Department of Chemical and Biological Engineering, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Phys Biol. 2020 Mar 19;17(3):036004. doi: 10.1088/1478-3975/ab725c.
We propose a biomechanical model for the extravasation of a tumor cell (TC) through the endothelium of a blood vessel. Based on prior in vitro observations, we assume that the TC extends a protrusion between adjacent endothelial cells (ECs) that adheres to the basement membrane via focal adhesions (FAs). As the protrusion grows in size and branches out, the actomyosin contraction along the stress fibers (SFs) inside the protrusion pulls the relatively rigid nucleus through the endothelial opening. We model the chemo-mechanics of the SFs and the FAs by following the kinetics of the active myosin motors and high-affinity integrins, subject to mechanical feedback. This is incorporated into a finite-element simulation of the extravasation process, with the contractile force pulling the nucleus of the TC against elastic resistance of the ECs. To account for the interaction between the TC nucleus and the endothelium, we consider two scenarios: solid-solid contact and lubrication by cytosol. The former gives a lower bound for the required contractile force to realize transmigration, while the latter provides a more realistic representation of the process. Using physiologically reasonable parameters, our model shows that the SF and FA ensemble can produce a contractile force on the order of 70 nN, which is sufficient to deform the ECs and enable transmigration. Furthermore, we use an atomic force microscope to measure the resistant force on a human bladder cancer cell that is pushed through an endothelium cultured in vitro. The magnitude of the required force turns out to be in the range of 70-100 nN, comparable to the model predictions.
我们提出了一个肿瘤细胞（TC）穿过血管内皮细胞外渗的生物力学模型。基于先前的体外观察，我们假设 TC 通过粘着斑（FA）在相邻的内皮细胞（EC）之间延伸一个突起，该突起附着在基底膜上。随着突起的增大和分支，沿着突起内的应力纤维（SF）的肌球蛋白收缩将相对刚性的核穿过内皮开口拉动。我们通过遵循活性肌球蛋白马达和高亲和力整合素的动力学来模拟 SF 和 FA 的化学生物力学，受机械反馈的影响。这被纳入到一个外渗过程的有限元模拟中，收缩力将 TC 的核拉向 EC 的弹性阻力。为了考虑 TC 核与内皮细胞之间的相互作用，我们考虑了两种情况：固体-固体接触和胞质溶胶的润滑。前者给出了实现迁移所需的收缩力的下限，而后者提供了该过程的更现实的表示。使用生理上合理的参数，我们的模型表明 SF 和 FA 集合可以产生大约 70 nN 的收缩力，足以使 EC 变形并实现迁移。此外，我们使用原子力显微镜测量了在体外培养的内皮细胞中推动的人膀胱癌细胞的阻力。所需力的大小为 70-100 nN，与模型预测相当。
