CXCL10 Promotes Osteolytic Bone Metastasis by Enhancing Cancer Outgrowth and Osteoclastogenesis
CXCL10 Promotes Osteolytic Bone Metastasis by Enhancing Cancer Outgrowth and Osteoclastogenesis
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DOI：
10.1158/0008-5472.can-12-0481
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发表时间：
2012-07-01
期刊：
影响因子：
11.2
通讯作者：
Lee, Zang Hee
中科院分区：
文献类型：
--
作者：
Lee, Jong-Ho;Kim, Ha-Neui;Lee, Zang Hee
趋化因子CXCL 10和RANKL的扩增已被认为促进破骨细胞分化和溶骨性骨转移，但内源性CXCL 10在这些过程中的功能尚未完全确定。在这项研究中，我们表明内源性CXCL 10是至关重要的招募癌细胞骨，支持破骨细胞分化和促进溶骨性骨转移的形成。中和CXCL 10抗体减少了表达CXCL 10受体CXCR 3的癌细胞的迁移，并且CXCR 3或CXCL 10的损失降低了体内骨肿瘤负荷。骨定植增加了CXCL 10的宿主产生，这是癌症生长和随后的骨质溶解所必需的。癌细胞和巨噬细胞之间的直接相互作用进一步刺激巨噬细胞产生CXCL 10。骨转移瘤的生长需要CXCL 10刺激的癌细胞与I型胶原的粘附以及RANKL介导的破骨细胞形成。总之，我们的研究结果表明，CXCL 10促进了表达CXCR 3的癌细胞向骨的运输，这增加了其自身的生产并促进了骨细胞分化。因此，CXCL 10可能代表溶骨性骨转移的治疗靶点。Cancer Res; 72（13）; 3175-86. (C)2012年AACR。
Amplification of the chemokines CXCL10 and RANKL has been suggested to promote osteoclast differentiation and osteolytic bone metastasis, but a function for endogenous CXCL10 in these processes is not well established. In this study, we show that endogenous CXCL10 is critical to recruit cancer cells to bone, support osteoclast differentiation and promote for the formation of osteolytic bone metastases. Neutralizing CXCL10 antibody reduced migration of cancer cells expressing the CXCL10 receptor CXCR3, and loss of CXCR3 or CXCL10 decreased bone tumor burden in vivo. Bone colonization augmented host production of CXCL10, which was required for cancer growth and subsequent osteolysis. Direct interactions between cancer cells and macrophages further stimulated CXCL10 production from macrophages. Growth of bone metastases required CXCL10-stimulated adhesion of cancer cells to type I collagen as well as RANKL-mediated osteoclast formation. Together, our findings show that CXCL10 facilitates trafficking of CXCR3-expressing cancer cells to bone, which augments its own production and promotes osteoclastic differentiation. CXCL10 therefore may represent a therapeutic target for osteolytic bone metastasis. Cancer Res; 72(13); 3175-86. (C) 2012 AACR.