Breast Adipocyte Co-culture Increases the Expression of Pro-angiogenic Factors in Macrophages

Abstract

Obese individuals with breast cancer have a poorer prognosis and higher risk of metastatic disease vs. non-obese patients. Adipose tissue in obese individuals is characterized by an enhanced macrophage infiltration, creating a microenvironment that favors tumor progression. Here, we demonstrate a role for adipocyte-macrophage interactions in the regulation of angiogenesis. Co-culture of THP-1 macrophages with human breast adipocytes led to increased expression of the pro-angiogenic growth factor, vascular endothelial growth factor A (VEGFA). Several adipocyte-derived proteins including leptin, insulin, IL-6, and TNF-α were each capable of increasing VEGFA expression in THP-1 macrophages, identifying these as possible mediators of the changes that were observed with co-culture. Furthermore, analysis of THP-1 culture media by antibody array revealed that THP-1 secrete several other pro-angiogenic signals in response to adipocyte co-culture, including interleukin 8 (IL-8), matrix metalloproteinase 9 (MMP9), pentraxin 3 (PTX3), and serpin E1 (plasminogen activator inhibitor 1, PAI1) after co-culture with human adipocytes. We used an in vitro endothelial tube formation assay with human vascular endothelial cells to evaluate the effects of THP-1 culture media on angiogenesis. Here, culture media from THP-1 cells previously exposed to human adipocytes stimulated endothelial tube formation more significantly than THP-1 cells cultured alone. In summary, we find that adipocyte co-culture stimulates the expression of pro-angiogenic mediators in macrophages and has pro-angiogenic effects in vitro, thus representing a possible mechanism for the enhanced risk of breast cancer progression in obese individuals.

Cancer-associated adipocytes: emerging supporters in breast cancer

“…Several adipokines including leptin, IL-6, and TNF-α are capable of increasing VEGFA expression in THP-1 macrophages co-cultured with adipocytes. Compared with THP-1 cells cultured alone, the medium of THP-1 cells previously exposed to human adipocytes stimulated endothelial tube formation more significantly [ 102 ]. Therefore, revealing the underlying mechanisms of adipocyte-driven immune cells and immune cascades is necessary to understand the role of adipokines in TME.…”

The pleiotropic roles of adipocyte secretome in remodeling breast cancer

“…The loss of adipocyte specification and necrosis directly activated macrophages and thus enhanced the inflammation state in TME. The combination of soluble breast adipocyte-derived leptin, insulin, IL-6, and TNF-α were inducers of the release of angiogenic mediators in macrophages, representing a potential mechanism for the enhanced risk of breast cancer progression in obese individuals [ 116 ]. Yadav et al indicated that some adipocyte-derived mediators, such as leptin, insulin, IL-6, and TNF-α, could facilitate VEGF content in THP-1 macrophages in co-culture model.…”

Current Landscape: The Mechanism and Therapeutic Impact of Obesity for Breast Cancer

“…Insulin can act synergistically with inflammation to promote BC growth and metastasis (58). Insulin could increase the expression of VEGFA in macrophages and have proangiogenic effects in vitro endothelial tube formation assay (33). Rabin-Court et al validated that the obesity-driven elevated insulin could upregulate mitochondrial glucose oxidation in obesity-associated tumor cell lines (BC, colon cancer, and prostate cancer cells) correlated with a dosedependent increase in cell division (59).…”