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The cellular mechanisms that account for the increase in osteoclast numbers and bone resorption in skeletal breast cancer metastasis are unclear. Osteoclasts are marrow-derived cells which form by fusion of mononuclear phagocyte precursors that circulate in the monocyte fraction. In this study we have determined whether circulating osteoclast precursors are increased in number or have an increased sensitivity to humoral factors for osteoclastogenesis in breast cancer patients with skeletal metastases (+/- hypercalcaemia) compared to patients with primary breast cancer and age-matched normal controls. Monocytes were isolated and cocultured with UMR 106 osteoblastic cells in the presence of 1,25 dihydroxyvitamin D3[1,25(OH)2D3] and human macrophage colony stimulating factor (M-CSF) on coverslips and dentine slices. Limiting dilution experiments showed that there was no increase in the number of circulating osteoclast precursors in breast cancer patients with skeletal metastases (+/- hypercalcaemia) compared to controls. Osteoclast precursors in these patients also did not exhibit increased sensitivity to 1,25(OH)2D3or M-CSF in terms of osteoclast formation. The addition of parathyroid hormone-related protein and interleukin-6 did not increase osteoclast formation. The addition of the supernatant of cultured breast cancer cell lines (MCF-7 and MDA-MB-435), however, significantly increased monocyte-osteoclast formation in a dose-dependent fashion. These results indicate that the increase in osteoclast formation in breast cancer is not due to an increase in the number/nature of circulating osteoclast precursors. They also suggest that tumour cells promote osteoclast formation in the bone microenvironment by secreting soluble osteoclastogenic factor(s).

Original publication

DOI

10.1054/bjoc.2001.1856

Type

Journal article

Journal

British journal of cancer

Publication Date

07/2001

Volume

85

Pages

78 - 84

Addresses

Nuffield Department of Pathology and Bacteriology, University of Oxford, John Radcliffe Hospital, Oxford, Headington, OX3 9DU, UK.

Keywords

Monocytes, Macrophages, Osteoclasts, Humans, Bone Neoplasms, Breast Neoplasms, Bone Resorption, Calcitriol, Parathyroid Hormone-Related Protein, Proteins, Macrophage Colony-Stimulating Factor, Interleukin-6, Culture Media, Conditioned, Coculture Techniques, Immunohistochemistry, Cell Differentiation, Aged, Aged, 80 and over, Middle Aged, Female