2022: 9 · 2021: 9 · 2020: 17 · 2019: 11 · 2018: 12 · 2017: 11 · 2016: 4
- FWCI
- 3.91
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Funders
- Università degli Studi di Milano
- Ministero della Salute
- Fondazione Umberto Veronesi
- Associazione Italiana per la Ricerca sul Cancro
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
- Keywords
- glioblastoma, CLIC1, extracellular vesicles, cancer stem cells, tumor growth, exosomes, microvesicles, protein transfer, cell proliferation, self-renewal, tumor microenvironment, circulating proteins, tumor progression markers, prognostic factors, therapeutic target, glioma stem cells, glioma-associated macrophages
- MeSH terms
- Extracellular Vesicles, Animals, Brain Neoplasms, Glioblastoma, Humans, Immunoenzyme Techniques, Mice, Nude, Tumor Cells, Cultured, Neoplastic Stem Cells, Blotting, Western, Apoptosis, Chloride Channels, Xenograft Model Antitumor Assays, Cell Proliferation, Mice, Nanoparticles, Exosomes
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