Abstract B48: Breast tumor cell TACE-shed MCSF promotes pro-angiogenic macrophages through NF-κB signaling

Mortalities associated with breast cancer, the most common malignancy in women, are mainly due to metastases. Tumor associated macrophages (TAMs) significantly contribute to the development of metastasis through promotion of the rate limiting step of angiogenesis through secretion of vascular endothelial growth factor (VEGF). Macrophage differentiation and migration are activated by macrophage colony stimulating factor (MCSF) and chemokine (C-C motif) ligand 2 (CCL2), respectively. Whereas tumor cells secrete CCL2, MCSF release is mediated by ectodomain shedding through tumor necrosis factor alpha converting enzyme activation (TACE). How tumor cells support macrophage promotion of angiogenesis remains unclear. In the present study, we determined whether MCSF shed by TACE from tumor cells promotes angiogenesis through the activation of NF-κB signaling in macrophages and subsequent VEGF release. These studies were modeled in vitro using a panel of murine mammary cells mimicking breast cancer progression from normal murine mammary gland (NMuMG) cells to metastatic 4T1 cells along with J774 macrophages. TACE and MCSF expressions were higher in metastatic cells compared to epithelial cells (p