title: Pharmacologic inhibition of bone resorption prevents cancer-induced osteolysis but enhances soft tissue metastasis in a mouse model of osteolytic breast cancer.
abstract: Osteoprotegerin (OPG) is a secreted member of the TNF receptor superfamily, which binds to the receptor activator of nuclear factor κB ligand (RANKL) and inhibits osteoclast activity and bone resorption. Systemic administration of recombinant OPG was previously shown to inhibit tumor growth in bone and to prevent cancer-induced osteolysis. In this study, we examined the effect of OPG, when produced locally by breast cancer cells located within bone, using a mouse model of osteolytic breast cancer. MDA-MB-231-TXSA breast cancer cells, tagged with a luciferase reporter gene construct and engineered to overexpress full-length human OPG, were transplanted directly into the tibial marrow cavity of nude mice. Overexpression of OPG by breast cancer cells protected the bone from breast cancer-induced osteolysis and diminished intra-osseous tumor growth but had no effect on extra-skeletal tumor growth. This effect was associated with a significant reduction in the number of osteoclasts that lined the bone surface, resulting in a net increase in bone volume. Despite limiting breast cancer-mediated bone loss, OPG overexpression resulted in a significant increase in the incidence of pulmonary metastasis. Our results demonstrate that inhibition of osteoclastic bone resorption by OPG when secreted locally by tumors in bone may affect the behaviour of cancer cells within the bone microenvironment and their likelihood of spreading and establishing metastasis elsewhere in the body.
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Irene
authors.initials: I
authors.lastname: Zinonos
authors.affiliation: Institute of Chinese Medicine and State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Hong Kong, P.R. China.
authors.forename: Ke-Wang
authors.initials: KW
authors.lastname: Luo
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Agatha
authors.initials: A
authors.lastname: Labrinidis
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Liapis
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Shelley
authors.initials: S
authors.lastname: Hay
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Panagopoulos
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Denichilo
authors.affiliation: Institute of Chinese Medicine and State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Hong Kong, P.R. China.
authors.forename: Chun-Hay
authors.initials: CH
authors.lastname: Ko
authors.affiliation: Institute of Chinese Medicine and State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Hong Kong, P.R. China.
authors.forename: Grace Gar-Lee
authors.initials: GG
authors.lastname: Yue
authors.affiliation: Institute of Chinese Medicine and State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Hong Kong, P.R. China.
authors.forename: Clara Bik-San
authors.initials: CB
authors.lastname: Lau
authors.affiliation: School of Medicine at the Basil Hetzel Institute, The Queen Elizabeth Hospital, Woodville and the Robinson Institute, University of Adelaide, Adelaide, Australia.
authors.forename: Wendy
authors.initials: W
authors.lastname: Ingman
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ponomarev
authors.affiliation: Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, Australia.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Atkins
authors.affiliation: Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Findlay
authors.affiliation: Myeloma Research Laboratory, School of Medical Sciences, Faculty of Health Science and Centre for Personalized Cancer Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Andrew C W
authors.initials: AC
authors.lastname: Zannettino
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Evdokiou
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000556:secondary*; D001862:Bone Resorption / Q000378:metabolism*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D010014:Osteolysis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D053244:Osteoprotegerin / Q000378:metabolism*; D012983:Soft Tissue Neoplasms / Q000556:secondary*; D014162:Transfection; D055114:X-Ray Microtomography
chemical_list: D053244:Osteoprotegerin