Membrane vesicles shed by oligodendroglioma cells induce neuronal apoptosis

D’Agostino, Stefania; Salamone, Monica; Liegro, Italia Di; Vittorelli, Maria Letizia

doi:10.3892/ijo.29.5.1075

Cited by 24 publications

(44 citation statements)

References 69 publications

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“…Tumor cells of glial origin were recently shown to release extracellular vesicles that contain the FAS ligand and induce apoptosis in rat cortical neurons in culture (12). We also found that neurons themselves can shed large extracellular vesicles that contain angiogenic factors such as FGF-2 and VEGF (13).…”

Section: Resultsmentioning

confidence: 61%

“…As it has been recently found that some glial tumor cells (oligodendroglioma cells) (12) as well as primary neurons in culture (13) are able to release extracellular vesicles, we investigated the possibility that astrocytes can do the same. We found that indeed astrocytes produce extracellular structures that contain FGF-2 and VEGF, together with ß1-integrin, a membrane protein reported by other authors (see, for example: 14) to be a component of a heterogeneous population of large extracellular vesicles, ranging in size from 100-1000 nm called microvesicles (MVs).…”

Section: Introductionmentioning

confidence: 99%

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Astrocytes shed extracellular vesicles that contain fibroblast growth factor-2 and vascular endothelial growth factor

Proia

Schiera²,

Mineo³

et al. 2008

Int J Mol Med

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Abstract. We previously set a three-cell-type coculture system in which neurons and astrocytes synergistically induce brain capillary endothelial cells to form a monolayer with permeability properties resembling those of the physiological blood-brain barrier. Moreover, we recently found that neurons produce fibroblast growth factor-2 and vascular endothelial growth factor and secrete them at least in part by shedding extracellular vesicles. In this study, on the basis of immunofluorescence, scanner electron microscopy and Western blot analyses, we concluded that also astrocytes in culture shed extracellular vesicles that contain the same angiogenic factors, as well as ß1-integrin, a membrane protein that is considered a marker of shedding. Vesicles released by astrocytes are smaller than the ones produced by neurons and have an average size of 150-500 nm. IntroductionWe previously found that neurons and astrocytes cooperate in controlling occludin expression and permeability in brain capillary endothelial cells (BCECs), in a three-cell-type in vitro model of the blood-brain barrier (BBB) (1-3). Since in this culture system physical contacts among the different cell types are not allowed, it is likely that neurons and astrocytes affect endothelial cells by releasing soluble factors. In support of this hypothesis it should be noted that other authors have reported that, in vivo, astrocytes not only form direct contacts with BCECs through astrocyte feet but also release soluble factors, such as basic fibroblast growth factor (bFGF or FGF-2) and vascular endothelial growth factor (VEGF) (4), which find receptors on BCECs. FGF-2 is a protein that lacks a standard signal sequence and cannot be sorted to the endoplasmic reticulum (5). It has been reported to be secreted by tumor cells through an unusual way, which involves shedding of extracellular vesicles from the plasma membrane (5). FGF-2 is a potent inducer of blood vessel formation (angiogenesis), with a fundamental role in the development and differentiation of various tissues (6,7), including the nervous system (7). In addition to a main polypeptide of 18 kDa, other FGF-2 isoforms have been described, ranging in size from 22 to 34 kDa (7).VEGF, another factor with well-known actions on endothelial cells, has also been reported to be associated with extracellular vesicles released by tumor cells (5,8). VEGF exists as a homodimer of isoforms of different sizes (i.e. 121, 145, 165, 189, 206), derived from alternative splicing of the same primary transcript (9). In addition to these smaller forms, a larger isoform, with an N-terminal extension of 200 amino acids and an apparent mass of 45 kDa has been described in the human and the mouse (10,11).As it has been recently found that some glial tumor cells (oligodendroglioma cells) (12) as well as primary neurons in culture (13) are able to release extracellular vesicles, we investigated the possibility that astrocytes can do the same. We found that indeed astrocytes produce extracellular structures that contain FGF-2...

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Section: Resultsmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Astrocytes shed extracellular vesicles that contain fibroblast growth factor-2 and vascular endothelial growth factor

Proia

Schiera²,

Mineo³

et al. 2008

Int J Mol Med

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“…Previous studies on oligodendroglioma cell cultures revealed that these cells shed MVs which inhibited neurite sprouting and caused apoptosis to primary fetal rat neurons, after 48-72 h of incubation (10). Proapoptotic effects of vesicles on neurons were dose-dependent and were induced also when concentrations of tumor-derived vesicles were similar to those probably occurring in vivo, when an oligodendroglioma tumor is growing inside the central nervous system (CNS).…”

Section: Introductionmentioning

confidence: 85%

“…This effect has been primarily attributed to compression on surrounding brain cells, caused by the increasing size of the tumor. More recently, it was suggested that G26/24 oligodendroglioma cells can actively induce neuronal damage by releasing molecules able to inhibit neurite sprouting and to eventually cause neuronal death (10). Interestingly, such molecules seem to be released through an unusual route involving shedding of extracellular membrane microvesicles (10).…”

Section: Discussionmentioning

confidence: 99%

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Oligodendroglioma cells shed microvesicles which contain TRAIL as well as molecular chaperones and induce cell death in astrocytes

Cicero

Schiera²,

Proia³

et al. 2011

Int J Oncol

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Abstract. Microvesicles (MVs) shed from G26/24 oligodendroglioma cells were previously reported to cause a reproducible, dose-dependent, inhibitory effect on neurite outgrowth, and eventually neuronal apoptosis, when added to primary cultures of rat cortical neurons. These effects were reduced but not abolished by functional monoclonal antibodies against Fas-L. In order to investigate whether MVs contain other factors able to induce cell death, we tested them for TRAIL and found clear evidence of its presence in the vesicles. This finding suggests the possibility that Fas-L and TRAIL cooperate in inducing brain cell death. Aimed at understanding the route through which the vesicles deliver their messages to the target cells, we labeled oligodendroglioma cells with radioactive methionine and then added the labeled vesicles shed from tumor cells to unlabeled astrocytes in culture. Here we report that labeled proteins were delivered to the test cells. In order to investigate whether astrocytes, like neurons, are sensitive to oligodendroglioma-derived vesicles, MVs were prepared from media conditioned by G26/24 oligodendroglioma cells and added to primary cultures of rat cortical astrocytes. These cells were clearly more resistant than neurons to microvesicle-induced damage: a high dose (40 µg) of shed MVs induced cell death in only about 40% of astrocytes. Finally, we demonstrated that Hsp70 is specifically enriched in MVs which also contain, even if at lower level, the Hsc70 constitutive chaperone. IntroductionA peculiar route for cell-to-cell communication could be mediated by extracellular membrane vesicles. Two distinct types of signaling vesicles have been identified up to now: i) vesicles with a diameter of 30-100 nm, known as exosomes, released from the cell by exocytosis of multivesicular bodies (MVBs), intracellular organelles of the endosomal system; ii) small vesicles, called shed vesicles (SVs), 100 nm -1 µm in diameter, released into the extracellular space by direct budding from the plasma membrane. Mixed vesicle populations, containing both shedding vesicles and exosomes, will be referred to as microvesicles (MVs) (1,2).Upon release, both types of microvesicles circulate in the extracellular space adjacent to the site of discharge where they can be broken down, often within a few minutes. Some of them, however, can move some distance by diffusion and can appear in biological fluids, such as cerebrospinal fluid, blood and urine. In some cases microvesicles deliver transmembrane signals which activate surface receptors (3); in other cases they function not only as messengers, but also as platforms necessary for the coordinate development of multisignaling processes (4). Being membrane-bound structures, microvesicles can fuse with their target cells. Because of these properties, MVs, which seem to be enriched in specific proteins and mRNAs (5), have been suggested to function in signaling as well as in the horizontal transfer of their membrane and/or cargo molecules (6).Different neural cells release MV...

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Membrane vesicles containing matrix metalloproteinase‐9 and fibroblast growth factor‐2 are released into the extracellular space from mouse mesoangioblast stem cells

Candela

Geraci

Turturici

et al. 2010

Journal Cellular Physiology

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Certain proteins, including fibroblast growth factor-2 (FGF-2) and matrix metalloproteinase-9 (MMP-9), have proved very effective in increasing the efficacy of mesoangioblast stem cell therapy in repairing damaged tissue. We provide the first evidence that mouse mesoangioblast stem cells release FGF-2 and MMP-9 in their active form through the production of membrane vesicles. These vesicles are produced and turned over continuously, but are stable for some time in the extracellular milieu. Mesoangioblasts shed membrane vesicles even under oxygen tensions that are lower than those typically used for cell culture and more like those of mouse tissues. These findings suggest that mesoangioblasts may themselves secrete paracrine signals and factors that make damaged tissues more amenable to cell therapy through the release of membrane vesicles.

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Membrane vesicles shed by oligodendroglioma cells induce neuronal apoptosis

Cited by 24 publications

References 69 publications

Astrocytes shed extracellular vesicles that contain fibroblast growth factor-2 and vascular endothelial growth factor

Astrocytes shed extracellular vesicles that contain fibroblast growth factor-2 and vascular endothelial growth factor

Oligodendroglioma cells shed microvesicles which contain TRAIL as well as molecular chaperones and induce cell death in astrocytes

Membrane vesicles containing matrix metalloproteinase‐9 and fibroblast growth factor‐2 are released into the extracellular space from mouse mesoangioblast stem cells

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