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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.

SUBMITTER: Setti M

PROVIDER: S-EPMC4741615 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Setti Matteo M Osti Daniela D Richichi Cristina C Ortensi Barbara B Del Bene Massimiliano M Fornasari Lorenzo L Beznoussenko Galina G Mironov Alexandre A Rappa Germana G Cuomo Alessandro A Faretta Mario M Bonaldi Tiziana T Lorico Aurelio A Pelicci Giuliana G

Oncotarget 20151001 31

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 viv ...[more]

PMID: 26429879

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Project description:The cellular dispersion and therapeutic control of glioblastoma, the most aggressive type of primary brain cancer, depends critically on the migration patterns after surgery and intracellular responses of the individual cancer cells in response to external biochemical cues in the microenvironment. Recent studies have shown that miR-451 regulates downstream molecules including AMPK/CAB39/MARK and mTOR to determine the balance between rapid proliferation and invasion in response to metabolic stress in the harsh tumor microenvironment. Surgical removal of the main tumor is inevitably followed by recurrence of the tumor due to inaccessibility of dispersed tumor cells in normal brain tissue. In order to address this complex process of cell proliferation and invasion and its response to conventional treatment, we propose a mathematical model that analyzes the intracellular dynamics of the miR-451-AMPK- mTOR-cell cycle signaling pathway within a cell. The model identifies a key mechanism underlying the molecular switches between proliferative phase and migratory phase in response to metabolic stress in response to fluctuating glucose levels. We show how up- or down-regulation of components in these pathways affects the key cellular decision to infiltrate or proliferate in a complex microenvironment in the absence and presence of time delays and stochastic noise. Glycosylated chondroitin sulfate proteoglycans (CSPGs), a major component of the extracellular matrix (ECM) in the brain, contribute to the physical structure of the local brain microenvironment but also induce or inhibit glioma invasion by regulating the dynamics of the CSPG receptor LAR as well as the spatiotemporal activation status of resident astrocytes and tumor-associated microglia. Using a multi-scale mathematical model, we investigate a CSPG-induced switch between invasive and non-invasive tumors through the coordination of ECM-cell adhesion and dynamic changes in stromal cells. We show that the CSPG-rich microenvironment is associated with non-invasive tumor lesions through LAR-CSGAG binding while the absence of glycosylated CSPGs induce the critical glioma invasion. We illustrate how high molecular weight CSPGs can regulate the exodus of local reactive astrocytes from the main tumor lesion, leading to encapsulation of non-invasive tumor and inhibition of tumor invasion. These different CSPG conditions also change the spatial profiles of ramified and activated microglia. The complex distribution of CSPGs in the tumor microenvironment can determine the nonlinear invasion behaviors of glioma cells, which suggests the need for careful therapeutic strategies.

Dataset Information

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

Publications

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

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