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The interplay between peritoneal mesothelial cells and ovarian cancer cells is critical for initiation, peritoneal dissemination, and ascites formation in ovarian cancer. Production of lysophosphatidic acid (LPA) by both peritoneal mesothelial cells and ovarian cancer cells has been shown to promote a metastatic phenotype in ovarian cancer. Herein, we report that exogenous addition or ectopic overexpression of the matricellular protein SPARC (Secreted Protein Acidic and Rich in Cysteine) significantly attenuated the LPA-induced proliferation, chemotaxis, and invasion in both highly metastatic SKOV3 and less metastatic OVCAR3 ovarian cancer cell lines. SPARC appears to modulate these functions in part through regulation of LPA receptor levels and attenuation of extracellular signal-regulated kinase (ERK)1/2 and protein kinase B/AKT signaling. Moreover, our results show that SPARC not only significantly inhibited both basal and LPA-induced interleukin (IL)-6 production in both cell lines, but also attenuated IL-6-induced mitogenic, chemotactic, and proinvasive effects in part through significant suppression of ERK1/2 and to a lesser extent of signal transducers and activators of transcription (STAT)3 signaling pathways. Our results strongly suggest that SPARC exerts a dual inhibitory effect on LPA-induced mesothelial-ovarian cancer cell crosstalk through regulation of both LPA-induced IL-6 production and function. Taken together, our findings underscore the use of SPARC as a potential therapeutic candidate in peritoneal ovarian carcinomatosis.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA