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Angiogenesis, Metastasis, and the Cellular Microenvironment

Normalization of the Ovarian Cancer Microenvironment by SPARC

¹ Vascular Biology Center and Departments of ² Physiology and ³ Pathology, Medical College of Georgia, Augusta, Georgia

Requests for reprints: Kouros Motamed, Vascular Biology Center, CB-3306, Medical College of Georgia, 1459 Laney Walker Boulevard, Augusta, GA 30912. Phone: 706-721-9796; Fax: 706-721-9799. E-mail: kmotamed{at}mcg.edu

Malignant ascites is a major source of morbidity and mortality in ovarian cancer patients. It functions as a permissive reactive tumor-host microenvironment and provides sustenance for the floating tumor cells through a plethora of survival/metastasis-associated molecules. Using a syngeneic, immunocompetent model of peritoneal ovarian carcinomatosis in SP^–/– mice, we investigated the molecular mechanisms implicated in the interplay between host secreted protein acidic and rich in cysteine (SPARC) and ascitic fluid prosurvival/prometastasis factors that result in the significantly augmented levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP). Ascitic fluid–enhanced ID8 invasiveness was mediated through VEGF via a positive feedback loop with MMP-2 and MMP-9 and through activation of _v and ß₁ integrins. Host SPARC down-regulated the VEGF-MMP axis at the transcriptional and posttranscriptional levels. In vitro, SPARC attenuated the basal as well as VEGF-induced integrin activation in tumor cells. SPARC inhibited the VEGF- and integrin-mediated ID8 proliferation in vitro and significantly suppressed their tumorigenicity in vivo. Relative to SP^+/+, SP^–/– ascitic fluid contained significantly higher levels of bioactive lipids and exerted stronger chemotactic, proinvasive, and mitogenic effects on ID8 cells in vitro. SP^–/– ascites also contained high levels of interleukin-6, macrophage chemoattractant protein-1, and 8-isoprostane (prostaglandin F₂) that were positively correlated with extensive infiltration of SP^–/– ovarian tumors and ascites with macrophages. In summary, our findings strongly suggest that host SPARC normalizes the microenvironment of ovarian cancer malignant ascites through down-regulation of the VEGF-integrin-MMP axis, decreases the levels and activity of bioactive lipids, and ameliorates downstream inflammation. (Mol Cancer Res 2007;5(10):1015–30)

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