S100A4 released from highly bone-metastatic breast cancer cells plays a critical role in osteolysis
S100A4 released from highly bone-metastatic breast cancer cells plays a critical role in osteolysis
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从高骨转移性乳腺癌细胞中释放的S100A4在骨质溶解中起关键作用
DOI：
10.1038/s41413-019-0068-5
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发表时间：
2019-09-23
期刊：
影响因子：
12.7
通讯作者：
Kim, Hong-Hee
中科院分区：
文献类型：
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作者：
Kim, Haemin;Kim, Bongjun;Kim, Hong-Hee
乳腺癌转移引起的骨质破坏会导致乳腺癌患者出现严重的并发症，包括死亡。转移性骨微环境中癌细胞和骨骼细胞之间的通讯是驱动肿瘤进展和骨溶解的主要因素。肿瘤衍生因素在这种形式的交流中发挥着重要作用。为了鉴定骨转移中癌细胞释放的可溶性因子，我们建立了 MDA-MB-231 乳腺癌细胞的高度骨转移亚系。该亚系（mtMDA）显示出分泌S100A4蛋白的能力显着提高，该蛋白通过表面受体RAGE直接刺激破骨细胞形成。重组 S100A4 在体外刺激破骨细胞生成，在体内刺激骨质流失。来自 mtMDA 细胞的条件培养基（其中 S100A4 被敲低）刺激破骨细胞的能力降低。此外，与对照敲低细胞相比，S100A4 敲低细胞在小鼠体内引起的骨破坏较少。此外，给予我们开发的抗 S100A4 单克隆抗体 (mAb) 可以减弱 mtMDA 对小鼠破骨细胞生成和骨质流失的刺激。综上所述，我们的结果表明乳腺癌细胞释放的 S100A4 在乳腺癌骨转移引起的骨溶解中发挥着重要作用。
Bone destruction induced by breast cancer metastasis causes severe complications, including death, in breast cancer patients. Communication between cancer cells and skeletal cells in metastatic bone microenvironments is a principal element that drives tumor progression and osteolysis. Tumor-derived factors play fundamental roles in this form of communication. To identify soluble factors released from cancer cells in bone metastasis, we established a highly bone-metastatic subline of MDA-MB-231 breast cancer cells. This subline (mtMDA) showed a markedly elevated ability to secrete S100A4 protein, which directly stimulated osteoclast formation via surface receptor RAGE. Recombinant S100A4 stimulated osteoclastogenesis in vitro and bone loss in vivo. Conditioned medium from mtMDA cells in which S100A4 was knocked down had a reduced ability to stimulate osteoclasts. Furthermore, the S100A4 knockdown cells elicited less bone destruction in mice than the control knockdown cells. In addition, administration of an anti-S100A4 monoclonal antibody (mAb) that we developed attenuated the stimulation of osteoclastogenesis and bone loss by mtMDA in mice. Taken together, our results suggest that S100A4 released from breast cancer cells is an important player in the osteolysis caused by breast cancer bone metastasis.