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Abstract
The role of the tumor microenvironment, especially of tumor associated macrophages (TAMs), in the progression and metastatic spread of breast cancer is well established. TAMs are activated in the breast tumor microenvironment to express primarily a M2 (wound-healing) phenotype with minimal cytotoxic activities. The factors involved in the activation of TAMs to display a pro-tumor phenotype are still debated although the key roles of immunomodulatory cytokines released by tumor cells including colony stimulating factor 1 (CSF1), tumor necrosis factor (TNF) and soluble TNF receptors 1 / 2, soluble vascular cell adhesion molecule 1 (sVCAM1), soluble interleukin 6 receptor (sIL6R) and amphiregulin (AREG) have been demonstrated. Notably, these factors are all released through the mechanism of ectodomain shedding by activities of tumor necrosis factor alpha converting enzyme (TACE, i.e., a disintegrin and metalloproteinase 17 (ADAM17)). The role of TACE activation leading to autocrine effects on tumor progression has been studied in detail. In contrast, limited information is available on the role of tumor cell TACE activities on TAM functions in breast cancer. TACE inhibitors, currently in development for clinical trials, may influence TAMs and subsequently treatment outcomes through the substrates TACE releases. However, the mechanisms altered in macrophages following exposure to tumor cell TACE-shed cytokines and/or cytokine receptors remain unclear. Therefore, we first outline (1) the current understanding of the roles of molecules released by TACE ectodomain shedding from breast tumor cells on TAM phenotypes and functions. Next, we report (2) that tumor cell TACE activities specifically promote the shedding of TNFRs, which binds to and sequesters exogenous TNF, thereby preventing its pro-migratory effects on macrophages. These effects are shown to be mediated by the protein kinase B (AKT) signaling molecule, a common downstream target of TNFR2 but not of TNFR1. Further we detail (3) how tumor cell TACE-shed MCSF in combination with secreted chemokine (C-C motif) ligand 2 (CCL2) promote the secretion of vascular endothelial growth factor (VEGF) and subsequent angiogenesis. The pro-angiogenic abilities of these macrophages are shown to be dependent of nuclear factor kappa B (NFĸB) signaling. Finally, (4) these new data are summarized and discussed in the larger perspective of future research and treatments, harnessing the tumor stroma as a target in breast cancer. Overall, this research highlights specific mechanisms mediated by mammary tumor cell TACE-shed substrates involved in macrophage migration and promotion of angiogenesis that provide useful insights in the use of TACE inhibitors for the treatment of cancer as well as other potential targets involved in tumor cell modulation of TAMs.