Abstract B09: IGF axis plays a pivotal role in the ovulation-induced malignant transformation of fallopian tube fimbrial epithelial cells

摘要: Owing to uncertain tissue-of-origin and elusive etiology, high-grade serous ovarian carcinoma (HGSC) is typically diagnosed at late stages with poor prognosis. Recent studies have unveiled the fallopian tube fimbria as major tissue of origin incessant ovulation main but mechanism cancer initiation remains elusive. In a series we found majority preovulatory follicular fluids (FF) contain high level ROS that induce DNA double-strand breaks well apoptosis fimbrial epithelial cells in vitro vivo. We also hemoglobin (Hb) pelvis, most likely contributed by retrograde menstruation previous cycles, reduces ovulatory extracellularly results shifting from apoptotic survival fate ROS-stressed cells. These initiating factors FF, although they may contribute TP53 mutation other early genetic hits genesis HGSC, cannot fully transform immortalized cell lines loss p53 Rb. Here show IGF axis proteins, including IGFBP2- IGFBP6-bound IGFs IGFBP-lytic enzyme PAPP-A, are abundant FF. Upon engaging glycosaminoglycans (GAG) on membrane cells, PAPP-A cleaves IGFBPs releases bioactive close proximity its receptor IGF-1R. Through PI3K/Akt/mTOR signaling pathway, FF-derived exerts transformation effects inducing anchorage independent growth xenograft tumorigenesis. By contrast, much less was noted when IGFBP2/6 or depleted GAG-docking blocked, IGF-1R ormTOR inhibited. Taken together, serial multiple where acts mutagen, serves surviving rescuer, transforming signal. Citation Format: Tang-Yuan Chu, Hsuan-Shun Huang, Che-Fang Hsu, Pao-Chu Chen. plays pivotal role ovulation-induced malignant [abstract]. In: Proceedings AACR Conference: Addressing Critical Questions Ovarian Cancer Research Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Res 2018;24(15_Suppl):Abstract nr B09.