University of Stavanger, Faculty of Science and Technology, 4068 Stavanger, Norway.
University of North Carolina at Chapel Hill and North Carolina State University, Joint Department of Biomedical Engineering, Chapel Hill, NC 27599, USA.
J Biomech. 2020 Feb 13;100:109568. doi: 10.1016/j.jbiomech.2019.109568. Epub 2019 Dec 19.
In this work we investigate fibroblast-enhanced tumor cell migration in an idealized tumor setting through a computational model based on a multiphase approach consisting of three phases, namely tumor cells, fibroblasts and interstitial fluid. The interaction between fibroblasts and tumor cells has previously been investigated through this model (Urdal et al., 2019) to comply with reported in vitro experimental results (Shieh et al., 2011). Using the information gained from in vitro single-cell behavior, what will the effect of fibroblast-enhanced tumor cell migration be in a tumor setting? In particular, how will tumor cells migrate in a heterogeneous tumor environment compared to controlled in vitro microfluidic-based experiments? From what we know about the behavior of a tumor, is that collective invasion into adjacent tissue is frequently observed. Here, we want to elucidate how fibroblasts may guide tumor cells towards draining lymphatics to which tumor cells may subsequently intravasate and thus spread to other parts of the body. Fibroblasts can act as leader cells, where they create tracks within the extracellular matrix (ECM) by matrix remodeling and contraction. In addition, a heterotypic mechanical adhesion between fibroblasts and tumor cells also assist the fibroblasts to act as leader cells. Our simulation results show how the interaction between the two cell types yields collective migration of tumor cells outwards from the tumor where fibroblasts dictate the direction of migration. The model also describes how this well-orchestrated invasive behavior is the result of a proper combination of different interaction forces between cell-ECM, fibroblast-ECM, fluid-ECM and cell-fibroblast.
在这项工作中，我们通过一个基于多相方法的计算模型研究了成纤维细胞增强肿瘤细胞在理想化肿瘤环境中的迁移，该模型由三个相组成，即肿瘤细胞、成纤维细胞和细胞间质液。先前已经通过该模型研究了成纤维细胞与肿瘤细胞之间的相互作用（Urdal 等人，2019），以符合已报道的体外实验结果（Shieh 等人，2011）。利用从体外单细胞行为中获得的信息，成纤维细胞增强的肿瘤细胞迁移在肿瘤环境中会产生什么影响？特别是，与受控的体外微流控实验相比，肿瘤细胞在异质肿瘤环境中会如何迁移？从我们对肿瘤行为的了解来看，经常观察到集体侵入相邻组织。在这里，我们想阐明成纤维细胞如何引导肿瘤细胞向引流淋巴管迁移，肿瘤细胞随后可能会通过这些淋巴管进入血管，并因此扩散到身体的其他部位。成纤维细胞可以作为引导细胞，通过基质重塑和收缩在细胞外基质 (ECM) 中创建轨迹。此外，成纤维细胞和肿瘤细胞之间的异型机械粘附也有助于成纤维细胞作为引导细胞。我们的模拟结果显示了两种细胞类型之间的相互作用如何导致肿瘤细胞从肿瘤向外集体迁移，其中成纤维细胞决定了迁移的方向。该模型还描述了这种协调良好的侵袭行为如何是细胞-ECM、成纤维细胞-ECM、流体-ECM 和细胞-成纤维细胞之间不同相互作用力的适当组合的结果。
