Ovulation sources coagulation protease cascade and hepatocyte growth factor to support physiological growth and malignant transformation

ABSTRACT The fallopian tube fimbrial epithelium (FTE), which is exposed to the follicular fluid (FF) contents of ovulation, is regarded as the main origin of ovarian high-grade serous carcinoma (HGSC). Previously, we found that growth factors in FF, such as IGF2, are responsible for the malignant transformation of FTE. However, ovulation is a monthly transient event, whereas carcinogenesis requires continuous, long-term exposure. Here, we found the transformation activity of FF sustained for more than 30 days after drainage into the peritoneal fluid (PF). Hepatocyte growth factor (HGF), activated through the ovulation injury-tissue factor–thrombin–HGFA–HGF cleavage cascade confers a sustained transformation activity to FTE, HGSC. Physiologically, the high reserve of the coagulation-HGF cascade sources a sustained level of HGF in PF, then to the blood circulation. This HGF axis promotes the growth of the corpus luteum and repair of tissue injury after ovulation. Graphical Abstract The fluid content of the ovulating ovarian follicle (follicular fluid [FF]) exerts a long-lasting transformation effect that is sustained after mixing with peritoneal fluid (PF). The coagulation protease cascade and hepatocyte growth factor (HGF) are responsible for the sustained activity. The high abundance of cascade proteins and pro-form HGF activator and HGF in FF/PF supports the constant supply of active-form HGF lasting for a whole month, covering the entire ovulation cycle. This sustained HGF activity promotes the proliferative repair of the ovarian surface and fallopian tube fimbrial epithelia as well as the growth of the corpus luteum. The same activity also inadvertently promotes the malignant transformation of the fimbrial epithelium, high-grade serous carcinoma, and epithelial ovarian cancer. In addition to the peritoneal cavity, ovulation sources HGF to blood circulation, which may serve an endocrine role. HIGHLIGHT Ovulatory follicular fluid (FF) exerts a long-lasting transformation activity covering throughout the ovulation cycle. The ovulation injury-coagulation proteases-hepatocyte growth factor (HGF) cascade is responsible for the sustained activity. Ovulation sources HGF into the peritoneal cavity, then into the blood circulation. This coagulation-HGF cascade promotes the transformation of fallopian tube epithelial cells and ovarian cancer cells. Physiologically, it promotes the growth of the corpus luteum and injured epithelium after ovulation.