Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate and its use in reducing osteoporosis and cancer-induced osteolysis is increasing. Recent findings indicated that ZOL has a direct effect on cancer cells. In this study, the effect of ZOL was examined on the aggressive MDA-MB-231 breast cancer cell line. ZOL induces an important inhibition of cell invasion at low concentrations (1 mM). This is not explained by modifications of proteases involved in cell invasiveness (matrix metalloproteinases and urokinase-type plasminogen activator), but by a disorganisation of actin cytoskeleton due to RhoA inhibition related to its defective prenylation as it was reversed by geranylgeraniol (GGOH) and mimicked by the Rho selective inhibitor C3 exoenzyme. In addition, ZOL inhibits the chemotactic effect induced by stromal cell-derived factor 1(SDF-1), a chemokine greatly involved in cancer metastasis to bone. This effect is related to both reduction of cell motility induced by RhoA inhibition and to a decreased expression of CXCR-4, the SDF-1 receptor. Finally, ZOL reduces Cox-2 expression and, consequently, the secretion of prostaglandins E2 (PGE2) in a RhoAindependent manner. This inhibition could contribute to bone protection in breast cancers because PGE2 stimulates osteoclastmediated bone resorption. In summary, new insights in the mechanism of ZOL action on aggressive breast cancer cells are demonstrated and could explain its beneficial action in both the reduction of osteolysis and prevention of metastasis.

In breast cancers, clinical symptoms of inflammation localised around the tumour at the time of diagnosis have been considered to have poor prognosis significance. In this study, the biological mechanisms responsible for the deleterious action of monocytes in cancer were investigated. The incubation of the breast-cancer-derived MDA-MB231 cells with monocytes resulted in an increase in factors involved in cell invasion (i.e. both cancer cells and monocytes-associated urokinase and Tissue Factor, and PAI-1 and MMP-9 secretion). Moreover, the functions of monocytes were also modified. Incubation of monocytes with MDA-MB231 cancer cells resulted in a downregulation in the secretion of the antiproliferative cytokine Oncostatin M, while the apoptotic factor TNF alpha was dramatically increased. However, MDA-MB231 cancer cells have been shown to be resistant towards the apoptotic action of TNF alpha. These findings demonstrate that incubation of MDA-MB231 cancer cells with monocytes induced a crosstalk, which resulted in an increased expression of factors involved in cancer cell invasiveness and in a modification of monocytes function against cancer cells, while inflammatory effects were increased. British Journal of Cancer (2003) The importance of stroma in cancer formation, growth and dissemination is now well established. In order to generate an invasive tumour, cancer cells need several mutations, but also formally necessitate sustenance from noncancer stroma cells, which supply and permit cancer cell growth and invasion. The presence of cytokines and inflammatory cells in cancer stroma, indicating defence reaction against cancer, generally correspond to a poor prognosis (Kleer et al, 2000). Furthermore, in breast cancer, initial presentation with clinical symptoms of inflammation indicates a particular aggressiveness and a worst prognosis than other breast cancers (Chevallier, 1993;Palangie et al, 1994;Kleer et al, 2000). However, the mechanisms leading to the pathological action of stroma-localised inflammatory cells in cancer, such as monocytes, remain poorly understood.The current study was undertaken to explore whether the factors of aggressiveness expressed by cancer cells were modified in the presence of monocytes. We also analysed the consequences of the incubation of monocytes with MDA-MB231 cancer cells on functions of monocytes both in the defence against tumour cells and in inflammatory functions. For this purpose, we tested the consequences of the interaction of the highly invasive breastderived MDA-MB231 cancer cells with monocytes with an in vitro system. MATERIAL AND METHODS Monocytes isolationA measure of 80 mm of blood from healthy volunteers was collected in sterile polypropylene tubes (Costar, Cambridge, MA, USA) containing 7.5 ml of ACD (38 mM citric acid, 74 mM citrate and 136 mM glucose). Platelet-rich plasma was removed by centrifugation (10 min, 100 g at room temperature). Mononuclear cells were collected after centrifugation (45 min, 400 g at room temperature) in Leucosep tubes (Costar, C...

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