Skeletal loading regulates breast cancer-associated osteolysis in a loading intensity-dependent fashion
Skeletal loading regulates breast cancer-associated osteolysis in a loading intensity-dependent fashion
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DOI：
10.1038/s41413-020-0083-6
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发表时间：
2020-02-14
期刊：
影响因子：
12.7
通讯作者：
Yokota, Hiroki
中科院分区：
文献类型：
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作者：
Fan, Yao;Jalali, Aydin;Yokota, Hiroki
骨细胞是一种机械敏感的骨细胞，但其对肿瘤细胞在机械刺激下的反应却知之甚少。我们处理乳腺癌细胞与骨细胞来源的条件培养基（CM）和流体流处理的条件培养基（FFCM）与0.25帕和1帕的剪切应力。值得注意的是，CM和FFCM在0.25 Pa诱导间充质-上皮转化（MET），但FFCM在1 Pa诱导上皮-间充质转化（EMT）。这表明流体流动对条件培养基的影响取决于流动强度。基于荧光共振能量转移（FRET）的Src活性和黏着斑蛋白分子力的评估表明，骨桥蛋白参与EMT和MET转换。使用1、2和5 N的动态胫骨载荷对肿瘤诱导的骨溶解小鼠模型进行测试。低1 N载荷抑制肿瘤诱导的骨质溶解，但这种有益作用分别在2 N和5 N载荷下丧失和逆转。改变体内负荷强度也导致血清TGF β水平和尿液中肿瘤相关挥发性有机化合物组成的变化。总的来说，这项研究证明了强度依赖性机械转导和骨桥蛋白在肿瘤-骨细胞通讯中的关键作用，表明生物物理因素可以切实改变肿瘤细胞在骨微环境中的行为。
Osteocytes are mechanosensitive bone cells, but little is known about their effects on tumor cells in response to mechanical stimulation. We treated breast cancer cells with osteocyte-derived conditioned medium (CM) and fluid flow-treated conditioned medium (FFCM) with 0.25 Pa and 1 Pa shear stress. Notably, CM and FFCM at 0.25 Pa induced the mesenchymal-to-epithelial transition (MET), but FFCM at 1 Pa induced the epithelial-to-mesenchymal transition (EMT). This suggested that the effects of fluid flow on conditioned media depend on flow intensity. Fluorescence resonance energy transfer (FRET)-based evaluation of Src activity and vinculin molecular force showed that osteopontin was involved in EMT and MET switching. A mouse model of tumor-induced osteolysis was tested using dynamic tibia loadings of 1, 2, and 5 N. The low 1 N loading suppressed tumor-induced osteolysis, but this beneficial effect was lost and reversed with loads at 2 and 5 N, respectively. Changing the loading intensities in vivo also led to changes in serum TGF beta levels and the composition of tumor-associated volatile organic compounds in the urine. Collectively, this study demonstrated the critical role of intensity-dependent mechanotransduction and osteopontin in tumor-osteocyte communication, indicating that a biophysical factor can tangibly alter the behaviors of tumor cells in the bone microenvironment.