Obesity Contributes to Ovarian Cancer Metastatic Success through Increased Lipogenesis, Enhanced Vascularity, and Decreased Infiltration of M1 Macrophages
Yueying Liu1,2, Matthew N. Metzinger2, Kyle A. Lewellen1,2, Stephanie N. Cripps3, Kyle D. Carey2, Elizabeth I. Harper4, Zonggao Shi1,2, Laura Tarwater2, Annie Grisoli2,5, Eric Lee2, Ania Slusarz6,7, Jing Yang1,2, Elizabeth A. Loughran1,2, Kaitlyn Conley1,2, Jeff J. Johnson1,2, Yuliya Klymenko2,5, Lana Bruney2,7, Zhong Liang1,2, Norman J. Dovichi1,2, Bentley Cheatham8, W. Matthew Leevy2,5, and M. Sharon Stack1,2,*
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy, with high mortality attributable to widespread intraperitoneal metastases. Recent meta-analyses report an association between obesity, ovarian cancer incidence, and ovarian cancer survival, but the effect of obesity on metastasis has not been evaluated. The objective of this study was to use an integrative approach combining in vitro, ex vivo, and in vivo studies to test the hypothesis that obesity contributes to ovarian cancer metastatic success. Initial in vitro studies using three-dimensional mesomimetic cultures showed enhanced cell–cell adhesion to the lipid-loaded mesothelium. Furthermore, in an ex vivo colonization assay, ovarian cancer cells exhibited increased adhesion to mesothelial explants excised from mice modeling diet-induced obesity (DIO), in which they were fed a 「Western」 diet. Examination of mesothelial ultrastructure revealed a substantial increase in the density of microvilli in DIO mice. Moreover, enhanced intraperitoneal tumor burden was observed in overweight or obese animals in three distinct in vivo models. Further histologic analyses suggested that alterations in lipid regulatory factors, enhanced vascularity, and decreased M1/M2 macrophage ratios may account for the enhanced tumorigenicity. Together, these findings show that obesity potently affects ovarian cancer metastatic success, which likely contributes to the negative correlation between obesity and ovarian cancer survival. Cancer Res; 75(23); 5046–57. ©2015 AACR.