Extracellular vesicle-mediated transfer of CLIC1 protein is a novel mechanism for the regulation of glioblastoma growth.
Extracellular vesicle-mediated transfer of CLIC1 protein is a novel mechanism for the regulation of glioblastoma growth.
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DOI：
10.18632/oncotarget.5105
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发表时间：
2015-10-13
期刊：
影响因子：
--
通讯作者：
Pelicci G
中科院分区：
文献类型：
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作者：
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
胶质母细胞瘤（GBM）是脑肿瘤中最具侵袭性和致命性的肿瘤，其治疗进展甚微。最近，我们已经证明，与正常组织相比，细胞内氯离子通道-1（CLIC 1）在GBM中过表达，在预后不良的患者中表达最高。此外，从人GBM患者分离的癌症干细胞（CSC）中的CLIC 1沉默在体外负面影响增殖能力和自我更新性质，并损害体内致瘤潜力。在这里，我们表明CLIC 1也作为循环蛋白存在，通过细胞系或GBM衍生的CSC释放的细胞外囊泡（EV）分泌。细胞外囊泡（EV），包括基于其组成和生物物理性质的外泌体和微囊泡，已显示在多种模型系统（包括GBM）中维持肿瘤生长。有趣的是，用含有CLIC 1的EV处理GBM细胞以CLIC 1剂量依赖性方式在体外和体内刺激细胞生长。源自CLIC 1过表达GBM细胞的EV是体外增殖和体内肿瘤植入的强诱导剂。这些刺激通过用源自CLIC 1沉默细胞的EV处理GBM细胞而显著减弱。然而，CLIC 1调制似乎没有直接的作用，EV结构，生物发生和分泌。这些发现表明，除了CLIC 1细胞库的功能外，EV中含有的CLIC 1是GBM生长的新调节剂。
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.