Ovulation Enhances Intraperitoneal and Ovarian Seedings of High-Grade Serous Carcinoma Cells Originating from the Fallopian Tube: Confirmation in a Bursa-Free Mouse Xenograft Model

Background: Recently, new paradigms for the etiology and origin of ovarian high-grade serous carcinoma (HGSC) have emerged. The carcinogens released during ovulation transform fallopian tube epithelial cells, exfoliating and metastasizing to the peritoneal organs, including the ovaries. Solid in vivo evidence of the paradigms in a mouse model is urgently needed but is hampered by the differing tubo-ovarian structures. In mice, there is a bursa structure surrounding the distal oviduct and ovary. This, on one hand, prevents the direct influence of ovulatory follicular fluid (FF) on the exfoliated tumor cells. On the other hand, it hinders the seeding of exfoliated tumor cells into the ovary. Methods: In this study, we created a bursa-free mouse xenograft model to examine the effect of superovulation on peritoneal and ovarian metastases of transformed human tubal epithelial cells after intraperitoneal injection in NSG mice. Results: The bursa-free mouse model showed a better effect of ovulation on peritoneal metastasis. In this model, superovulation increased the number of transformed human tubal epithelial cell seedlings after intraperitoneal injection. Compared to the bursa-intact state, bursa-free ovaries were more vulnerable to external tumor seeding in either normal ovulation or superovulation state. Conclusions: This study provides the first in vivo evidence that intraperitoneal spreading of tubal HGSC cells is enhanced by ovulation. This study also demonstrated a mouse model for studying ovary-peritoneum interaction in cancer development.