| Anticancer efficacy of Apo2L/TRAIL is retained in the presence of high and biologically active concentrations of osteoprotegerin in vivo. | |
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MedLine Citation:
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PMID: 20818644 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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Osteoprotegerin (OPG) is a secreted member of the tumor necrosis factor (TNF) receptor superfamily that binds to the ligand for receptor activator of nuclear factor κB (RANKL) and inhibits bone resorption. OPG can also bind and inhibit the activity of the TNF-related apoptosis-inducing ligand (Apo2L/TRAIL), raising the possibility that the anticancer efficacy of soluble Apo2L/TRAIL may be abrogated in the bone microenvironment where OPG expression is high. In this study we used a murine model of breast cancer growth in bone to evaluate the efficacy of recombinant soluble Apo2L/TRAIL against intratibial tumors that were engineered to overexpress native full-length human OPG. In vitro, OPG-overexpressing breast cancer cells were protected from Apo2L/TRAIL-induced apoptosis, an effect that was reversed with the addition of soluble RANKL or neutralizing antibodies to OPG. In vivo, mice injected intratibially with cells containing the empty vector developed large osteolytic lesions. In contrast, OPG overexpression preserved the integrity of bone and prevented breast cancer-induced bone destruction. This effect was due primarily to the complete absence of osteoclasts in the tibias of mice inoculated with OPG-transfected cells, confirming the biologic activity of the transfected OPG in vivo. Despite the secretion of supraphysiologic levels of OPG, treatment with Apo2L/TRAIL resulted in strong growth inhibition of both empty vector and OPG-overexpressing intratibial tumors. While Apo2L/TRAIL-induced apoptosis may be abrogated in vitro by OPG overexpression, the in vivo anticancer efficacy of recombinant soluble Apo2L/TRAIL is retained in the bone microenvironment even in the presence of biologically active OPG at supraphysiologic concentrations. © 2011 American Society for Bone and Mineral Research. |
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Authors:
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Irene Zinonos; Agatha Labrinidis; Michelle Lee; Vasilios Liapis; Shelley Hay; Vladimir Ponomarev; Peter Diamond; David M Findlay; Andrew Cw Zannettino; Andreas Evdokiou |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Volume: 26 ISSN: 1523-4681 ISO Abbreviation: J. Bone Miner. Res. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-02-21 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8610640 Medline TA: J Bone Miner Res Country: United States |
Other Details:
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Languages: eng Pagination: 630-43 Citation Subset: IM |
Copyright Information:
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Copyright © 2011 American Society for Bone and Mineral Research. |
Affiliation:
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Discipline of Orthopaedics and Trauma, Adelaide Cancer Research Institute, University of Adelaide, Adelaide, South Australia, Australia. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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