Abstract 1653: Complement roles in endometriosis and endometriosis-associated ovarian cancer
Authors: Suryawanshi Swati Maruti , Huang Xin , Budiu Raluca , Kim SungHwan , Tseng George , Elishaev Esther , Klein-Patel Marcia , Lee Ted , Mansuria Suketu , Edwards Robert , Vlad Anda 
Published: May 2015

Introduction: Endometriosis is a largely benign, chronic inflammatory disease defined by the presence of endometrial-like glands surrounded by stroma. Epidemiologic studies suggest that endometriosis is an independent risk factor for endometrioid and clear cell epithelial ovarian tumors, collectively called endometriosis-associated ovarian cancers (EAOC). Histopathology findings demonstrate that EAOC occur in the presence of atypical endometriosis (AE), often found in direct continuity with the tumor, suggesting AE as the transitioning entity from benign lesions to malignant variants. Although it is widely accepted that chronic inflammation drives cancer, immune deregulation in chronic precursor lesions to ovarian cancer have not been studied in a systematic way.

Experimental procedure: We extracted RNA from 135 paraffin tissue blocks comprising of normal endometrium (n=32), benign endometriosis consisting of ovarian and extra ovarian endometriosis cases (n=30,) atypical endometriosis (n=15) and EAOC, (n=43). Serous tumors (n=15) were included as non-endometriosis associated controls. Using Nanostring and the nCounter® GX Human Immunology Kit, we profiled a total of 511 immune genes. Cluster analyses and differential expressions (DE) were calculated using EdgeR. Protein expression of candidate proteins was validated with immunohistochemistry (IHC). To identify mechanisms of complement activation during early stages of genomic instability, we used murine cell lines derived from mice with conditional mutations in Kras and Pten pathways.

Results: Nanostring immune gene expression profile eveal the predominant role of adaptive immunity and of the adaptive-innate immune cross-talk. The complement pathway was most prominently expressed, suggesting its roles as one of the major immune pathways involved in the transition from chronic endometriosis to atypical (premalignant) endometriosis and to EAOC. Complement pathway genes were upregulated in human endometriosis and atypical endometriosis. Tissue deposition of several complement components and changes in peripheral blood were confirmed by IHC and ELISA, respectively. Genomic instability in murine ovarian cancer cell lines with conditional mutations resulted in upregulation of complement genes expression in epithelial cells, but without an advantage on cell death. These findings further support a paradigm shift on complement roles in cancer, suggesting its pro-tumorigenic roles.

Conclusions: We performed the first comprehensive gene profile of the tissue immune microenvironment in benign endometriosis, EAOC and precursor lesions and identified the previously unrecognized roles for the complement pathway. Complement activation may be an early trigger of inflammation and an early link between epithelium and immune environment.

These findings have high translational potential for immune therapy and prevention in EAOC.

Citation Format: Swati Maruti Suryawanshi, Xin Huang, Raluca Budiu, SungHwan Kim, George Tseng, Esther Elishaev, Marcia Klein-Patel, Ted Lee, Suketu Mansuria, Robert Edwards, Anda Vlad. Complement roles in endometriosis and endometriosis-associated ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1653. doi:10.1158/1538-7445.AM2014-1653