Abstract 4853: Omental milky-spots serve as a niche for ovarian cancer metastatic colonization

Abstract

Abstract Metastatic ovarian cancer remains an urgent clinical problem. The homing and invasion of cancer cells into the omental adipose tissue, the preferred site of ovarian cancer metastasis, is a rate-limiting step in disease progression. Improving patient outcomes requires a mechanistic understanding of how cancer cells colonize the omentum and ultimately give rise to widespread peritoneal metastases. Unlike other peritoneal adipose, omental adipose contains functional immune aggregates known as milky spots, which contain macrophages, B, T, natural killer (NK), and stromal cells within capillary nests. In addition to their role in peritoneal homeostasis and immune defense, our data shows that milky spots play an active role in ovarian cancer metastatic colonization. We hypothesize that omental microenvironment plays a crucial role in instructing the ovarian cancer cells to achieve an aggressive phenotype that enables wide spread metastases. Well-established in vitro migration assays and in vivo experimental metastasis assays were used to answer the following questions: Does cancer cell localization depend upon the immune composition of the milky spots? Do cancer cells utilize the native milky spot microenvironment, or does it undergo remodeling during colonization? Answers to these questions will be the foundation for mechanism-based studies aimed at identifying ovarian cancer-omental interactions that can be targeted therapeutically. Human (SKOV3ip.1, CaOV3, HeyA8), and murine (ID8) ovarian cancer cells rapidly localized to omental milky spots and not adipose lacking milky spots. Use of genetic models (C57BL/6, Athymic Nude, Beige Nude, Rag1-/-, Igh6-/- mice) ruled out a requirement of B, T, and NK cells in ovarian cancer cell homing to milky spots suggesting a critical role for macrophages in this process. Quantitative data found no difference in the incidence of cancer cell foci in the omentum across these strains. Our recent data shows that depletion of omental adipose tissue macrophages (ATM) abrogates cancer cell colonization of milky spots. In vitro assays have found that omental adipose-conditioned media causes 75% more cell migration and contains a higher concentration of macrophage-secreted cytokines than media conditioned by adipose lacking milky spots. Importantly, our data shows that factors secreted by omental ATMs have an enhanced ability to promote ovarian cancer migration compared to factors secreted by other peritoneal ATMs. We have shown that omental milky spots are required for cancer colonization of peritoneal adipose. Further, we have identified omental macrophages as the key mediators of colonization. Future studies are focused on understanding the cancer cell-macrophage interactions that can be targeted therapeutically to disrupt metastatic growth and extend disease-free survival. Acknowledgement: The DOD (W81XWH-09-1-0127), NCI/NIH (2RO1CA089569) and Marsha Rivkin Center Pilot Study Award. Note: This abstract was not presented at the meeting. Citation Format: Venkatesh Krishnan, Robert Clark, Carrie Rinker-Schaeffer. Omental milky-spots serve as a niche for ovarian cancer metastatic colonization. [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 4853. doi:10.1158/1538-7445.AM2014-4853