Abstract 3471: Anti-NMP autoantibodies together with serum levels of death receptor 6 (DR6) detect ovarian tumors at early stage .
Authors: Barua Animesh , Abramowicz Jacques S. , Bahr Janice M. , Grasso Salvatore A. , Sharma Sameer , Basu Sanjib , Rotmensch Jacob , Bitterman Pincas 
Published: August 2014

Background: High rate mortality in patients with ovarian cancer (OVCA) is attributed to the lack of an effective early detection test. OVCA progression differs from other malignancies in that the tumor typically spreads in a diffuse intra-abdominal manner. Thus tumor microenvironment plays an important role both in the inhibition, as well as progression of ovarian cancer. Malignant nuclear transformation is an early step in OVCA development which sheds nuclear matrix proteins (NMP) in circulation. The immune system responds to secreted NMPs by producing anti-NMP antibodies. Conversely, the tumor evolves immunosuppressive mechanisms to escape anti-tumor immunity. Death receptor 6 (DR6) has been suggested as an immunosuppressive agent expressed in several malignancies including OVCA. Thus, serum anti-NMP antibodies and DR6 may represent early markers of OVCA. However, association of anti-NMP antibodies and DR6 expression during OVCA development is unknown.

Objectives: The goal of this study was to determine if serum anti-NMP antibodies and DR6 levels are associated with malignant ovarian transformation and to examine their feasibility in detecting OVCA at early stage.

Materials and Methods: Access to OVCA patients at early stage is very difficult. We used laying hen model of spontaneous OVCA. 3-4 years old normal, low or stopped egg-laying hens were selected by ultrasound scanning, sera were collected, hens were euthanized and tissues were processed for histology, immunohistochemistry (IHC) and RT-PCR. Sera were processed for ELISA for DR6 and anti-NMP antibodies. Immunoreactions were confirmed by immunoproteomics. Tumor stage and their histological types were determined by gross inspection and routine histology. Samples were divided into 3 groups namely, normal (n= 20), early (n=15) and late (n = 17) stages of OVCA.

Results: Prevalence of anti-NMP antibodies was detected in approx. 75% hens at early stage and 94% hens at late stage OVCA. All serum samples from tumor hens detected NMP antigens of 30-80kDa in immunoproteomic studies. The expression of DR6 by ovarian malignant epithelium was significantly (p&lt;0.001) higher in hens with early stage OVCA than normal hens and increased further in hens with late stage OVCA. Similar patterns were observed in immunoblotting and gene expression studies. Serum levels of DR6 were significantly (p&lt;0.001) higher in hens with early and late stages of OVCA. Increase in serum DR6 levels were positively correlated with the prevalence of serum anti-NMP antibodies.

Conclusion: Results of this study suggest a concurrent prevalence of immune responses and immunosuppression to ovarian tumors. Anti-NMP antibodies and DR6 are associated with tumor initiation and progression. Thus, serum anti-NMP antibodies together with DR6 levels may detect OVCA at early stage. This study will provide a foundation for clinical study. Support: DOD Award # W81XWH-10-1-0523

Citation Format: Animesh Barua, Jacques S. Abramowicz, Janice M. Bahr, Salvatore A. Grasso, Sameer Sharma, Sanjib Basu, Jacob Rotmensch, Pincas Bitterman. Anti-NMP autoantibodies together with serum levels of death receptor 6 (DR6) detect ovarian tumors at early stage . [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 3471. doi:10.1158/1538-7445.AM2013-3471