Fan Yao, Jalali Aydin, Chen Andy, Zhao Xinyu, Liu Shengzhi, Teli Meghana, Guo Yunxia, Li Fangjia, Li Junrui, Siegel Amanda, Yang Lianxiang, Liu Jing, Na Sungsoo, Agarwal Mangilal, Robling Alexander G, Nakshatri Harikrishna, Li Bai-Yan, Yokota Hiroki
1Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, 150081 China.
2Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202 USA.
Bone Res. 2020 Feb 14;8:9. doi: 10.1038/s41413-020-0083-6. eCollection 2020.
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 TGFβ 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.
骨细胞是机械敏感的骨细胞，但关于它们在机械刺激下对肿瘤细胞的影响知之甚少。我们用骨细胞衍生的条件培养基（CM）和经0.25 Pa和1 Pa剪切应力流体流动处理的条件培养基（FFCM）处理乳腺癌细胞。值得注意的是，0.25 Pa的CM和FFCM诱导了间充质-上皮转化（MET），但1 Pa的FFCM诱导了上皮-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）对Src活性和纽蛋白分子力的评估表明，骨桥蛋白参与了EMT和MET的转换。使用1、2和5 N的动态胫骨负荷对肿瘤诱导的骨溶解小鼠模型进行了测试。低1 N负荷抑制了肿瘤诱导的骨溶解，但这种有益作用分别在2 N和5 N负荷下丧失并逆转。体内改变负荷强度还导致血清TGFβ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骨微环境中肿瘤细胞的行为。
