Direct Crosstalk Between Cancer and Osteoblast Lineage Cells Fuels Metastatic Growth in Bone via Auto-Amplification of IL-6 and RANKL Signaling Pathways

Authors

  • Yu Zheng,

    Corresponding author
    1. Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia
    2. The Kinghorn Cancer Centre and Cancer Research Program, Garvan Institute of Medical Research, Sydney, Australia
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  • Shu-Oi Chow,

    1. Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia
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  • Katja Boernert,

    1. Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia
    2. Rheumatology and Clinical Immunology, Charité University Medicine and German Rheumatism Research Center (DRFZ), Berlin, Germany
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  • Dennis Basel,

    1. Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia
    2. Rheumatology and Clinical Immunology, Charité University Medicine and German Rheumatism Research Center (DRFZ), Berlin, Germany
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  • Anastasia Mikuscheva,

    1. Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia
    2. Rheumatology and Clinical Immunology, Charité University Medicine and German Rheumatism Research Center (DRFZ), Berlin, Germany
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  • Sarah Kim,

    1. Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia
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  • Colette Fong-Yee,

    1. Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia
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  • Trupti Trivedi,

    1. Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia
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  • Frank Buttgereit,

    1. Rheumatology and Clinical Immunology, Charité University Medicine and German Rheumatism Research Center (DRFZ), Berlin, Germany
    2. Berlin-Brandenburg Center of Regenerative Therapies (BCRT), Berlin, Germany
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  • Robert L Sutherland,

    1. The Kinghorn Cancer Centre and Cancer Research Program, Garvan Institute of Medical Research, Sydney, Australia
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  • Colin R Dunstan,

    1. Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia
    2. Department of Biomedical Engineering, University of Sydney, Sydney, Australia
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  • Hong Zhou,

    1. Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia
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  • Markus J Seibel

    Corresponding author
    1. Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia
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ABSTRACT

The bone microenvironment and its modification by cancer and host cell interactions is a key driver of skeletal metastatic growth. Interleukin-6 (IL-6) stimulates receptor activator of NF-κB ligand (RANKL) expression in bone cells, and serum IL-6 levels are associated with poor clinical outcomes in cancer patients. We investigated the effects of RANKL on cancer cells and the role of tumor-derived IL-6 within the bone microenvironment. Using human breast cancer cell lines to induce tumors in the bone of immune-deficient mice, we first determined whether RANKL released by cells of the osteoblast lineage directly promotes IL-6 expression by cancer cells in vitro and in vivo. We then disrupted of IL-6 signaling in vivo either via knockdown of IL-6 in tumor cells or through treatment with specific anti-human or anti-mouse IL-6 receptor antibodies to investigate the tumor effect. Finally, we tested the effect of RANK knockdown in cancer cells on cancer growth. We demonstrate that osteoblast lineage-derived RANKL upregulates secretion of IL-6 by breast cancers in vivo and in vitro. IL-6, in turn, induces expression of RANK by cancer cells, which sensitizes the tumor to RANKL and significantly enhances cancer IL-6 release. Disruption in vivo of this auto-amplifying crosstalk by knockdown of IL-6 or RANK in cancer cells, or via treatment with anti-IL-6 receptor antibodies, significantly reduces tumor growth in bone but not in soft tissues. RANKL and IL-6 mediate direct paracrine-autocrine signaling between cells of the osteoblast lineage and cancer cells, significantly enhancing the growth of metastatic breast cancers within bone. © 2014 American Society for Bone and Mineral Research.

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