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IGF-axis confers transformation and regeneration of fallopian tube fimbria epithelium upon ovulation.
- Source :
-
EBioMedicine [EBioMedicine] 2019 Mar; Vol. 41, pp. 597-609. Date of Electronic Publication: 2019 Mar 07. - Publication Year :
- 2019
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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.<br />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.<br />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.<br />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).<br /> (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Carcinogenesis
Chromosome Aberrations
DNA Copy Number Variations
Epithelial Cells cytology
Epithelial Cells metabolism
Epithelial Cells transplantation
Fallopian Tubes cytology
Female
Follicular Fluid chemistry
Humans
Insulin-Like Growth Factor Binding Proteins metabolism
Mice
Mice, Inbred NOD
Mice, Knockout
Pregnancy-Associated Plasma Protein-A metabolism
RNA Interference
RNA, Small Interfering metabolism
Receptor, IGF Type 1
Receptors, Somatomedin antagonists & inhibitors
Receptors, Somatomedin genetics
Receptors, Somatomedin metabolism
Signal Transduction
Tumor Suppressor Protein p53 deficiency
Tumor Suppressor Protein p53 genetics
Follicular Fluid metabolism
Insulin-Like Growth Factor II metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2352-3964
- Volume :
- 41
- Database :
- MEDLINE
- Journal :
- EBioMedicine
- Publication Type :
- Academic Journal
- Accession number :
- 30852161
- Full Text :
- https://doi.org/10.1016/j.ebiom.2019.01.061