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Suryawanshi S , Huang X , Elishaev E , Budiu RA , Zhang L , Kim S , Donnellan N , Mantia-Smaldone G , Ma T , Tseng G , Lee T , Mansuria S , Edwards RP , Vlad AM
Complement pathway is frequently altered in endometriosis and endometriosis-associated ovarian cancer
Clin Cancer Res. 2014 Dec 1;20(23) :6163-74
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PURPOSE: Mechanisms of immune dysregulation associated with advanced tumors are relatively well understood. Much less is known about the role of immune effectors against cancer precursor lesions. Endometrioid and clear-cell ovarian tumors partly derive from endometriosis, a commonly diagnosed chronic inflammatory disease. We performed here a comprehensive immune gene expression analysis of pelvic inflammation in endometriosis and endometriosis-associated ovarian cancer (EAOC). EXPERIMENTAL DESIGN: RNA was extracted from 120 paraffin tissue blocks comprising of normal endometrium (n = 32), benign endometriosis (n = 30), atypical endometriosis (n = 15), and EAOC (n = 43). Serous tumors (n = 15) were included as nonendometriosis-associated controls. The immune microenvironment was profiled using Nanostring and the nCounter GX Human Immunology Kit, comprising probes for a total of 511 immune genes. RESULTS: One third of the patients with endometriosis revealed a tumor-like inflammation profile, suggesting that cancer-like immune signatures may develop earlier, in patients classified as clinically benign. Gene expression analyses revealed the complement pathway as most prominently involved in both endometriosis and EAOC. Complement proteins are abundantly present in epithelial cells in both benign and malignant lesions. Mechanistic studies in ovarian surface epithelial cells from mice with conditional (Cre-loxP) mutations show intrinsic production of complement in epithelia and demonstrate an early link between Kras- and Pten-driven pathways and complement upregulation. Downregulation of complement in these cells interferes with cell proliferation. CONCLUSIONS: These findings reveal new characteristics of inflammation in precursor lesions and point to previously unknown roles of complement in endometriosis and EAOC.
Suryawanshi, Swati Huang, Xin Elishaev, Esther Budiu, Raluca A Zhang, Lixin Kim, SungHwan Donnellan, Nicole Mantia-Smaldone, Gina Ma, Tianzhou Tseng, George Lee, Ted Mansuria, Suketu Edwards, Robert P Vlad, Anda M ENG P50 CA159981/CA/NCI NIH HHS/ R01 CA163462/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 2014/10/09 06:00 Clin Cancer Res. 2014 Dec 1;20(23):6163-74. doi: 10.1158/1078-0432.CCR-14-1338. Epub 2014 Oct 7.