Abstract 1086: Paracrine interactions between macrophages, adipocytes and tumor cells in the breast cancer microenvironment of the obese female mouse contribute to tumor progression

Abstract

Most studies linking obesity and cancer focus on the systemic effects of adiposity in tumorigenesis. The mammary gland has white adipose tissue required for normal gland development, yet the plausible role that this local breast fat may play in breast cancer, especially in obese females, has been overlooked. Whether obesity also promotes breast cancer through its effect in local adipose tissue inflammation and innate immune signaling in the breast, where cancer occurs, has not been thoroughly investigated. Adipocytes and tumor cells in the breast may recruit macrophages to the tumor microenvironment contributing to tumor progression, particularly in obese females. We examined the interplay between these three cell types and its effects on macrophage chemotaxis in an in vitro setting, using co-cultures of mouse peritoneal macrophages, E0771 murine mammary tumor cells and in vitro differentiated or ex vivo isolated adipocytes from murine obese fat tissue. We also exposed macrophages in vitro to the individual or mixed paracrine factors leptin, lauric acid, estrogen and CCL2 produced by fat and mammary tumor cells to study macrophage chemotaxis, cellular differentiation and M1/M2 activation profiles. Specific signaling inhibitors of these paracrine factors were used to analyze reversion of these actions and proteomics analyses was undertaken to identify novel molecules secreted by adipocytes and mammary tumor cells with actions on macrophages or on the tumor microenvironment. We centered on the adipokine leptin, which has a main role in breast cancer progression, and we showed that leptin decreases pro-inflammatory IL-12, nitric oxide and VEGF production in macrophages but does not alter IL-10 production. A novel leptin-signaling inhibitor peptide was also used in in vivo experiments with diet-induced obese female C57BL6 mice bearing the syngeneic E0771 mammary tumor cells to analyze reduction of tumor progression, tumor-associated macrophage recruitment, crown-like structures in the breast adipose tissue and tumor angiogenesis. Our results underscore the relevance of the interactions between macrophages, adipocytes and tumor cells in the breast cancer microenvironment for tumor progression and demonstrate that the synergistic actions of various paracrine factors from these different cell types play the most crucial role in macrophage recruitment and tumor progression. Citation Format: Ana M. Santander, Tulay Koru-Sengul, Olivia Casas, Lidia Sanchez, Osvaldo Perez, Marta Torroella-Kouri. Paracrine interactions between macrophages, adipocytes and tumor cells in the breast cancer microenvironment of the obese female mouse contribute to tumor progression. [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 1086. doi:10.1158/1538-7445.AM2014-1086