Department of Chemical and Biological Engineering, Iowa State University, United States.
Department of Chemistry and Physics, Grand View University, United States.
Acta Biomater. 2018 Jan 15;66:248-257. doi: 10.1016/j.actbio.2017.11.039. Epub 2017 Nov 28.
Cancer cell metastasis is responsible for approximately 90% of deaths related to cancer. The migration of cancer cells away from the primary tumor and into healthy tissue is driven in part by contact guidance, or directed migration in response to aligned extracellular matrix. While contact guidance has been a focus of many studies, much of this research has explored environments that present 2D contact guidance structures. Contact guidance environments in 3D more closely resemble in vivo conditions and model cell-ECM interactions better than 2D environments. While most cells engage in directed migration on potent 2D contact guidance cues, there is diversity in response to contact guidance cues based on whether the cell migrates with a mesenchymal or amoeboid migration mode. In this paper, rotational alignment of collagen gels was used to study the differences in contact guidance between MDA-MB-231 (mesenchymal) and MTLn3 (amoeboid) cells. MDA-MB-231 cells migrate with high directional fidelity in aligned collagen gels, while MTLn3 cells show no directional migration. The collagen stiffness was increased through glycation, resulting in decreased MDA-MB-231 directionality in aligned collagen gels. Interestingly, partial inhibition of cell contractility dramatically decreased directionality in MDA-MB-231 cells. The directionality of MDA-MB-231 cells was most sensitive to ROCK inhibition, but unlike in 2D contact guidance environments, cell directionality and speed are more tightly coupled. Modulation of the contractile apparatus appears to more potently affect contact guidance than modulation of extracellular mechanical properties of the contact guidance cue.
Collagen fiber alignment in the tumor microenvironment directs migration, a process called contact guidance, enhancing the efficiency of cancer invasion and metastasis. 3D systems that assess contact guidance by locally orienting collagen fiber alignment are lacking. Furthermore, cell type differences and the role of extracellular matrix stiffness in tuning contact guidance fidelity are not well characterized. In this paper rotational alignment of collagen fibers is used as a 3D contact guidance cue to illuminate cell type differences and the role of extracellular matrix stiffness in guiding cell migration along aligned fibers of collagen. This local alignment offers a simple approach by which to couple collagen alignment with gradients in other directional cues in devices such as microfluidic chambers.
癌细胞转移是导致约 90%癌症相关死亡的原因。癌细胞从原发性肿瘤迁移到健康组织部分是由接触引导驱动的，或者说是对排列整齐的细胞外基质的定向迁移。虽然接触引导一直是许多研究的焦点，但其中许多研究都探索了呈现 2D 接触引导结构的环境。3D 中的接触引导环境更接近体内条件，并且比 2D 环境更好地模拟细胞-细胞外基质相互作用。虽然大多数细胞在强烈的 2D 接触引导线索下进行定向迁移，但基于细胞是否以间质或阿米巴样迁移模式迁移，对接触引导线索的反应存在多样性。在本文中，通过旋转排列胶原凝胶来研究 MDA-MB-231（间质）和 MTLn3（阿米巴样）细胞之间接触引导的差异。MDA-MB-231 细胞在排列整齐的胶原凝胶中以高方向保真度迁移，而 MTLn3 细胞则没有定向迁移。通过糖基化增加胶原的刚性，导致 MDA-MB-231 细胞在排列整齐的胶原凝胶中的方向性降低。有趣的是，部分抑制细胞收缩力会显著降低 MDA-MB-231 细胞的方向性。MDA-MB-231 细胞的方向性对 ROCK 抑制最敏感，但与 2D 接触引导环境不同，细胞方向性和速度的耦合更紧密。调节收缩装置似乎比调节接触引导线索的细胞外机械性能更能有效地影响接触引导。
肿瘤微环境中的胶原纤维排列指导迁移，这一过程称为接触引导，增强了癌症侵袭和转移的效率。缺乏局部定向胶原纤维排列的 3D 系统来评估接触引导。此外，细胞类型差异和细胞外基质刚度在调节接触引导保真度方面的作用尚未得到很好的描述。在本文中，旋转排列胶原纤维作为 3D 接触引导线索，用于阐明细胞类型差异以及细胞外基质刚度在引导细胞沿着胶原纤维对齐纤维迁移方面的作用。这种局部排列为通过旋转排列胶原纤维提供了一种简单的方法，可与微流控室等设备中的其他定向线索的梯度相结合。
