Abstract 5202: Pigment epithelium-derived factor promotes tumor dissemination of ovarian cancer cells through an interaction with peritoneal immune system
Authors: Ueno Sayaka , Sugihara Eiji , Sudo Tamotsu , Saya Hideyuki 
Published: August 2018

Ovarian cancer is a gynecological malignancy with a high mortality rate. Patients with ovarian cancer are diagnosed at an advanced stage of the disease with massive peritoneal dissemination. However, the underlying mechanism by which ovarian cancer cells preferentially colonize the omentum is still poorly understood. In this study, we have identified the factors and mechanisms which promote ovarian cancer dissemination by regulating peritoneal immune system. First, we established a mouse ovarian cancer cell line, ID8GO2, with an increased ability to disseminate in the peritoneal cavity by in vivo passage of ID8 cells in B6J mice. To determine the candidate genes that drive the dissemination, we examined the differences in gene expression profiles between two cell lines. Expression of the candidate genes in human ovarian cancer tissues and their correlation with the clinical outcomes of patients were also analyzed using public database. We found that pigment epithelium-derived factor (PEDF) was the most relevant gene associated with poor prognosis. To clarify whether PEDF contributes to peritoneal dissemination, ID8 cells were retrovirally transduced with mouse PEDF (ID8-PEDF) or empty vector (ID8-EV) and transplanted into the syngeneic mouse peritoneal cavity. All mice transplanted with ID8-PEDF cells developed intraperitoneal dissemination more rapidly and the overall survival time was significantly shorter than that in mice transplanted with ID8-EV cells. Moreover, ID8-PEDF cells survived longer in the peritoneal cavity. We further found that ID8 cells originally consisted of clones with varied PEDF expression. Transplantation of the PEDF-high clones resulted in faster development of intraperitoneal dissemination and shorter overall survival than that of the PEDF-low clones. These findings suggest that PEDF contributes to peritoneal dissemination of ovarian cancer cells, and cells with high initial PEDF expression are selected during dissemination. Next, to clarify the mechanism underlying the role of PEDF in peritoneal dissemination, intraperitoneal immune cell subsets in tumor bearing mice were analyzed. Peritoneal macrophages in mice transplanted with ID8-PEDF cells displayed alternative activated macrophage phenotype (F4/80+ CD206+) and high IL10 expression. Interestingly, at later time point, regulatory T and regulatory B cells were induced in the peritoneal cavity. Collectively, these findings suggest that PEDF plays an important role in the peritoneal dissemination of ovarian cancer cells potentially by regulating macrophages and regulatory lymphocytes to evade the peritoneal immune system.

Citation Format: Sayaka Ueno, Eiji Sugihara, Tamotsu Sudo, Hideyuki Saya. Pigment epithelium-derived factor promotes tumor dissemination of ovarian cancer cells through an interaction with peritoneal immune system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5202.