Introduction

The phenomenon of lymph node metastasis has been known for a long time. However, the underlying mechanism by which malignant tumor cells are able to break loose from the primary tumor site remains unclear. In particular, two competing fluid sensitive migration mechanisms have been reported in the experimental literature: (i) autologous chemotaxis (Shields et al. in Cancer Cell 11:526–538, 2007) which gives rise to downstream migration; (ii) an integrin-mediated and strain-induced upstream mechanism (Polacheck et al. in PNAS 108:11115–11120, 2011). How can these two competing mechanisms be used as a means for metastatic behavior in a realistic tumor setting? Excessive fluid flow is typically produced from leaky intratumoral blood vessels and collected by lymphatics in the peritumoral region giving rise to a heterogeneous fluid velocity field and a corresponding heterogeneous cell migration behavior, quite different from the experimental setup.

Method

In order to shed light on this issue there is a need for tools which allow one to extrapolate the observed single cell behavior in a homogeneous microfluidic environment to a more realistic, higher-dimensional tumor setting. Here we explore this issue by using a computational multiphase model. The model has been trained with data from the experimental results mentioned above which essentially reflect one-dimensional behavior. We extend the model to an envisioned idealized two-dimensional tumor setting.

Result

A main observation from the simulation is that the autologous chemotaxis migration mechanism, which triggers tumor cells to go with the flow in the direction of lymphatics, becomes much more aggressive and effective as a means for metastasis in the presence of realistic IF flow. This is because the outwardly directed IF flow generates upstream cell migration that possibly empowers small clusters of tumor cells to break loose from the primary tumor periphery. Without this upstream stress-mediated migration, autologous chemotaxis is inclined to move cells at the rim of the tumor in a homogeneous and collective, but space-demanding style. In contrast, inclusion of realistic IF flow generates upstream migration that allows two different aspects to be synthesized: maintain the coherency and solidity of the the primary tumor and at the same time cleave the outgoing waves of tumor cells into small clusters at the front that can move collectively in a more specific direction.

中文翻译：

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肿瘤细胞如何在转移策略中利用间质液流动。

介绍

淋巴结转移现象早已为人所知。然而，恶性肿瘤细胞能够从原发肿瘤部位脱离的潜在机制仍不清楚。特别是，实验文献中报道了两种相互竞争的流体敏感迁移机制：（i）自体趋化性（Shields et al. in Cancer Cell 11:526–538, 2007），导致下游迁移；(ii) 整合素介导和应变诱导的上游机制（Polacheck 等人在 PNAS 108:11115–11120, 2011）。这两种竞争机制如何在现实的肿瘤环境中用作转移行为的手段？过多的流体流动通常由渗漏的瘤内血管产生，并由瘤周区域的淋巴管收集，从而产生异质的流体速度场和相应的异质细胞迁移行为，这与实验设置完全不同。

方法

为了阐明这个问题，需要一种工具，使人们能够将在均质微流体环境中观察到的单细胞行为外推到更现实、更高维度的肿瘤环境中。在这里，我们通过使用计算多相模型来探索这个问题。该模型已经使用来自上述实验结果的数据进行了训练，这些数据基本上反映了一维行为。我们将模型扩展到设想的理想化二维肿瘤环境。

结果

模拟的一个主要观察结果是，触发肿瘤细胞沿淋巴管方向流动的自体趋化性迁移机制在存在真实的 IF 流的情况下作为一种转移手段变得更具侵略性和有效性。这是因为向外定向的 IF 流会产生上游细胞迁移，这可能使小簇肿瘤细胞从原发性肿瘤周围脱离。如果没有这种上游压力介导的迁移，自体趋化性倾向于以均匀和集体但需要空间的方式移动肿瘤边缘的细胞。相比之下，包含现实的 IF 流会产生上游迁移，从而可以综合两个不同的方面：