Journal Article

Regulation of cancer cell migration and bone metastasis by RANKL

Nakashima, Tomoki, Rubin, Evelyn, Sims, Stephen M., Jones, D. Holstead, Kozieradzki, Ivona, Komarova, Svetlana V., Wada, Teiji, Hojilla, Carlo V., Sanchez, Otto H., Sarosi, Ildiko, Dixon, S. Jeffrey, Khokha, Rama, Morony, Sean, Sarao, Renu, Penninger, Josef M., Schreiber, Martin, Komnenovic, Vukoslav, Kong, Young-Yun

2006

Overview

Cancer cells that express the receptor protein RANK migrate to bone tissue where the RANK ligand, RANKL, is found. This contributes to bone metastases and offers a potential therapeutic approach to prevent cancer metastases. 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-κB 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.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Animals / Biological and medical sciences / Bone Neoplasms - metabolism / Bone Neoplasms - pathology / Bone Neoplasms - secondary / Bones / Breast cancer / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer / Carrier Proteins - genetics / Carrier Proteins - metabolism / Cell adhesion & migration / Cell Death / Cell Differentiation / Cell Line, Tumor / Cell Movement / Cell Proliferation / Dissemination / Epithelial Cells - pathology / Female / Humanities and Social Sciences / Humans / letter / Medical sciences / Melanoma / Melanoma - metabolism / Melanoma - pathology / Membrane Glycoproteins - genetics / Membrane Glycoproteins - metabolism / Mice / multidisciplinary / Neoplasm Metastasis - pathology / Neutralization / Organ Specificity / Organs / Pain / Paralysis / RANK Ligand / Receptor Activator of Nuclear Factor-kappa B / Rodents / Science / Science (multidisciplinary) / Signal Transduction / Tumor cell / Tumors