Bone metastases are a frequent complication of many cancers that result in severe disease burden and pain^{1, 2, 3}. Since the late nineteenth century, it has been thought that the microenvironment of the local host tissue actively participates in the propensity of certain cancers to metastasize to specific organs, and that bone provides an especially fertile 'soil'⁴. In the case of breast cancers, the local chemokine milieu is now emerging as an explanation for why these tumours preferentially metastasize to certain organs⁵. However, as the inhibition of chemokine receptors in vivo only partially blocks metastatic behaviour⁶, other factors must exist that regulate the preferential metastasis of breast cancer cells. Here we show that the cytokine RANKL (receptor activator of NF-B ligand)^{7, 8} triggers migration of human epithelial cancer cells and melanoma cells that express the receptor RANK. RANK is expressed on cancer cell lines and breast cancer cells in patients. In a mouse model of melanoma metastasis⁹, in vivo neutralization of RANKL by osteoprotegerin results in complete protection from paralysis and a marked reduction in tumour burden in bones but not in other organs. Our data show that local differentiation factors such as RANKL have an important role in cell migration and the tissue-specific metastatic behaviour of cancer cells.

1. IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr Gasse 3, A-1030 Vienna, Austria
2. Department of Medical Biophysics and
3. Department of Immunology, University of Toronto, 610 University Avenue, Toronto, Ontario M5G 2C1, Canada
4. Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, Ontario M5G 2C1, Canada
5. Faculty of Dentistry, McGill University, Montreal, Quebec H3A 1A4, Canada
6. Amgen Inc., Thousand Oaks, California 91320-1799, USA
7. Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, 790-784 Kyungbuk, South Korea
8. Medical University of Vienna, Department of Obstetrics and Gynecology, Waehringer Guertel 18-20, A-1090 Vienna, Austria
9. CIHR Group in Skeletal Development and Remodeling, Department of Physiology and Pharmacology and Division of Oral Biology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada
10. †Present address: Faculty of Health Sciences, University of Ontario Institute of Technology, 2000 Simcoe Street North, Oshawa, Ontario L1H 7K4, Canada
11. *These authors contributed equally to this work

Correspondence to: Josef M. Penninger^1,2,3 Correspondence and requests for materials should be addressed to J.M.P. (Email: josef.penninger@imba.oeaw.ac.at).

Received 11 November 2005 | Accepted 12 December 2005

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