Pigment epithelium–derived factor promotes peritoneal dissemination of ovarian cancer through induction of immunosuppressive macrophages

Peritoneal dissemination of ovarian cancer (OC) correlates with poor prognosis, but the mechanisms underlying the escape of OC cells from the intraperitoneal immune system have remained unknown. We here identify pigment epithelium–derived factor (PEDF) as a regulator of OC cell dissemination, which functions through induction of CD206+ IL-10–producing macrophages. High PEDF gene expression was associated with poor prognosis in OC patients. Concentrations of PEDF in ascites and serum were significantly higher in OC patients than those with more benign tumors and correlated with early recurrence of OC patients, suggesting that PEDF might serve as a prognostic biomarker. Bromodomain and extraterminal (BET) inhibitors were found to reduce PEDF expression and limit both OC cell survival and CD206+ macrophage induction in the peritoneal cavity. Our results thus implicate PEDF as a driver of OC dissemination and identify a BET protein–PEDF–IL-10 axis as a promising therapeutic target for OC. To characterize the mechanisms by which OC cells disseminate into the peritoneal cavity, we established a new cell line through in vivo selection of ID8 mouse OC cells that express GFP (ID8G cells). 3 to 4 months after i.p. injection of ID8G cells, GFP-positive cells were isolated from omental tumors by the cell sorter and were termed GO cells. GO cells were subsequently recycled with i.p. injection. GFP-positive cells isolated from the resulting omental tumors were designated GO2 cells. To identify the genes involved in peritoneal dissemination of ovarian cancer,we compared global gene expression profiles in ID8G and GO2 cells using Agilent mouse genome microarray.