Perturbation of the Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Cascade in Ovarian Cancer: Overexpression of FLIPL and Deregulation of the Functional Receptors DR4 and DR5

Abstract

PURPOSE: Epithelial ovarian cancer is the most common cause of mortality from gynecologic malignancies. Due to advanced stage at diagnosis, most patients need systemic treatment in addition to surgery. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family with a promising toxicity profile and synergistic activity with chemotherapeutic agents. EXPERIMENTAL DESIGN: We used an arrayed panel of epithelial ovarian cancer tissue to assess the protein expression of TRAIL and the clinically most relevant members of its pathway death receptors 4 and 5 (DR4 and DR5) and the long form of FLICE inhibitory protein (FLIPL). RESULTS: We could show that a majority (66.2%) of the tumor tissues displayed either reduced DR4/DR5 expression (20.6%), increased FLIPL expression (39.7%), or both (5.9%) as determined by immunohistochemistry. Furthermore, higher TRAIL expression in the surrounding connective tissue but not in the tumor cells is significantly (P<0.05) linked with favorable overall survival in advanced-stage patients. CONCLUSIONS: Mechanisms to escape the immune surveillance mediated by TRAIL are developed by ovarian cancer cells in a high percentage. TRAIL expression in the ovarian cancer microenvironment has an effect on overall survival. These findings enhance our understanding of ovarian cancer pathology and might be helpful in guiding TRAIL-based therapy in future.