Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue.

Ana Santander,Eduardo Lamas-Basulto,Olivia Casas,Marta Torroella-Kouri,Margot Cleary,Roberto Carrio,Omar Lopez-Ocejo,Thais Agostini,Lidia Sanchez,Ruben Gonzalez-Perez

doi:10.3390/cancers7010143

Abstract

The relationship between obesity and breast cancer (BC) has focused on serum factors. However, the mammary gland contains adipose tissue (AT) which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT) is inflamed in obese females and plays a major role in breast cancer development. The effects of this interplay on macrophage chemotaxis were examined in vitro, using co-cultures of mouse macrophages, mammary tumor cells and adipocytes. Macrophages were exposed to the adipocyte and tumor paracrine factors leptin, CCL2 and lauric acid (alone or in combinations). In cell supernatants Luminex identified additional molecules with chemotactic and other pro-tumor functions. Focus on the adipokine leptin, which has been shown to have a central role in breast cancer pathogenesis, indicated it modulates macrophage phenotypes and functions. In vivo experiments demonstrate that mammary tumors from obese mice are larger and that bAT from obese tumor-bearers contains higher numbers of macrophages/CLS and hypertrophic adipocytes than bAT from lean tumor-bearers, thus confirming it is more inflamed. Also, bAT distal from the tumor is more inflamed in obese than in lean mice. Our results reveal that bAT plays a role in breast cancer development in obesity.

Highlights

To determine how lipolysis within adipocytes in the breast gland could be modulated by the breast tumor microenvironment, we measured the release of free fatty acid (FFA) by adipocytes in the presence of mammary tumor cells and macrophages
Our data demonstrate (Figure 1) that co-culturing adipocytes with either macrophages or tumor cells resulted in less FFA detected in the cell co-culture supernatant, with a greater downregulation exerted when adipocytes were co-cultured with tumor cells than with macrophages, and the strongest decrease detected upon co-culture of adipocytes with both other cell types, a setting that mimics the breast tumor microenvironment
Our work demonstrates that crosstalk of adipocytes from obese adipose tissue with mammary tumor cells and macrophages contributes to monocyte recruitment and to the expression of diverse molecules that are chemotactic to macrophages and to other inflammatory cells in the tumor microenvironment

Summary

Introduction

Obesity has been recently recognized as a new disease and one of the leading health problems in the United States [1,2], associated with increased risk of cardiovascular disorders, diabetes and cancer [3].Breast cancer, the most common cancer in women and the second leading cause of mortality from this disease in our country, is a more prevailing and aggressive disease in overweight and obese women [4].Obesity increases the risk of developing ER+ postmenopausal breast cancer, there are contradictory evidences that obesity [5] or rather circulatory estrogen [6] protects against premenopausal breast cancer, while there are indications that it is associated with poor breast cancer prognosis regardless of menopausal status [7]. Obesity has been recently recognized as a new disease and one of the leading health problems in the United States [1,2], associated with increased risk of cardiovascular disorders, diabetes and cancer [3]. The most common cancer in women and the second leading cause of mortality from this disease in our country, is a more prevailing and aggressive disease in overweight and obese women [4]. Obesity increases the risk of developing ER+ postmenopausal breast cancer, there are contradictory evidences that obesity [5] or rather circulatory estrogen [6] protects against premenopausal breast cancer, while there are indications that it is associated with poor breast cancer prognosis regardless of menopausal status [7]. In previous studies we have shown that blood monocytes and peripheral and tumor-associated macrophages (TAMs) from mammary tumor-bearing mice are impacted to different degrees in their phenotypes and functions by the tumors and the factors they secrete [16,17,18,19,20]

Results

Discussion

Conclusion