Regulation of cancer cell migration and bone metastasis by RANKL
Regulation of cancer cell migration and bone metastasis by RANKL
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DOI：
10.1038/nature04524
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发表时间：
2006-03-30
期刊：
影响因子：
64.8
通讯作者：
Penninger, JM
中科院分区：
文献类型：
--
作者：
Jones, DH;Nakashima, T;Penninger, JM
骨转移是许多癌症的常见并发症，导致严重的疾病负担和疼痛（1-3）。自世纪后期以来，人们一直认为局部宿主组织的微环境积极参与某些癌症转移到特定器官的倾向，并且骨骼提供了特别肥沃的“土壤”4。在乳腺癌的情况下，局部趋化因子环境现在正在成为为什么这些肿瘤优先转移到某些器官的解释（5）。然而，由于体内趋化因子受体的抑制仅部分阻断转移行为（6），因此必须存在调节乳腺癌细胞优先转移的其他因素。在这里，我们发现细胞因子RANKL（NF-κ B配体的受体激活剂）（7，8）触发表达受体RANK的人上皮癌细胞和黑色素瘤细胞的迁移。RANK在患者的癌细胞系和乳腺癌细胞上表达。在黑色素瘤转移的小鼠模型中（9），骨保护素对RANKL的体内中和作用可完全防止瘫痪，并显著降低骨中的肿瘤负荷，但在其他器官中则不然。我们的数据表明，局部分化因子如RANKL在癌细胞的细胞迁移和组织特异性转移行为中具有重要作用。
Bone metastases are a frequent complication of many cancers that result in severe disease burden and pain(1-3). 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-kappa B 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.