Pharmacologic inhibition of bone resorption prevents cancer-induced osteolysis but enhances soft tissue metastasis in a mouse model of osteolytic breast cancer

Zinonos,Irene; Luo,Ke-Wang; Labrinidis,Agatha; Liapis,Vasilios; Hay,Shelley; Panagopoulos,Vasilios; Denichilo,Mark; Ko,Chun-Hay; Yue,Grace  Gar-Lee; Lau,Clara  Bik-San; Ingman,Wendy; Ponomarev,Vladimir; Atkins,Gerald  J.; Findlay,David  M.; Zannettino,Andrew C.W.; Evdokiou,Andreas

doi:10.3892/ijo.2014.2468

Pharmacologic inhibition of bone resorption prevents cancer-induced osteolysis but enhances soft tissue metastasis in a mouse model of osteolytic breast cancer

Authors:
- Irene Zinonos
- Ke-Wang Luo
- Agatha Labrinidis
- Vasilios Liapis
- Shelley Hay
- Vasilios Panagopoulos
- Mark Denichilo
- Chun-Hay Ko
- Grace Gar-Lee Yue
- Clara Bik-San Lau
- Wendy Ingman
- Vladimir Ponomarev
- Gerald J. Atkins
- David M. Findlay
- Andrew C.W. Zannettino
- Andreas Evdokiou
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Affiliations: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, Australia, 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, School of Medicine at the Basil Hetzel Institute, The Queen Elizabeth Hospital, Woodville and the Robinson Institute, University of Adelaide, Adelaide, Australia, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA, Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, Australia, Myeloma Research Laboratory, School of Medical Sciences, Faculty of Health Science and Centre for Personalized Cancer Medicine, University of Adelaide, Adelaide, Australia
Published online on: May 27, 2014 https://doi.org/10.3892/ijo.2014.2468
Pages: 532-540
Copyright: © Zinonos et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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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.

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