Ovulatory Wound: The Site Of Origin For Ovarian Serous Carcinoma

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: New clinical and molecular studies suggest that HGSOC originates from the neighboring fallopian tubes, rather than the surface epithelial layer of the ovary. However, very little is known about the process of tubal malignant cells migrating and implanting into ovary. Our research focuses on understanding how the extraovarian malignant cells implant into the ovary and how ovulation affects the process of their migration and implantation. Method: Tumor initiating cells (TICs) isolated from human HGSOC were labeled by red fluorescent protein (RFP)-expressing lentivirus and subcutaneously or intrauterine injected to immunocompromised mice. Hormones (PMS and HCG) were interperitoneally injected to induce superovulation in mice. In the in vitro models, TICs were cultured with the granulosa cell conditional medium and the extra cellular matrix (ECM) extracted from ovarian stroma cells to evaluate their effects on the migration and attachment of TICs Result: Superovulation increased the ovarian tumor-forming rate from 38% (15/39 in control group) to 100% (24/24 in supervolation group). The increased frequency of ovulation enhances the formation of ovarian tumors in mouse models. In the intrauterine injection model, we were able to trace the migration of TICs towards ovaries and capture the early implantation of TICs inside ovaries in 5-10 days after the injection. We detected stage I ovarian tumors in mice. The tumors are encapsulated in the ovary and covered by the intact surface epithelial layer. These tumor cells closely interacted with the stroma of ovary, particularly the structure of corpus luteum. The granulosa cells secreted stromal cell-derived factor 1 (SDF-1, also known as CXCL12). SDF-1 attracts TICs that express CXCR4 (the receptor of SDF-1) to ovulatory wounds. Upon ovulation the ovulatory wounds expose the stroma of ovary, which provides a collagen enriched ECM for TICs to attach. Conclusion: The unique ovulatory wound microenvironment attracts the malignant cells to migrate towards the ovary and creates access for the malignant cells to implant in the collagen-enriched ECM in the stroma of ovary. The new mechanisms revealed by our data may explain why increased ovulation is associated with epithelial ovarian cancer. Our findings support the “extra-ovarian origin” theory and will help us better understand the initiation and progression of HGSOC. Citation Format: Yang Yang-Hartwich, Marta Gurrea, Natalia Sumi, Jennie Holmberg, Vinicius Craveiro, Ayesha Alvero, Gil Mor. Ovulatory wound: the site of origin for ovarian serous carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1974. doi:10.1158/1538-7445.AM2014-1974