Normalization of the Ovarian Cancer Microenvironment by SPARC

• Published in: Molecular cancer research 2007-10, Vol.5 (10), p.1015-1030
• Main Authors: Said, Neveen, Socha, Matthew J, Olearczyk, Jeffrey J, Elmarakby, Ahmed A, Imig, John D, Motamed, Kouros
• Format: Article
• Language: English
• Subjects: Animals; ascites; Ascitic Fluid - chemistry; Ascitic Fluid - metabolism; Ascitic Fluid - pathology; Carcinoma - metabolism; Carcinoma - secondary; Cell Adhesion; Cell Proliferation; Cell Survival; Chemokine CCL2 - analysis; Dinoprost - analogs & derivatives; Dinoprost - analysis; Female; inflammation; Inflammation - metabolism; Inflammation - pathology; integrins; Integrins - metabolism; Interleukin-6 - analysis; Metalloendopeptidases - metabolism; Mice; Mice, Mutant Strains; Osteonectin - metabolism; ovarian cancer; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Peritoneal Neoplasms - metabolism; Peritoneal Neoplasms - secondary; SPARC; Tissue Inhibitor of Metalloproteinases - metabolism; Vascular Endothelial Growth Factor A - antagonists & inhibitors; VEGF
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-07-0001

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 α v and β 1 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 F 2 α) 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)