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Clinical & Experimental Metastasis

, Volume 31, Issue 8, pp 921–933 | Cite as

Targeting IL-6 and RANKL signaling inhibits prostate cancer growth in bone

  • Yu ZhengEmail author
  • Dennis Basel
  • Shu-Oi Chow
  • Colette Fong-Yee
  • Sarah Kim
  • Frank Buttgereit
  • Colin R. Dunstan
  • Hong Zhou
  • Markus J. SeibelEmail author
Research Paper

Abstract

In prostate cancer metastases to bone, cancer cell-derived cytokines stimulate RANKL expression by cells of the osteoblast lineage, which in turn activates osteoclastic bone resorption. However, it is unclear whether cells of the osteoblast lineage signal back to prostate cancer cells, and if so, whether such direct cross-talk can be targeted therapeutically. Using the human prostate cancer cell line, PC3, we identified two novel signalling pathways acting between cells of the osteoblast lineage and cancer cells. First, exposure to RANKL stimulated the expression and release of IL-6 by PC3 cells in vitro (which is known to promote RANKL expression by osteoblasts). Second, treatment of PC3 cells with IL-6 increased the expression of RANK, the cognate receptor of RANKL, and enhanced the RANKL-induced release of IL-6 by PC3 cells. Third, targeted disruption of IL-6 signaling with tocilizumab, a clinically available antibody against the human IL-6 receptor, inhibited skeletal tumor growth in vivo and reduced serum RANKL levels as well as RANK expression by PC3-derived bone tumors. Similar effects were achieved when RANK expression was knocked down in PC3 cells. In contrast, disruption of IL-6 or RANK/RANKL signalling had no effect on PC3 tumor growth in soft tissues, indicating that these signalling pathways act specifically within the bone microenvironment. In conclusion, prostate cancer cells and cells of the osteoblast lineage communicate via two inter-dependent signaling pathways, which through auto-amplification strongly enhance metastatic prostate cancer growth in bone. Both pathways may be targeted for effective therapeutic intervention.

Keywords

Bone metastasis Prostate cancer Interleukin-6 RANK RANKL Osteoblasts 

Notes

Acknowledgments

This work has been supported in part by the following Grants: Cure Cancer Foundation of Australia (Y.Z), Cancer Institute New South Wales (Y.Z), Cancer Council New South Wales (M.J.S, Y.Z, H.Z, C.R.D), Prostate Cancer Foundation of Australia (PCFA) (M.J.S, Y.Z, H.Z, C.R.D), University of Sydney Cancer Research Fund (M.J.S), National Health and Medical Research Council, Australia (NHMRC) (Y.Z, Early Career Fellowship 596870) and Bundesministerium für Bildung und Forschung (BMBF) and the State of Berlin (K.B. F.B., BCRT-Grant I and II). We thank Dr. Matthew Foley and the staff at the Australian Centre for Microscopy & Microanalysis, The University of Sydney for the facilities as well as scientific and technical assistance.

Conflict of interest

The authors disclose no potential conflicts of interest.

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Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Yu Zheng
    • 1
    Email author
  • Dennis Basel
    • 1
    • 3
  • Shu-Oi Chow
    • 1
  • Colette Fong-Yee
    • 1
  • Sarah Kim
    • 1
  • Frank Buttgereit
    • 2
    • 3
  • Colin R. Dunstan
    • 1
    • 4
  • Hong Zhou
    • 1
  • Markus J. Seibel
    • 1
    • 5
    Email author
  1. 1.Bone Research Program, ANZAC Research InstituteUniversity of SydneySydneyAustralia
  2. 2.Berlin-Brandenburg Center of Regenerative Therapies (BCRT)BerlinGermany
  3. 3.Rheumatology and Clinical ImmunologyCharité University Medicine and German Rheumatism Research Center (DRFZ)BerlinGermany
  4. 4.Department of Biomedical EngineeringUniversity of SydneySydneyAustralia
  5. 5.Department of Endocrinology and MetabolismConcord HospitalSydneyAustralia

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