Fig. 7.

An integrative mechanism of ovulation induced transformation of the fallopian tube fimbrial epithelium.

(a) A summary of regeneration and transformation of fallopian tube fimbrial epithelium by IGF axis in FF. Upon ovulation, fallopian tube fimbrial epithelium is exposed to IGF axis proteins. After tethering to the membrane GAG, PAPP-A cleaves IGFBP2 and releases IGF2 to bind with IGF-1R on fimbrial epithelial cells. Subsequent activation of the AKT/OCT4/NANOG and AKT/mTOR pathways leads to activation of stem cells to regenerate injured fimbrial epithelium, or clonal expansion and malignant transformation of initiated cancer cells. (b) Ovulatory ROS acts as the mutagen to induce DNA mutations such as double strand breaks (DSB) [12] and IGF acts as the stem cell growth factor to expand the mutant clone. By consuming H₂O₂ extracellularly, hemoglobin (Hb) from retrograde menstruation rescues the ROS stressed cells from p53-mediated or, when p53 is lost, NOX-mediated apoptosis [16]. This allows expansion of TP53-mutated stem/progenitor cells to form the p53 signature. On the other hand, progesterone (P4) from luteinized follicle would induce necroptosis of TP53-mutated cells, effectively eradicates the precursor lesions [45]. It is up to the loss of progesterone receptor (PR), fails of homologous recombination repair proteins (BRCA1/2) as well the incessant driving of mutagenesis and clonal expansion by ovulation that allows progression to STIC, and eventually metastasize to form the ovarian and peritoneal HGSC.