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 organs 5 . However, as the inhibition of chemokine receptors in vivo only partially blocks metastatic behaviour 6 , other factors must exist that regulate the preferential metastasis of breast cancer cells. Here we show that the cytokine RANKL (receptor activator of NF-kB 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 metastasis 9 , 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.

Extracellular matrix (ECM) fragments or cryptic sites unmasked by proteinases have been postulated to affect tissue remodeling and cancer progression. Therefore, the elucidation of their identities and functions is of great interest. Here, we show that matrix metalloproteinases (MMPs) generate a domain (DIII) from the ECM macromolecule laminin-5. Binding of a recombinant DIII fragment to epidermal growth factor receptor stimulates downstream signaling (mitogen-activated protein kinase), MMP-2 gene expression, and cell migration. Appearance of this cryptic ECM ligand in remodeling mammary gland coincides with MMP-mediated involution in wild-type mice, but not in tissue inhibitor of metalloproteinase 3 (TIMP-3)–deficient mice, supporting physiological regulation of DIII liberation. These findings indicate that ECM cues may operate via direct stimulation of receptor tyrosine kinases in tissue remodeling, and possibly cancer invasion.

Matrix metalloproteinases (MMPs) were initially recognised for their extracellular matrix (ECM)-degrading capability during tissue remodelling. Their importance was further highlighted by their role in metastasis. Clinical trials have since evaluated the potential of MMP inhibitors as anticancer therapeutics, but without success. These initial studies point to the complex, multifunctional capacity of MMPs in cancer as shown by their function, not only as strident mediators of advanced malignancies, but also as effectors of early stage tumorigenesis. Research now shows that MMPs, and their tissue inhibitors, affect tumour initiation and growth through loss of cell adhesion, evasion of apoptosis, and deregulation of cell division. The extracellular nature of the metalloproteinase axis situates it as a master regulator of cell fate.