Abstract AS16: Ovulation and extraovarian origin of ovarian cancer
Authors: Yang-Hartwich Yang 
Published: August 2015

Abstract
High grade serous ovarian carcinoma (HGSOC) accounts for 70% of the approximately 26,000 diagnosed epithelial ovarian cancer cases every year. The majority of HGSOC patients are diagnosed at advanced stage when tumors have metastasized. The efforts of improving the prognosis and survival rate are hindered by our limited knowledge about the origin of ovarian cancer. Recent studies have revealed that the fallopian tube epithelial cells are the origin of HGSOC. Pre-malignant precursor lesions have been found in the fallopian tubes. Studies of genetically engineered mouse models supported the fallopian tube origin theory. However, one of the main questions that arise is how the malignant fallopian tube cells form tumors inside the ovary. In our study, we sought to identify the key factors and related pathways that can promote the extraovarian malignant cells to migrate toward the ovary and establish ovarian tumors.
In the ovary, the rupture and repair process during menstrual cycles repeatedly creates a local inflammatory microenvironment, in which chemokines, cytokines, and growth factors are produced. During ovulation, the ovary is a plausible source of chemotactic factors that can attract the movement of extraovarian malignant cells towards the ovary. Inside the ovary, the post-ovulatory inflammatory and pro-repair environment can provide tumorigenic factors that support malignant transformation or maintain malignant cell survival.
We utilized in vitro, ex vivo, xenograft, and allograft mouse models to recreate the process of extraovarian malignant cells migrating to the ovary to form tumors. Using in vitro migration assay, we demonstrated that SDF-1 secreated by ovarian granulosa cell attracts the migration of ovarian cancer cells. In the ex vivo organ culture model, we cocultured fluorescence-labeled ovarian cancer cells with mouse ovaries and observed the adhesion of cancer cells to the ovulatory wound areas. We further proved that ovarian stromal cell extracellular matrix provides better support to the adhesion of cancer cells than the ovarian surface epithelial cells. We also demonstrate that in mice the intra-vaginally injected extraovarian malignant cells can travel through the reproductive tract to the ovary and form ovarian tumors. With the superovulation model in mice, we showed that ovulation promoted the migration and adhesion of malignant cells to the ovary by disrupting the ovarian surface epithelium and releasing chemokines/cytokines. The exposure of collagen IV-enriched ovarian stroma at ovulatory wounds provides scaffold supporting the adhesion of malignant cells. These ovulation-associated factors contribute to ovarian tumor formation.
We conclude that during ovulation the ovary-secreted chemotactic factors can attract the movement of malignant cells towards the ovary. The unique microenvironment in the ovary supports the survival of cancer cells and triggers the progression of tumors. Our findings revealed the molecular mechanism behind the initiation of ovarian cancer and the association between increased ovulation and the risk of ovarian cancer in the epidemiological studies.
Citation Format: Yang Yang-Hartwich. Ovulation and extraovarian origin of ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS16.