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

EBioMedicine. 2019 Mar:41:597-609. doi: 10.1016/j.ebiom.2019.01.061. Epub 2019 Mar 7.

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).

Keywords: Fallopian tube fimbriae; Follicular fluid; IGF axis; Ovarian high-grade serous carcinoma; Stemness.

MeSH terms

  • Animals
  • Carcinogenesis
  • Chromosome Aberrations
  • DNA Copy Number Variations
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Epithelial Cells / transplantation
  • Fallopian Tubes / cytology
  • Female
  • Follicular Fluid / chemistry
  • Follicular Fluid / metabolism*
  • Humans
  • Insulin-Like Growth Factor Binding Proteins / metabolism
  • Insulin-Like Growth Factor II / 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

Substances

  • IGF1R protein, human
  • Insulin-Like Growth Factor Binding Proteins
  • RNA, Small Interfering
  • Receptors, Somatomedin
  • Tumor Suppressor Protein p53
  • Insulin-Like Growth Factor II
  • Receptor, IGF Type 1
  • Pregnancy-Associated Plasma Protein-A
  • PAPPA protein, human