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- Title
Mechanism of pro-tumorigenic effect of BMP-6: neovascularization involving tumor-associated macrophages and IL-1a.
- Authors
Kwon, Seok Joo; Lee, Geun Taek; Lee, Jae-Ho; Iwakura, Yoichiro; Kim, Wun-Jae; Kim, Isaac Yi
- Abstract
INTRODUCTION. Overexpression 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. METHODS. Tramp C2 murine and LNCaP human prostate cancer cell lines were co-cultured with RAW 264.7 and THP-1 cells, respectively. IL-1a knockout mice were used to confirm the role of BMP-6/IL-1a loop in vivo. Lastly, conditional macrophage null mice cd11b-DTR was used. RESULTS. The results demonstrated that BMP-6 induced the expression of IL-1a in macrophages via a cross-talk between NF-kB1 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-1a neutralizing antibody, endothelial tube formation was blocked. In vivo, tumor growth and neovascularization decreased significantly when BMP-6 was expressed in IL-1a knockout and conditional macrophage-null mice. CONCLUSIONS. Prostate cancer-derived BMP-6 stimulates tumor-associated macrophages to produce IL-1a through a crosstalk between Smad1 and NF-kB1; IL-1a, in turn, promotes angiogenesis and prostate cancer growth.
- Publication
The Prostate, 2014, Vol 74, Issue 2, p121
- ISSN
1097-0045
- Publication type
Journal Article
- DOI
10.1002/pros.22734