Mechanism of Pro-Tumorigenic Effect of BMP-6: Neovascularization Involving Tumor-Associated Macrophages and IL-1α

INTRODUCTIONOverexpression of bone morphogenetic protein-6 (BMP-6) has been reported in human prostate cancer tissues. Previously we have demonstrated that BMP-6 enhances prostate cancer growth in mice and not in tissue culture. Herein, we have investigated the mechanism of BMP-6's pro-tumorigenic effect in prostate cancer. METHODSTramp C2 murine and LNCaP human prostate cancer cell lines were co-cultured with RAW 264.7 and THP-1 cells, respectively. IL-1 knockout mice were used to confirm the role of BMP-6/IL-1 loop in vivo. Lastly, conditional macrophage null mice cd11b-DTR was used. RESULTSThe results demonstrated that BMP-6 induced the expression of IL-1 in macrophages via a cross-talk between NF-B1 p50 and Smad1. When endothelial cells were treated with conditioned media harvested from macrophages incubated with BMP-6, tube formation was detected. In the presence of IL-1 neutralizing antibody, endothelial tube formation was blocked. In vivo, tumor growth and neovascularization decreased significantly when BMP-6 was expressed in IL-1 knockout and conditional macrophage-null mice. CONCLUSIONSProstate cancer-derived BMP-6 stimulates tumor-associated macrophages to produce IL-1 through a crosstalk between Smad1 and NF-B1; IL-1, in turn, promotes angiogenesis and prostate cancer growth. Prostate 74:121-133, 2014. (c) 2013 Wiley Periodicals, Inc.