Ao Mingfang, Brewer Bryson M, Yang Lijie, Franco Coronel Omar E, Hayward Simon W, Webb Donna J, Li Deyu
Department of Biological Sciences, Vanderbilt University, Nashville, TN.
Department of Mechanical Engineering, Vanderbilt University, Nashville, TN.
Sci Rep. 2015 Feb 9;5:8334. doi: 10.1038/srep08334.
Most investigations of cancer-stroma interactions have focused on biochemical signaling effects, with much less attention being paid to biophysical factors. In this study, we investigated the role of mechanical stimuli on human prostatic fibroblasts using a microfluidic platform that was adapted for our experiments and further developed for both repeatable performance among multiple assays and for compatibility with high-resolution confocal microscopy. Results show that mechanical stretching of normal tissue-associated fibroblasts (NAFs) alters the structure of secreted fibronectin. Specifically, unstretched NAFs deposit and assemble fibronectin in a random, mesh-like arrangement, while stretched NAFs produce matrix with a more organized, linearly aligned structure. Moreover, the stretched NAFs exhibited an enhanced capability for directing co-cultured cancer cell migration in a persistent manner. Furthermore, we show that stretching NAFs triggers complex biochemical signaling events through the observation of increased expression of platelet derived growth factor receptor α (PDGFRα). A comparison of these behaviors with those of cancer-associated fibroblasts (CAFs) indicates that the observed phenotypes of stretched NAFs are similar to those associated with CAFs, suggesting that mechanical stress is a critical factor in NAF activation and CAF genesis.
大多数关于癌症-基质相互作用的研究都集中在生化信号传导效应上，而对生物物理因素的关注则少得多。在本研究中，我们使用了一个微流控平台来研究机械刺激对人前列腺成纤维细胞的作用，该平台是为我们的实验而设计的，并进一步开发以实现多种检测之间的可重复性能以及与高分辨率共聚焦显微镜的兼容性。结果表明，正常组织相关成纤维细胞（NAFs）的机械拉伸会改变分泌的纤连蛋白的结构。具体而言，未拉伸的NAFs以随机的网状排列沉积和组装纤连蛋白，而拉伸后的NAFs产生具有更有序、线性排列结构的基质。此外，拉伸后的NAFs表现出更强的能力，能够持续引导共培养的癌细胞迁移。此外，通过观察血小板衍生生长因子受体α（PDGFRα）表达的增加，我们发现拉伸NAFs会触发复杂的生化信号事件。将这些行为与癌症相关成纤维细胞（CAFs）的行为进行比较表明，拉伸后NAFs的观察到的表型与CAFs相关的表型相似，这表明机械应力是NAF激活和CAF发生的关键因素。
