CANCER Why Bone Is Such an Attractive Target

Many cancers, including breast cancer malignant melanoma, metastasize to the bone, and the local factors in the host tissues that contribute to metastatic colonization are beginning to be uncovered. Chemokines in the target tissue to which the cancer cells will metastasize are important, and Jones et al. show that the cytokine RANKL (receptor activator of nuclear factor B ligand) is another factor that governs metastasis to bone for tumor cells that express the receptor RANK. RANK was detected in primary human tumor samples from breast and prostate cancer, as well as in several cancer cell lines. Cancer cell lines (human breast and prostate and mouse melanoma) responded to RANKL with actin reorganization, activation of several signaling pathways, and cell migration. The decoy receptor osteoprotegerin (OPG) blocked actin polymerization and cell migration induced by RANKL. Injection of the mouse melanoma cell line B16F10 into the hearts of mice led to metastasis of the cancer cells to multiple organs, including the bones, which produced paralysis and ultimately death. Treatment of the mice with OPG specifically reduced metastasis to the bones, eliminated paralysis over the course of the experiment, and increased the survival of the mice. Thus, RANKL appears to be a key factor contributing to bone metastasis and may be a clinical target for reducing morbidity and pain associated with cancers that metastasize to the bone. Interestingly, RANK was found on normal untransformed mouse mammary epithelial cells, and RANKL stimulated the migration of these cells, suggesting that RANKL plays a role in normal breast tissue.

D. H. Jones, T. Nakashima, O. H. Sanchez, I. Kozieradzki, S. V. Komarova, I. Sarosi, S. Morony, E. Rubin, R. Sarao, C. V. Hojilla, V. Komnenovic, Y.-Y. Kong, M. Schreiber, S. J. Dixon, S. M. Sims, R. Khokha, T. Wada, J. M. Penninger, Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440, 692-696 (2006). [PubMed]