Abstract 3646: Expression of death receptor 6 (DR6) increases in association with ovarian tumor development and progression

Abstract

Abstract Background: Because of the lack of an early detection test, ovarian cancer (OVCA) remains a lethal malignancy of women. OVCA differs from other malignancies in its specific dissemination pattern that the tumor typically spreads in a diffuse intra-pelvic and abdominal manner. Thus tumor microenvironment plays an important role in tumor dissemination and suppression of anti-tumor immunity is a hallmark of tumor progression. Although the precise mechanism of immune evasion by the tumor is not known, expression of death receptor 6 (DR6) has been suggested to be associated with tumor progression in several malignancies. DR6 is a member of the TNF receptor superfamily and a regulator of immune function. Expression of DR6 by ovarian tumors is unknown. Access to patients at early stage OVCA is very difficult. Laying hens develop OVCA spontaneously with histopathology similar to humans. Objectives: The goal of the present study was to determine whether DR6 is expressed by ovarian tumors at early stage and to examine whether DR6 expression is associated with OVCA tumor progression in the laying hen model of human OVCA. Materials and Methods: 3 years old normal, low or stopped egg-laying hens were scanned by ultrasound, sera were collected, hens were euthanized and ovarian tissues were processed for paraffin and frozen sections, immunoblotting and mRNA extraction. Stages of OVCA were confirmed at gross morphology and routine histology. Samples were divided into 3 groups: normal (control), early and late stages of OVCA. Sera were tested for DR6 levels by ELISA and confirmed by 2D-Western blot (WB). Expression of DR6 by normal and tumor ovaries was examined by immunohistochemistry (IHC), WB and RT-PCR. Results: DR6 was expressed by the epithelium of the ovarian tumor and angiogenic microvessels in the tumor stroma. The population of DR6+ microvessels and serum levels of DR6 was significantly higher in hens with ovarian tumors than the normal hens. Immunoblotting and gene expression analysis confirmed IHC observations. There was a significant increase in DR6 expression in hens with early stage OVCA (including microscopic tumor) suggesting that serum DR6 may be a potential indicator of ovarian tumors at very early stage. The frequencies of DR6+ cells were significantly higher in hens with late stage OVCA than early stage suggesting that DR6 may be involved in ovarian tumor development and progression in laying hens. Conclusion: For the first time, this study showed that epithelial cells in ovarian tumors express DR6 and results suggest that changes in serum levels as well as tissue expression of DR6 are associated with tumor initiation and progression. Thus serum DR6 may be useful as a surrogate maker of OVCA, target for anti-tumor immunotherapy as well as molecular imaging. This study will provide a foundation for a clinical study. Support: DOD (OC#093303), NCI-POCRC (P50 CA83636) and the Elmer Sylvia and Sramek Foundation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3646. doi:1538-7445.AM2012-3646