Secreted Protein Acidic and Rich in Cysteine (SPARC) Inhibits Integrin-Mediated Adhesion and Growth Factor-Dependent Survival Signaling in Ovarian Cancer

Abstract

The matricellular glycoprotein SPARC (secreted protein acidic and rich in cysteine) has been accorded major roles in regulation of cell adhesion and proliferation, as well as tumorigenesis and metastasis. We have recently reported that in addition to its potent antiproliferative and proapoptotic functions, SPARC also abrogates ovarian carcinoma cell adhesion, a key step in peritoneal implantation. However, the underlying molecular mechanism through which SPARC ameliorates peritoneal ovarian carcinomatosis seems to be multifaceted and has yet to be delineated. Herein, we show that SPARC significantly inhibited integrin-mediated ovarian cancer cell adhesion to extracellular matrix proteins, as well as to peritoneal mesothelial cells. This counteradhesive effect of SPARC was shown to be mediated in part through significant attenuation of cell surface expression and clustering of ␣ v -integrin subunit, ␣ v ␤ 3 -and ␣ v ␤ 5 -heterodimers, and ␤ 1 -subunit, albeit to a lesser extent, in ovarian cancer cells. Moreover, SPARC significantly suppressed both anchorage-dependent and -independent activation of AKT and mitogen-activated protein kinase survival signaling pathways in ovarian cancer cells in response to serum and epidermal growth factor stimulation. In summary, we have identified a novel role of SPARC as a negative regulator of both integrin-mediated adhesion and growth factor-stimulated survival signaling pathways in ovarian cancer.

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

“…6). SPARC can be secreted to regulate local growth factor, ECM, and matrix metalloproteinase (MMP) activity, to modulate cell morphology and migration responses, angiogenesis, and cell proliferation and survival (Rempel et al, 2001;Francki et al, 2004;Barker et al, 2005a;Yan et al, 2005;Said et al, 2007a). In vitro, SPARC acts on many cell types as a deadhesive factor that induces cell rounding and inhibits cell migration (Sage et al, 1989b;Bradshaw and Sage, 2001), including on neuronal and glial cell lines (Ikemoto et al, 2000).…”

“…However, SPARC is thought to act in vivo as a contextual regulator of cellular adhesion strength (Greenwood and Murphy-Ullrich, 1998), and is required for fibroblast migration during dermal wound healing (Basu et al, 2001), leukocyte infiltration after immune challenge (Kelly et al, 2007;Rempel et al, 2007), and tumor invasiveness (Rempel et al, 2001;Framson and Sage, 2004). SPARC modulates cell morphology, migration, and survival via signaling pathways that include integrin-linked kinase (ILK), focal adhesion kinase (FAK), mitogen-associated protein kinase (MAPK), and AKT/protein kinase B (Shi et al, 2004(Shi et al, , 2007Barker et al, 2005a;Said et al, 2007a).…”

“…SPARC, expressed by cells adjacent to candidate neural stem cells, could potentially regulate the quiescence of the neural stem cell niche by modulating the activity of growth factors and matrix remodeling factors to inhibit cell cycle progression and regulate survival (Funk and Sage, 1991;Shi et al, 2007). SPARC negatively regulates signaling by various growth factors known to be involved in neural stem cell proliferation and differentiation, including fibroblast growth factor 2 (FGF2) , epidermal growth factor (EGF) (Said et al, 2007a), insulin-like growth factor-1 (IGF-1) (Francki et al, 2003), and transforming growth factor ␤ (TGF␤) (Schiemann et al, 2003;Francki et al, 2004). However, the expression of SPARC is in turn regulated by each of these factors; decreased by FGF2 and EGF, increased by IGF-1, and reciprocally regulated by TGF␤ (Wrana et al, 1991;Chandrasekhar et al, 1994;Delany and Canalis, 1998;Shiba et al, 1998Shiba et al, , 2001.…”

“…However, the expression of SPARC is in turn regulated by each of these factors; decreased by FGF2 and EGF, increased by IGF-1, and reciprocally regulated by TGF␤ (Wrana et al, 1991;Chandrasekhar et al, 1994;Delany and Canalis, 1998;Shiba et al, 1998Shiba et al, , 2001. Furthermore, SPARC can positively and negatively modulate growth factor-and adhesion-dependent cell survival signaling (Shi et al, 2004(Shi et al, , 2007Said et al, 2007a), with the potential to maintain neural stem cell equilibrium. Thus, SPARC may also contribute to the generation of the neural stem niche by a similar mechanism to that of the matricellular protein, tenascin-C, which orchestrates growth , and delineates the outer membrane at (F) nodes of Ranvier (arrow) and surrounding (G) myelin (P0ϩ).…”

Normalization of the Ovarian Cancer Microenvironment by SPARC

“…Recent reports highlight the role of this molecule as a positive or negative modulator in the pathogenesis of different malignancies (18)(19)(20)(21)(22)(23)(24). We and others have shown that SPARC functions as a tumor suppressor in ovarian cancer (25)(26)(27)(28). As a tumor suppressor, effect of SPARC in different cancers was attributed not only to its counteradhesive, antiproliferative functions but also to its role in modulating angiogenesis as well as regulation of the production, assembly, and organization of the structural extracellular matrix proteins including type I collagen and fibronectin (23,25,(29)(30)(31)(32).…”