Mechanism of pro-tumorigenic effect of BMP-6: Neovascularization involving tumor-associated macrophages and IL-1α

Seok Joo Kwon, Geun Taek Lee, Jae Ho Lee, Yoichiro Iwakura, Wun Jae Kim, Isaac Kim

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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-1α knockout mice were used to confirm the role of BMP-6/IL-1α loop in vivo. Lastly, conditional macrophage null mice cd11b-DTR was used. RESULTS The results demonstrated that BMP-6 induced the expression of IL-1α in macrophages via a cross-talk between NF-κB1 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-1α neutralizing antibody, endothelial tube formation was blocked. In vivo, tumor growth and neovascularization decreased significantly when BMP-6 was expressed in IL-1α knockout and conditional macrophage-null mice. CONCLUSIONS Prostate cancer-derived BMP-6 stimulates tumor-associated macrophages to produce IL-1α through a crosstalk between Smad1 and NF-κB1; IL-1α, in turn, promotes angiogenesis and prostate cancer growth. Prostate 74:121-133, 2014.

Original languageEnglish (US)
Pages (from-to)121-133
Number of pages13
JournalProstate
Volume74
Issue number2
DOIs
StatePublished - Feb 1 2014

All Science Journal Classification (ASJC) codes

  • Oncology
  • Urology

Keywords

  • IL-1α
  • NF-κB
  • Smads
  • angiogenesis
  • bone morphogenetic proteins
  • macrophages
  • prostate cancer

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