Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
Cancer Res. 2012 Jul 1;72(13):3175-86. doi: 10.1158/0008-5472.CAN-12-0481. Epub 2012 May 4.
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.
趋化因子 CXCL10 和 RANKL 的扩增被认为可促进破骨细胞分化和溶骨性骨转移，但内源性 CXCL10 在这些过程中的作用尚未得到充分证实。本研究表明，内源性 CXCL10 对于招募癌细胞到骨骼、支持破骨细胞分化和促进溶骨性骨转移的形成至关重要。中和 CXCL10 抗体可减少表达 CXCL10 受体 CXCR3 的癌细胞的迁移，而 CXCR3 或 CXCL10 的缺失可减少体内骨肿瘤负担。骨定植增强了宿主 CXCL10 的产生，这对于肿瘤生长和随后的骨溶解是必需的。癌细胞与巨噬细胞之间的直接相互作用进一步刺激了巨噬细胞中 CXCL10 的产生。骨转移的生长需要 CXCL10 刺激的癌细胞与 I 型胶原的黏附以及 RANKL 介导的破骨细胞形成。总之，我们的研究结果表明，CXCL10 促进表达 CXCR3 的癌细胞向骨骼转移，从而增强了其自身的产生并促进了破骨细胞分化。因此，CXCL10 可能成为溶骨性骨转移的治疗靶点。
