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

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Abstract

Most deaths associated with breast cancer, the most common malignancy in women, are caused by metastasis. Tumor associated macrophages significantly contribute to breast cancer progression and development of metastasis through the promotion of angiogenesis which involves a central regulator of macrophage functions: nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Macrophages are activated by macrophage colony stimulating factor (MCSF) and chemokine (C–C motif) ligand 2 (CCL2) to secrete angiogenic factors including vascular endothelial growth factor (VEGF). The release of MCSF from tumor cells is mediated by ectodomain shedding through tumor necrosis factor alpha converting enzyme activation (TACE). Here we determined whether tumor cells TACE-shed MCSF promotes angiogenesis through activation of the NF-κB pathway in macrophages and the subsequent release of VEGF. These interactions were modeled in vitro using a panel of mammary cells mimicking the breast cancer progression from normal murine mammary gland cells to metastatic 4T1 cells along with J774 macrophages, all derived from BALB/c mice. TACE and MCSF expressions were higher in metastatic cells compared to epithelial cells (p < 0.05). Tumor conditioned medias activated the expression of VEGF by macrophages through stimulation of the NF-κB pathway and resulting macrophage secretions that promoted high levels of endothelial cell tubes. Furthermore, the combinations of CCL2, also highly expressed by tumor cells, and MCSF promoted pro-angiogenic macrophages. These results highlight the key role of tumor cell TACE-shed MCSF and secreted CCL2 in stimulating pro-angiogenic macrophages.

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Acknowledgments

We would like to thank Amritha Kidiyoor for her diligent review of this manuscript. This work was supported by grants from the Department of Defense (Era of Hope program # BC044778) and the National Science Foundation (EFRI program # CBE0736007).

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The authors have no conflicts of interest to declare.

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  1. Cell and Molecular Division, Department of Biology, University of North Carolina, Charlotte, 9201 University City Blvd., Charlotte, NC, 28223, USA

    Stephen L. Rego, Rachel S. Helms & Didier Dréau

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Rego, S.L., Helms, R.S. & Dréau, D. Breast tumor cell TACE-shed MCSF promotes pro-angiogenic macrophages through NF-κB signaling. Angiogenesis 17, 573–585 (2014). https://doi.org/10.1007/s10456-013-9405-2

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