SPARC upregulates MT1-MMP expression, MMP-2 activation, and the secretion and cleavage of galectin-3 in U87MG glioma cells

McClung, Heather; Thomas, Stacey L.; Osenkowski, Pamela; Tóth, Márta; Menon, Priya M.; Raz, Avraham; Fridman, Rafael; Rempel, Sandra A.

doi:10.1016/j.neulet.2007.04.037

Cited by 86 publications

(64 citation statements)

References 28 publications

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“…Increased SPARC expression correlates with glioma invasion in vitro (32,33) and in vivo (33)(34)(35). This is accomplished by up-regulation and activation of MMP-2, and a possible mechanism involved in increased SPARC-dependent ECM degradation via MMP may involve galectin-3 (36). However, the effects of SPARC are complex, and the ability of SPARC to promote invasion depends on the level of its secretion and to the local tumor environment (35).…”

Section: Discussionmentioning

confidence: 99%

Glioma-astrocyte interaction modifies the astrocyte phenotype in a co-culture experimental model

et al. 2009

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Abstract. As the majority of gliomas arise through malignant transformation of astrocytes, we aimed at investigating the interaction between malignant glioma cells and astrocytes in a co-culture experimental model. For this purpose we analyzed the expression of genes and proteins involved in tumor promotion and invasion, such as glial fibrillary acidic protein (GFAP), matrix metalloproteinase-2 (MMP-2), tissue inhibitor of MMP-2 (TIMP-2), transforming growth factor-ß1 (TGF-ß1), secreted protein acidic and rich in cysteine (SPARC), and connexin 43 (CX43). Co-cultures of human neural stem cell-derived astrocytes and U87 MG astrocytoma cells were performed in a transwell system. Gene expression was evaluated by real-time RT-PCR, and protein analysis was performed by Western blotting, SDS-zymography, and immunofluorescence. GFAP tended to be up-regulated in astrocytes co-cultivated with U87, suggesting a reactive response induced by glioma cells. CX43 mRNA tended to be down-regulated in co-cultured astrocytes, as well as the nonphosphorylated isoform at the protein level. MMP-2 mRNA tended to be up-regulated, and MMP-2 protein levels were significantly increased in astrocytes co-cultivated with U87. TIMP-2 and SPARC mRNA decreased in astrocytes cocultivated with U87, showing lower expression in glioma cells. By contrast, SPARC protein expression was strongly induced in supernatants of co-cultured astrocytes. TGF-ß1 was not modified. Our results suggest that U87 cells elicit phenotype modifications in the neighbouring resident astrocytes very likely mediated by soluble factors. Glioma/ astrocyte interaction could possibly trigger an astrocyte phenotype modification consistent with a malignant transformation, and favouring a more permissive environment for glioma cells invasion.

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Section: Discussionmentioning

confidence: 99%

Glioma-astrocyte interaction modifies the astrocyte phenotype in a co-culture experimental model

et al. 2009

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“…Different tenascin-R peptide fragments can either inhibit or promote microglial migration (Liao et al, 2005). SPARC can similarly be cleaved by proteases and MMPs to yield peptides with distinct functions (Lane et al, 1994;Iruela-Arispe et al, 1995;Sasaki et al, 1997), and can also regulate protease expression and activation (Brekken and Sage, 2000;McClung et al, 2007). Since many proteases are up-regulated after injury by microglia and other cells (Yong, 2005;del Zoppo et al, 2007), it is possible that cleavage of SPARC might facilitate the rapid process motility and chemotaxis of activated microglia (Davalos et al, 2005;Nimmerjahn et al, 2005;Kurpius et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

SPARC is expressed by macroglia and microglia in the developing and mature nervous system

Vincent

Lau

Roskams

2008

Developmental Dynamics

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SPARC (secreted protein, acidic and rich in cysteine) is a matricellular protein that is highly expressed during development, tissue remodeling, and repair. SPARC produced by olfactory ensheathing cells (OECs) can promote axon sprouting in vitro and in vivo. Here, we show that in the developing nervous system of the mouse, SPARC is expressed by radial glia, blood vessels, and other pial-derived structures during embryogenesis and postnatal development. The rostral migratory stream contains SPARC that becomes progressively restricted to the SVZ in adulthood. In the adult CNS, SPARC is enriched in specialized radial glial derivatives (Mü ller and Bergmann glia), microglia, and brainstem astrocytes. The peripheral glia, Schwann cells, and OECs express SPARC throughout development and in maturity, although it appears to be down-regulated with maturation. These data suggest that SPARC may be expressed by glia in a spatiotemporal manner consistent with a role in cell migration, neurogenesis, synaptic plasticity, and angiogenesis.

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“…These may explain the paradoxical situation that both low and high levels of SPARC can promote more aggressive invasion than intermediate levels (8). Although the molecular mechanism of SPARC on glioma invasion remains unclear, SPARC has been reported to activate membrane type 1-matrix metalloproteinase (MMP) and MMP-2 (29). SPARC siRNA reduced the activation of phosphorylation of AKT, focal adhesion kinase, and integrinlinked kinase (28,30).…”

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confidence: 99%

Downregulation of SPARC expression inhibits cell migration and invasion in malignant gliomas

Seno

Harada²,

Kohno³

et al. 2009

Int J Oncol

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Abstract. The secreted protein acidic and rich in cysteine (SPARC) is a secreted glycoprotein that plays an essential role in promoting the motility of invasive tumor cells. In the present study, we investigated the role of SPARC in the motile and invasive activities of human glioma cells by silencing the SPARC gene. Introduction of SPARC-targeted small interfering RNA (siRNA) into glioma cell lines resulted in downregulation of SPARC expression, and significantly suppressed glioma cell migration in vitro. Furthermore, invasiveness was significantly reduced in the cells transfected with SPARC siRNA compared with those transfected with control siRNA. In an organotypic brain slice model, coculture of glioma spheroids and rat brain slices showed that SPARC siRNA-transfected glioma cells failed to invade the surrounding normal brain tissue. In addition, intracerebral injection of glioma cells transfected with SPARC siRNA in nude mice resulted in the formation of a non-invasive tumor, whereas injection of cells transfected with control siRNA resulted in diffuse invasive tumors. Since SPARC was exclusively expressed in the invasive zone of the tumor margin and the area surrounding tumor necrosis, we investigated the relationship between SPARC expression and hypoxic stress. SPARC expression was upregulated under hypoxic stress of 1% oxygen concentration in glioma cells. Silencing hypoxia-inducible factor-1· with siRNA reduced the overexpression of SPARC induced under hypoxic conditions. These results suggest that SPARC plays an essential role in the invasive activity of human glioma cells, under hypoxic conditions. Downregulation of SPARC may be a novel antiinvasion therapeutic strategy for malignant gliomas.

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SPARC upregulates MT1-MMP expression, MMP-2 activation, and the secretion and cleavage of galectin-3 in U87MG glioma cells

Cited by 86 publications

References 28 publications

Glioma-astrocyte interaction modifies the astrocyte phenotype in a co-culture experimental model

Glioma-astrocyte interaction modifies the astrocyte phenotype in a co-culture experimental model

SPARC is expressed by macroglia and microglia in the developing and mature nervous system

Downregulation of SPARC expression inhibits cell migration and invasion in malignant gliomas

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