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

Abstract

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.

Insulin‐like growth factor (IGF) and hepatocyte growth factor (HGF) in follicular fluid cooperatively promote the oncogenesis of high‐grade serous carcinoma from fallopian tube epithelial cells: Dissection of the molecular effects

“…In addition to the mutagenic effect, FF enhanced the full course of FTE transformation 24,25 . A broad spectrum of cell transformation phenotypes, such as stemness, clonal expansion, anchorage‐independent growth (AIG), migration, invasion, anoikis resistance, and peritoneal attachment, were all found to be enhanced by FF 24,26 .…”

“…23 In addition to the mutagenic effect, FF enhanced the full course of FTE transformation. 24,25 A broad spectrum of cell transformation phenotypes, such as stemness, clonal expansion, anchorageindependent growth (AIG), migration, invasion, anoikis resistance, and peritoneal attachment, were all found to be enhanced by FF. 24,26 Besides the ROS, we have identified insulin-like growth factor (IGF2) and hepatocyte growth factor (HGF) as the essential oncogenic growth factors in FF.…”

Ovulation provides excessive coagulation and hepatocyte growth factor signals to cause postoperative intraabdominal adhesions

“…xenograft tumorigenesis mouse experiment where, compared to the pro-tumorigenic effect of normal ovulation, superovulation did not increase the severity of the intraperitoneal seeding of high-grade serous carcinoma cells. 32 The same study also showed that the bursa-removed ovary ovulated normally and readily released FF to enhance tumor growth, thus clarifying whether bursectomy would compromise ovulation function. 32 Meanwhile, we also, chose ovariectomy surgery in the i.p.…”

“… 32 The same study also showed that the bursa-removed ovary ovulated normally and readily released FF to enhance tumor growth, thus clarifying whether bursectomy would compromise ovulation function. 32 Meanwhile, we also, chose ovariectomy surgery in the i.p. FF injection mouse model to avoid the disturbance of endogenous ovulation and specifically examine the effect of exogenous FF exposure on wound healing.…”

Molecular Histopathology for Establishing Diagnostic Method and Clinical Therapy for Ovarian Carcinoma

“…Molecular biology is characterized by TP53 mutations in almost all cases, resulting in high rates of genomic and chromosomal instabilities during carcinogenesis. Several lines of evidence now indicate that these tumors may originate from the epithelium of the fimbrial portion of the fallopian tube and/or the ovarian surface epithelium [18][19][20][21]. Uterine serous carcinoma (USC) is an overlooked component of breast cancer susceptibility gene 1/2 (BRCA1/2)-associated hereditary breast and ovarian cancer (HBOC) syndrome.…”