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

Abstract

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