Abstract 1651: Regulation of omental seeding of ovarian cancer cells by SPARC.

Abstract Epithelial Ovarian cancer is the leading cause of death from malignant gynecologic tumors, as most patients have extensive late metastatic disease at the time of diagnosis. Ovarian cancer (OvCa) cells have specific predilection to metastasize to omentum, a condition known as “peritoneal ovarian carcinomatosis, POC” but rarely leave the peritoneal cavity. Despite aggressive surgical debulking and cytoreduction, recurrence of omental implants is high with poor patient survival. We have recently reported that the tumor suppressor role of matricellular glycoprotein SPARC (secreted protein acidic and rich in cysteine) in POC through differential effects on OvCa cells and their interactions with components of the peritoneal microenvironment. Given that SPARC is the first known matricellular protein involved in adipose tissues homeostasis, we sought to elucidate the potential roles of SPARC on the omental adipocyte-OvCa cells cross-talk and its impact on POC, in vivo and in vitro. Using primary omental SP−/− and SP+/+ omental stromal cells, we found that adipocyte-SPARC delayed the adipogenic differentiation of omental stromal cells. SP−/- omental adipocytes expressed significantly higher levels of adipogeneic markers and accumulated significantly less oil droplets than SP+/+. Primary SP−/− adipocytes promoted homing of ID8 murine OvCa cells to the omentum in vivo and their migration and invasion in 3D-cocultures in vitro. Mechanistic studies using human and murine adipocyte-OvCa genetically manipulated for SPARC expression in 3D co-cultures, revealed that the effect of SPARC suppressing adipocyte-OvCa cell cross-talk mediated by the effect suppressing the activation of cEBP-β, NFκB and AP-1 in OvCa cells as well as in adipocytes with subsequent decrease in chemokines/adipokines as well as fatty acid exchange between OvCa cells and adipocytes. Our data indicates the metastasis suppressor effect of SPARC in POC is mediated in part via inhibiting the key transcription factors involved in adipocytes differentiation and OvCa progression identifying SPARC as a potential inhibitor of OvCa cell omental seeding and dormancy. Citation Format: Dylan P. Matthews, Neveen A. Said. Regulation of omental seeding of ovarian cancer cells by SPARC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1651. doi:10.1158/1538-7445.AM2013-1651