SPARC ameliorates ovarian cancer-associated inflammation

4202 Background: We have recently identified that the role of secreted protein acidic and rich in cysteine (SPARC) in amelioration of peritoneal ovarian carcinomatosis is mediated, in part, through a mesothelial cell/LPA-induced inflammatory response in ovarian cancer cells. The aim of this study was to elucidate the underlying molecular mechanisms through which SPARC regulates interactions between tumor cells and the cellular components of the ovarian cancer peritoneal microenvironment, specifically, mesothelial cells and macrophages.
 Methods: Co-cultures of macrophages and epithelial ovarian cancer (EOC) cells, or triple-cultures of EOC cells/macrophages/mesothelial cells were used to assess the role of SPARC in macrophage chemoattractant protein-1 (MCP-1) production, as well as its mitogenic, chemotactic, and pro-invasive effects. Ectopic overexpression of SPARC in EOC cells was achieved by adenoviral transduction. Changes in the levels and activity of vascular endothelial growth factor (VEGF), interleukin (IL)-6, prostanoids (prostaglandins E2 and 8-isoprostanes), as well as that of matrix metalloproteinases (MMPs) and urokinase plasminogen activator (u-PA) were determined by ELISA, gelatin zymography, and colorimetric u-PA activity assays, respectively.
 Results: We found that SPARC not only significantly reduced macrophage MCP-1 production and its macrophage chemotactic effect, but also attenuated the response of ovarian cancer cells to the mitogenic, chemotactic, and proinvasive effects of MCP-1. Ectopic overexpression of SPARC in ovarian cancer cells significantly attenuated macrophage- and mesothelial cell-induced production and activity of VEGF, IL-6, prostanoids, as well as that of MMP-2, MMP-9, and u-PA. Moreover, these effects of SPARC overexpression in ovarian cancer cells were mediated, in part, through inhibition of NFκB promoter activation.
 Conclusion: Taken together, our results indicate, for the first time, that the effects of tumor SPARC as a negative regulator of ovarian cancer are mediated not only through decreased recruitment of macrophages, but also by down-regulation of the associated inflammation.