Migration dynamics of breast cancer cells in a tunable 3D interstitial flow chamber
Migration dynamics of breast cancer cells in a tunable 3D interstitial flow chamber
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DOI：
10.1039/c1ib00128k
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发表时间：
2012-01-01
影响因子：
2.5
通讯作者：
Swartz, Melody A.
中科院分区：
文献类型：
--
作者：
Haessler, Ulrike;Teo, Jeremy C. M.;Swartz, Melody A.
白细胞、肿瘤细胞和成纤维细胞等细胞在3D基质中的迁移是调节体内平衡和免疫以及推动发病的关键。在炎症和肿瘤微环境中，通过细胞外基质的间质流动可以显著增加，可以通过多种方式影响细胞迁移。白细胞和肿瘤细胞对血流的迁移反应是不同的，但大多数3D迁移研究使用的是代表平均特征的终点测量。在这里，我们提出了一种强大的新的微流控设备，用于3D培养，在良好控制的流动条件下进行实时成像，并比较了描述异质细胞群体迁移行为的分析方法。然后，我们使用该模型来提供关于间质血流如何影响MDA-MB-231乳腺癌细胞侵袭的新见解，这是从平均或终点测量中看不到的现象。具体地说，我们发现间质血流增加了细胞迁移的百分比，并加快了大约20%的细胞的迁移速度。它还增加了亚群(细胞的5%-10%)在正或负流动方向上的迁移持久性。向上游迁移的细胞移动速度更快，但方向性较差，而向着流动方向迁移的细胞移动速度较慢，但方向性较高。这些发现表明，肿瘤微环境中的液体流动可以通过引导肿瘤细胞亚群沿流动方向，即流向引流淋巴管这一主要转移途径来增强肿瘤细胞的侵袭能力。
The migration of cells such as leukocytes, tumor cells, and fibroblasts through 3D matrices is critical for regulating homeostasis and immunity and for driving pathogenesis. Interstitial flow through the extracellular matrix, which can substantially increase during inflammation and in the tumor microenvironment, can influence cell migration in multiple ways. Leukocytes and tumor cells are heterogeneous in their migration responses to flow, yet most 3D migration studies use endpoint measurements representing average characteristics. Here we present a robust new microfluidic device for 3D culture with live imaging under well-controlled flow conditions, along with a comparison of analytical methods for describing the migration behavior of heterogeneous cell populations. We then use the model to provide new insight on how interstitial flow affects MDA-MB-231 breast cancer cell invasion, phenomena that are not seen from averaged or endpoint measurements. Specifically, we find that interstitial flow increases the percentage of cells that become migratory, and increases migrational speed in about 20% of the cells. It also increases the migrational persistence of a subpopulation (5-10% of cells) in the positive or negative flow direction. Cells that migrated upstream moved faster but with less directedness, whereas cells that migrated in the direction of flow moved at slower speeds but with higher directedness. These findings demonstrate how fluid flow in the tumor microenvironment can enhance tumor cell invasion by directing a subpopulation of tumor cells in the flow direction; i.e., towards the draining lymphatic vessels, a major route of metastasis.