Abstract A079: G-CSF released from ovulation recruits and activates neutrophils in the peritoneum to aid transformation, seeding, and invasion of high-grade serous carcinoma

Abstract

Abstract The incidence and mortality burden of ovarian high-grade serous carcinoma (HGSC) is increasing rapidly in Taiwan and many urbanized countries. The etiology of HGSC, especially that responsible for the rapid and advanced seeding of the tumor in the peritoneum, which causes late diagnosis and poor prognosis, is elusive. Epidemiological and molecular studies have demonstrated incessant ovulation is the main culprit of ovarian cancer. Our previous studies also elucidated some transforming factors in the ovulatory follicular fluid (FF). We unveiled the oncogenic activities of ovulation on the malignant transformation of fallopian tube fimbria epithelial cells (FTEC), the primary origin of HGSC. We hypothesized that ovulation could also promote the intraperitoneal spreading of tube originated HGSC. First, in both human and mouse specimens, we observed a dramatic influx of neutrophils in the peritoneal fluid during ovulation after LH surge. Ovulatory FF from IVF women, when injected to the mouse peritoneum cavity, readily induced neutrophil influx and activated neutrophil extracellular trap (NET) formation (NETosis). Among the different neutrophil activators in FF, we found G-CSF is responsible for the ROS and PAD4 increases and histone citrullination in NETosis. This FF-GCSF-induced NETosis increases anchoring independent growth (AIG), cell adhesions, and matrigel invasion of STIC-mimicking FTEC and HGSC cells. Interestingly, while the AIG-promoting activity of the ovulation-activated NET showed cell autonomous, the adhesion and invasion activities were non-autonomous conferred by the conditioned medium of the activated neutrophils. Shown by a FF plus tumor cell i.p. coinjection mouse xenograft model, intraperitoneal seeding was increased by the coinjection and was inhibited by the inhibitor (GSK) of NETosis. Taken together, we disclosed an unprecedented intraperitoneal neutrophil influx/activation activity of ovulation. This activity, presumably acting as an antimicrobial to prevent ascending infection during fertilization, is utilized to aid the peritoneal seedings of tubal-origin HGSC. Citation Format: Hsuan Shun Huang, Tang-Yuan Chu. G-CSF released from ovulation recruits and activates neutrophils in the peritoneum to aid transformation, seeding, and invasion of high-grade serous carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A079.