Abstract B14: IGF axis proteins are the main carcinogens in ovulatory follicular fluid: Evidences from a mammary fat pad tumorigenesis model

Abstract

Abstract Ovarian high-grade serous carcinoma (HGSC) is the most devastating gynecologic cancer with elusive etiology and poor prognosis. Previous studies have disclosed that TP53 mutation is the universal and earliest genetic hit in its origin in the fallopian tube fimbriae. We and others have reported that ROS in ovulatory follicular fluid (FF) is the main mutagen that induces DNA double-strand breaks in fimbrial epithelial cells. However, ROS alone could not explain the transformation activity of FF found by our early study. In parallel studies (abstract by Chu TY et al.), we disclosed the presence of inactive IGF axis proteins in FF, including IGFBP-bonded IGFs and the GAG-free PAPP-A cleaving enzyme. Upon docking to the cell membrane at GAG sites, PAPP-A cleaves IGFBP, frees IGF to bind with IGF-1R, activates the downstream PI3K/Akt/mTOR signaling pathway, and results in the full transformation of the p53/Rb-null immortalized fimbrial epithelial cells. In this study, we established a tumorigenesis induction model in Trp53-/- mice to study the carcinogenic activity of FF. Upon repeated injection of ROS-high FF into the mammary fat pad of Trp53-/- mice, 10 of the 18 (56%) mice grew tumor around the injection site within 8 weeks. The histology showed small and mature B cell non-Hodgkin lymphoma. In contrast, no tumor growth was noted by 16 weeks when FF was injected subcutaneously or when mice were castrated. When IGF2 was depleted from the FF by monoclonal antibody, there was no tumor growth 8 weeks after the same repeated fat pad injections. By contrast, repeated injection of 100ng/ml IGF2 resulted in tumorigenesis in 33% (2/6) of the mice. The study provides in vivo evidence showing that other than ROS, IGF axis proteins are the main carcinogen in ovulatory follicular fluid. Citation Format: Hsuan-Shun Huang, Sung-Chao Chu, Tang-Yuan Chu. IGF axis proteins are the main carcinogens in ovulatory follicular fluid: Evidences from a mammary fat pad tumorigenesis model. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B14.