Cellular mechanisms of bone resorption in breast carcinoma

Abstract

Bone destruction is a major complication of advanced malignant disease. It causes bone pain, pathological fracture and hypercalcaemia. Tumour-associated osteolysis and hypercalcaemia is seen in association with haematological malignancies (e.g. myeloma, lymphoma) and solid tumours, mainly carcinomas, where it may occur both in the presence (e.g. cancer of the lung, breast, thyroid, kidney, etc.) and absence (e.g. cancer of the lung, breast, head and neck, kidney, ovary, etc.) of bone metastases (Mundy, 1991;Dodwell, 1992). Bone is one of the commonest sites of metastasis in breast cancer and hypercalcaemia is seen in about one half of patients with clinical evidence of breast carcinoma.The cellular and molecular mechanisms that account for the bone destruction and consequent hypercalcaemia which occurs in patients with advanced malignant disease are poorly understood. Osteoclasts, multinucleated cells which form part of the mononuclear phagocyte system (Athanasou, 1996), effect the bone resorption in patients with skeletal metastasis (Galasko, 1976;Taube et al, 1994). Osteoclasts are formed by fusion of circulating mononuclear precursors cells of haematopoietic origin. In vitro studies have defined the ontogeny of the osteoclast and characterized the essential cellular and humoral factors which are required for osteoclast differentiation from haematopoietic and circulating osteoclast precursors. In both mouse and man, mononuclear osteoclast precursors circulate in the monocyte fraction and express a monocyte/macrophage rather than an osteoclast phenotype (Udagawa et al, 1990;Quinn et al, 1996;Fujikawa et al, 1996). Osteoclast differentiation from these circulating precursors requires the presence of M-CSF and involves a receptor-ligand interaction with osteoblasts which express a membrane-bound osteoclast differentiation factor (ODF) Yasuda et al, 1998).In previous studies we have shown that tumour-associated macrophages (TAMs) isolated from primary human breast and mouse mammary carcinomas, when cocultured with bone-derived stromal cells in the presence of 1,25(OH) 2 D 3 and M-CSF, are able to differentiate into multinucleated osteoclasts that are capable of extensive lacunar bone resorption (Quinn et al, 1994(Quinn et al, , 1998. This finding is of interest with regard to the pathogenesis of tumour osteolysis in breast cancer as, in addition to an increase in osteoclast number, a prominent macrophage infiltrate is commonly found in metastatic breast carcinomas (Bugelski et al, 1987;Van Ravenswaay Claasen et al, 1992). Moreover, osteoclasts are required for growth of breast cancer metastases in bone and tumour osteolysis involves recruitment of osteoclast precursors and activation of mature osteoclasts (Clohisy et al, 1996a(Clohisy et al, , 1996bClohisy and Ramnaraine, 1998).In this study, our aim has been to analyse the cellular mechanisms of bone resorption in breast cancer. As TAMs in metastases of breast cancer are derived from circulating monocytes (Mantovani et al, 1992), we have sought to determine wheth...

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