The propensity of cancers to metastasize to specific organs is poorly understood. Previous studies have demonstrated a role for chemokines and their receptors in determining the metastatic destination of tumour cells, but they are not the only factors involved; in Nature, Josef Penninger and colleagues now show that the tumour necrosis family member RANKL specifically promotes metastasis into bones.

RANKL is highly expressed in bone marrow, where it mediates osteoclast differentiation, and in mammary epithelial cells where it is involved in the development of the lactating mammary gland during pregnancy. RANKL's receptor, RANK (receptor activator of NF-kB), is constitutively expressed in normal mammary gland epithelial cells and, as the authors of this study show, in a variety of human cancer cells taken from patients.

Treatment of RANK-positive human breast or prostate cancer cells with recombinant RANKL induces actin polymerization and cell migration in a concentration-dependent manner. Similar effects were observed with murine B16F10 melanoma cells, which like breast or prostate cancer cells, metastasize to bone in vivo but do not stimulate osteoclast resorption. In all cases, RANKL-stimulated migration was blocked with osteoprotegerin (OPG), a soluble decoy receptor that prevents RANKL from binding to RANK.

To study the effects of RANKL on tumour metastasis in vivo, the authors examined whether OPG-mediated inhibition of RANKL signalling altered metastasis into the bones of mice injected with B16F10 melanoma cells. While inhibition of RANKL did not alter the rate of metastasis into ovaries, brain and the adrenal glands, it did markedly reduce tumour formation in bones.

These findings have promising therapeutic implications and may help to combat the high incidence of cancers that metastasize to bones, leading to severe bone destruction and pain. The precise mechanism through which RANKL induces cancer cell migration towards bones remains to be elucidated, but future studies may determine whether inhibition of RANKL signalling with OPG-mimics, for example, could prevent bone metastasis in humans.

Author: Monica Hoyos-Flight