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

Abstract

• Ovulatory follicular fluid 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. The fallopian tube fimbrial epithelium, which is exposed to the follicular fluid (FF) contents of ovulation, is regarded as the main origin of ovarian high-grade serous carcinoma. Previously, we found that growth factors in FF, such as IGF2, are responsible for the malignant transformation of fallopian tube epithelium. 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–HGF activator (HGFA)–HGF cleavage cascade confers a sustained transformation activity to fallopian tube epithelium, high-grade serous carcinoma. 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.