3D Traction Stresses Activate Protease-Dependent Invasion of Cancer Cells
3D Traction Stresses Activate Protease-Dependent Invasion of Cancer Cells
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DOI：
10.1016/j.bpj.2014.07.078
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发表时间：
2014-12-02
影响因子：
3.4
通讯作者：
Varghese, Shyni
中科院分区：
文献类型：
--
作者：
Aung, Aereas;Seo, Young N.;Varghese, Shyni
例如，在癌症转移中发生的细胞侵袭和迁移植根于细胞通过由细胞外基质施加的不同水平的物理约束的能力。癌细胞可以以蛋白酶非依赖性或蛋白酶依赖性方式侵入基质。影响细胞侵入模式的一个新兴的关键组分是细胞响应于细胞外基质的物理结构特性而产生的牵引应力。在这项研究中，我们已经开发了一种无参考的定量分析，用于测量三维（3D）的牵引应力产生的细胞在入侵到矩阵施加不同程度的机械阻力的初始阶段。我们的研究结果表明，当细胞遇到更高的机械阻力时，它们中的一大部分转移到蛋白酶介导的侵袭，并且这个过程开始于细胞侵袭深度的较低值。另一方面，发现在蛋白酶介导的侵袭开始时由细胞产生的压缩应力与基质硬度无关，这表明3D牵引应力是触发蛋白酶介导的癌细胞侵袭的关键因素。在低的3D压缩牵引应力下，细胞利用泡形成以蛋白酶非依赖性方式覆盖基质。然而，在较高的应力值下，细胞利用侵袭伪足样结构介导蛋白酶依赖性侵入3D基质。在从蛋白酶独立的侵入模式到蛋白酶依赖的侵入模式的过渡处的压缩牵引应力的临界值被发现类似于165 Pa。
Cell invasion and migration that occurs, for example, in cancer metastasis is rooted in the ability of cells to navigate through varying levels of physical constraint exerted by the extracellular matrix. Cancer cells can invade matrices in either a protease-independent or a protease-dependent manner. An emerging critical component that influences the mode of cell invasion is the traction stresses generated by the cells in response to the physicostructural properties of the extracellular matrix. In this study, we have developed a reference-free quantitative assay for measuring three-dimensional (3D) traction stresses generated by cells during the initial stages of invasion into matrices exerting varying levels of mechanical resistance. Our results show that as cells encounter higher mechanical resistance, a larger fraction of them shift to protease-mediated invasion, and this process begins at lower values of cell invasion depth. On the other hand, the compressive stress generated by the cells at the onset of protease-mediated invasion is found to be independent of matrix stiffness, suggesting that 3D traction stress is a key factor in triggering protease-mediated cancer cell invasion. At low 3D compressive traction stresses, cells utilize bleb formation to indent the matrix in a protease independent manner. However, at higher stress values, cells utilize invadopodia-like structures to mediate protease-dependent invasion into the 3D matrix. The critical value of compressive traction stress at the transition from a protease-independent to a protease-dependent mode of invasion is found to be similar to 165 Pa.