Role of the Omental Microenvironment in Ovarian Cancer Metastatic Colonization

摘要

In order to control ovarian cancer metastasis formation, there is significant interest in identifying the tissue microenvironments involved in cancer cell colonization of the omentum. Omental adipose is a site of prodigious metastasis in both ovarian cancer models and clinical disease. It is unusual as it contains milky spots, structures consisting of immune cells, stromal cells and structural elements surrounding glomerulus-like capillary beds. Contrary to studies reporting that omental colonization is adipocyte- driven, work presented herein shows that milky spots and adipocytes play distinct, complementary roles in omental metastatic colonization. Specifically, in vivo assays showed that ID8, CaOV3, HeyA8 and SKOV3ip.1 cancer cells preferentially lodge and grow within omental and splenoportal fat, which contain milky spots, as compared to other peritoneal fat depots. Similarly, media conditioned by milky spot-containing adipose tissue caused 75% more cell migration than media conditioned by milky spot-deficient adipose. Studies using a panel of immune-deficient mice showed that the mouse genetic background does not alter omental milky spot number and size, nor does it affect ovarian cancer colonization. Finally, consistent with the role for lipids as an energy source for cancer cell growth, in vivo time-course studies found an inverse relationship between metastatic burden and omental adipocyte content. Our findings provide new insights into the critical role milky spots play in omental metastatic colonization, the critical first step in the development of widespread peritoneal disease.