Regulation of cancer cell migration and bone metastasis by RANKL.
Bone metastases are a frequent complication of many cancers that result in severe disease burden and pain. 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'. 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. However, as the inhibition of chemokine receptors in vivo only partially blocks metastatic behaviour, other factors must exist that regulate the preferential metastasis of breast cancer cells. Here we show that the cytokine RANKL (receptor activator of NF-kappaB ligand) 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, 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.
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr Gasse 3, A-1030 Vienna, Austria.
D Holstead
DH
Jones
Tomoki
T
Nakashima
Otto H
OH
Sanchez
Ivona
I
Kozieradzki
Svetlana V
SV
Komarova
Ildiko
I
Sarosi
Sean
S
Morony
Evelyn
E
Rubin
Renu
R
Sarao
Carlo V
CV
Hojilla
Vukoslav
V
Komnenovic
Young-Yun
YY
Kong
Martin
M
Schreiber
S Jeffrey
SJ
Dixon
Stephen M
SM
Sims
Rama
R
Khokha
Teiji
T
Wada
Josef M
JM
Penninger
D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology*; D009928:Organ Specificity; D010243:Paralysis; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D015398:Signal Transduction
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse