Ascites from epithelial ovarian cancer contain high levels of functional decoy receptor 3 (DcR3) and is associated with platinum resistance

• Published in: Gynecologic oncology Vol. 111; no. 2; pp. 330 - 335
• Main Authors: Connor, Joseph P, Felder, Mildred
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2008
• Subjects: Apoptosis; Apoptosis - physiology; Ascites - metabolism; DcR3; Disease-Free Survival; Drug Resistance, Neoplasm; Enzyme-Linked Immunosorbent Assay; Fas Ligand Protein - antagonists & inhibitors; Fas Ligand Protein - metabolism; Fas-ligand; Female; Hematology, Oncology and Palliative Medicine; Humans; Immunohistochemistry; Jurkat Cells; Middle Aged; Obstetrics and Gynecology; Organoplatinum Compounds - pharmacology; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Platinum resistance; Receptors, Tumor Necrosis Factor, Member 6b - metabolism; DcR3; Platinum resistance; Fas-ligand; Apoptosis
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2008.07.012

Abstract Objective Decoy receptor 3 (DcR3), a soluble tumor necrosis factor receptor is a known binding partner of multiple apoptotic ligands inhibiting apoptosis. The expression of DcR3 by cancers has been reported in gastrointestinal cancers yet it has not been described in ovarian cancer. Abnormalities in apoptosis pathways are seen in ovarian cancer and we theorized that the presence of DcR3 is a component of the dysregulation. Methods Ascites samples from 44 women with advanced ovarian cancer were tested for DcR3 by ELISA. The ability of ascites to inhibit Fas-ligand mediated apoptosis was determined by chromium release assays using cell surface or soluble Fas-ligand. Clinical parameters including, response to platinum and progression free and overall survival were compared between patients with high or low levels of DcR3. Results DcR3 was found in all 44 cases by ELISA. Ascites fluid significantly inhibited Fas-ligand mediate apoptosis using both surface Fas-ligand (KFL-9 cells) and soluble Fas-ligand. Blocking DcR3 with antibodies restores the cytolytic effects in both assays. HIGH DcR3 level was associated with stage IV disease and more than double the incidence of platinum resistant disease. In this modest sample size Low DcR3 cases had longer PFI and overall survival however neither difference was statistically significant. Conclusions DcR3 is expressed by epithelial ovarian cancers, concentrated in ascites and inhibits Fas-ligand mediated apoptosis. Together with a trend toward poor patient outcome these results indicate that expression of DcR3 by ovarian cancers is worthy of further investigation in a larger population to allow multivariate analysis.