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Differential expression and tumor necrosis factor-mediated regulation of TNFRSF11b/osteoprotegerin production by human melanomas

Authors

  • Janine L. Oliver,

    1. Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA
    Current affiliation:
    1. Division of Urologic Surgery, Washington University School of Medicine, St. Louis, MO, USA
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  • Matthew P. Alexander,

    1. Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
    2. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
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  • Allison G. Norrod,

    1. Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA
    Current affiliation:
    1. Department of Ophthalmology, West Virginia University School of Medicine, Morgantown, WV, USA
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  • Irene M. Mullins,

    1. Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
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  • David W. Mullins

    Corresponding author
    1. Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
    2. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
    • Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA
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Correspondence David W. Mullins, e-mail: david.w.mullins@dartmouth.edu

Summary

Tumors escape host immune responses, in part, through the release of immunomodulatory factors and decoy receptors into their microenvironment. Several cancers express surface-bound and soluble members of the tumor necrosis factor (TNF) receptor superfamily, including TNFRSF11b/osteoprotegerin (OPG). In its physiologic role, OPG regulates bone remodeling through competition for osteoclast-activating cytokines and protects newly forming bone from T cell-mediated apoptosis. In multiple tumor types, OPG production is associated with an aggressive phenotype and increased metastasis to bone, but no study has examined OPG production in human metastatic melanoma. We demonstrate that a significant proportion of human metastatic melanomas constitutively produces OPG through a mechanism governed by membrane-bound TNF-α signaling through TNF receptor 1 (TNFR1). These observations both define a specific mechanism that regulates melanoma production of OPG and establish a new molecular target for the therapeutic regulation of OPG.

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