骨転移とRANKL

Bone and Calcium Abnormalities in Malignancy. Bone metastasis and RANKL.

　RANKL（receptor activator of NF-κB ligand）/RANK欠損マウスの乳腺は，性成熟まで正常に発生するが，妊娠期の乳腺上皮増殖が障害され乳腺葉構造が形成されず，仔マウスは死に至る。また，ホルモン補充療法に使用されるプロゲステロン誘導体と乳がんの発症リスクが相関することが以前から知られており，乳腺上皮細胞特異的なRANK欠損マウスやトランスジェニックマウスを用いた検討から，プロゲスチンがRANKLを誘導して乳がんを発症させることが明らかになった。さらに，RANKシグナルの薬理学的阻害は，乳がんの発症や骨への転移を顕著に抑制できることが見出され，RANKL/RANK経路を標的とした乳がんの新たな制御法に繋がりつつある。

　The mice with a disruption of Rank or Rankl exhibit normal mammary development during puberty, but their mammary epithelium fails to proliferate and form lobuloalveolar structures during pregnancy, resulting in the death of newborns. Hormone replacement therapy is associated with an increased risk of breast cancer. Importantly, specific deletion of RANK in mammary epithelium cells prevents both the onset and progression of medroxyprogesterone acetate（MPA）-driven mammary cancer and impairs self-renewal of breast cancer stem cells. Furthermore, RANK is highly expressed in several cancer cells. Functionally, it has been shown that RANKL can stimulate the directed migration of mammary epithelial cells as well as prostate cancer and melanoma cells toward a source of RANKL. In an in vivo metastasis model, OPG reduced the tumor burden in bones and ameliorated clinical paralysis, but did not affect the frequency of the spread of metastases into other tissues. These findings show that the RANK/RANKL system is crucial for mammary development, breast tumorigenesis and bone metastasis.