Mechanism of pro-tumorigenic effect of BMP-6: neovascularization involving tumor-associated macrophages and IL-1a.

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.

• Authors: Seok Joo Kwon, Geun Taek Lee, Jae-Ho Lee, Yoichiro Iwakura, Wun-Jae Kim, Isaac Yi Kim
• Journal: The Prostate (Prostate) Vol. 74 Issue 2 Pg. 121-33 (Feb 2014) ISSN: 1097-0045 [Electronic] United States
• PMID: 24185914 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Wiley Periodicals, Inc.

Chemical References

• Bone Morphogenetic Protein 6
• Interleukin-1alpha
• NF-kappa B
• Smad1 Protein

Topics

• Animals
• Bone Morphogenetic Protein 6 (physiology)
• Carcinogenesis (pathology)
• Cell Differentiation (physiology)
• Cell Line, Tumor
• Cell Proliferation
• Coculture Techniques
• Endothelium, Vascular (pathology)
• Humans
• Interleukin-1alpha (deficiency, genetics, physiology)
• Macrophages (pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (physiology)
• Neovascularization, Pathologic (physiopathology)
• Prostatic Neoplasms (blood supply, pathology)
• Signal Transduction (physiology)
• Smad1 Protein (physiology)