Abstract GMM-056: IGF-AXIS SIGNALING DURING OVULATION IS RESPONSIBLE FOR THE STEMNESS CELL EXPANSION AND TRANSFORMATION OF FALLOPIAN TUBE FIMBRIAL EPITHELIUM

Abstract

Abstract Recent studies have unveiled the fallopian tube fimbria as the major tissue-of-origin and incessant ovulation as the main etiological risk factor of ovarian high-grade serous carcinoma (HGSC) but the mechanism of cancer initiation remains elusive. In a series of study we have found a subset 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 hemoglobin 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 may contributes to the TP53 mutation and other early genetic hits in the genesis of HGSC, cannot fully transform the immortalized fimbrial epithelial cells, with loss of p53 and Rb. In this study, we demonstrated that IGF axis proteins, including IGFBP2- and IGFBP6-bound IGF2 as well as the IGFBP-lytic enzyme PAPP-A are abundantly present in ovulatory FF, and disclosed their effect on the fallopian tube fimbrial epithelium. Upon engaging with glycosaminoglycans (GAG) on the membrane of fimbrial epithelial cells, PAPP-A cleaves IGFBPs and releases bioactive IGF2 in close proximity to its receptor IGF-1R. This leads to stemness activation and clonal expansion of primary and immortalized fimbrial epithelial cells, and to malignant transformation of p53/Rb- and p53/CCNE1-disrupted fimbrial secretory cells. By antibody depletion, we proved each component of this IGF axis is essential and confers the majority of the transformation/regeneration activities in FF. Two signaling pathways, IGF-1R/ AKT/mTOR and IGF-1R/AKT/NANOG, are responsible for the phenotypes. Among them, IGF-1R and NANOG were critical since blocking their expression or function lead to a complete loss of the transformation. Given that ovulation is an acute inflammatory process inevitably damaging the ovarian surface and the fimbriae, IGF axis in FF takes a role of tissue repair and, in situations when the ROS-induced TP53/Rb mutations accumulated in stem cells, may lead to carcinogenesis of the fallopian tube fimbria. Citation Format: Tang-Yuan Chu, Che-Fang Hsu, Hsuan-Shun Huang. IGF-AXIS SIGNALING DURING OVULATION IS RESPONSIBLE FOR THE STEMNESS CELL EXPANSION AND TRANSFORMATION OF FALLOPIAN TUBE FIMBRIAL EPITHELIUM [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-056.