IGF-axis confers transformation and regeneration of fallopian tube fimbria epithelium upon ovulation

Abstract

Background The fallopian tube fimbria is regarded as the main tissue of origin and incessant ovulation as the main risk factor of ovarian high-grade serous carcinoma. Previously, we discovered the tumorigenesis activity of human ovulatory follicular fluid (FF) upon injection to the mammary fat pad of Trp53-null mice. We also found a mutagenesis activity of FF-ROS and a apoptosis-rescuing activity of Hb from retrograde menstruation. However, neither of them can explain the tumorigenesis activities of FF. Methods From two cohorts of ovulatory FF retrieved from IVF patients, the main growth factor responsible for the transformation of human fimbrial epithelial cells was identified. Mechanism of activation, ways of signal transduction of the growth factor, as well as the cellular and genetic phenotypes of the malignant transformation was characterized. Findings In this study, we showed that insulin-like growth factor (IGF)-axis proteins, including IGFBP-bound IGF2 as well as the IGFBP-lytic enzyme PAPP-A, are abundantly present in FF. Upon engaging with glycosaminoglycans on the membrane of fimbrial epithelial cells, PAPP-A cleaves IGFBPs and releases IGF2 to bind with IGF-1R. Through the IGF-1R/AKT/mTOR and IGF-1R/AKT/NANOG pathways, FF-IGF leads to stemness and survival, and in the case of TP53/Rb or TP53/CCNE1 loss, to clonal expansion and malignant transformation of fimbrial epithelial cells. By depleting each IGF axis component from FF, we proved that IGF2, IGFBP2/6, and PAPP-A are all essential and confer the majority of the transformation and regeneration activities. Interpretation This study revealed that the FF–IGF axis functions to regenerate tissue damage after ovulation and promote the transformation of fimbrial epithelial cells that have been initiated by p53- and Rb-pathway disruptions. Fund The study was supported by grants of the Ministry of Science and Technology, Taiwan (MOST 106-2314-B-303-001-MY2; MOST 105-2314-B-303-017-MY2; MOST 107-2314-B-303-013-MY3), and Buddhist Tzu Chi General Hospital, Taiwan (TCMMP104-04-01).

WNT and inflammatory signaling distinguish human Fallopian tube epithelial cell populations

“…The increased expression of TNFAIP2 and IGF2 in the cells isolated from the proximal TE lends further credibility to the inflammatory hypothesis. IGF2 is present in follicular fluid and has recently been shown to promote malignant transformation in immortalized TE cell lines (Hsu et al, 2019). TNFAIP2 is thought to be involved in inflammatory angiogenesis and has been reported to down regulate NF-κB (Jia et al, 2018;Thair et al, 2015).…”

Ovulatory Follicular Fluid Facilitates the Full Transformation Process for the Development of High-Grade Serous Carcinoma

“…During ovulation, the fallopian tube fimbria juxtaposes the ovulation site and directly exposes to the fluid released from the ovarian follicle. We have previously reported multiple evidences supporting the transformation activity of FF [ 20 , 21 , 22 ]. When injected directly into the mammary fat pad of Trp53 -null mice, FF induced early-onset lymphoma in a reactive oxygen species (ROS)-dependent and tissue-specific manner [ 20 , 22 ].…”

Human fallopian tube epithelial cells exhibit stemness features, self-renewal capacity, and Wnt-related organoid formation

“…Thus the fallopian tube fimbria epithelium is one of the tissues with most abundant stemness activity [9]. Previoiusly, we have showed that exposure to the insulin-like growth factor axis proteins in the follicular fluid leads to stemness activation and clonal expansion of the human fimbrial epithelial cells [10]. However, characteristics of the stem-like cell (FTESC) especially the cell surface marker in this epithelium is still obscur [11][12][13].…”