title: 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.forename: Seok Joo
authors.initials: SJ
authors.lastname: Kwon
authors.forename: Geun Taek
authors.initials: GT
authors.lastname: Lee
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.forename: Isaac Yi
authors.initials: IY
authors.lastname: Kim
mesh_terms: D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000502:physiology*; D063646:Carcinogenesis / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000473:pathology; D006801:Humans; D053582:Interleukin-1alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D051898:Smad1 Protein / Q000502:physiology
chemical_list: D055418:Bone Morphogenetic Protein 6; D053582:Interleukin-1alpha; D016328:NF-kappa B; D051898:Smad1 Protein