title: Differential expression and tumor necrosis factor-mediated regulation of TNFRSF11b/osteoprotegerin production by human melanomas.
abstract: 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.
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA.
authors.forename: Janine L
authors.initials: JL
authors.lastname: Oliver
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Alexander
authors.forename: Allison G
authors.initials: AG
authors.lastname: Norrod
authors.forename: Irene M
authors.initials: IM
authors.lastname: Mullins
authors.forename: David W
authors.initials: DW
authors.lastname: Mullins
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008545:Melanoma / Q000276:immunology / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010010:Osteoclasts / Q000378:metabolism; D053244:Osteoprotegerin / Q000378:metabolism*; D010641:Phenotype; D011379:Prognosis; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D016207:Cytokines; D053244:Osteoprotegerin; C506030:TNFRSF11B protein, human; D014409:Tumor Necrosis Factor-alpha