揭示肿瘤细胞在空间受限环境中快速迁移的机制

导读：在一项研究中，美国州大学伯克利分校生物工程教授Sanjay Kumar实验室发现肿瘤细胞在体内有限空间中能够迁移得更快。

在一项研究中，美国州大学伯克利分校生物工程教授Sanjay Kumar实验室发现肿瘤细胞在体内有限空间中能够迁移得更快。2012年6月11日，这篇研究论文在线发表在PNAS期刊上，共同作者为Sanjay Kumar和博士后研究员Amit Pathak。

科学家们知道，肿瘤对组织的浸润受到组织机械性能如硬度和组织微观结构特性如孔径大小的调节。但是，过去试图详细地研究和理解这些机制的努力一直受到限制，这是因为人们非常难以只改变一种性能而不影响其他性能。

Kumar实验室利用新开发的技术而首次显示这两项性能以一种非常不同的方式调节肿瘤迁移，而且更令人吃惊的是，相比于在开放和宽广的空间中，细胞处在有限空间中实际上能够让它们更快速地和更加定向地运动。

研究人员已开发出一种微加工的平台，从而能够构建大小和硬度可以独立确定的三维通道。这种结构允许他们更加集中注意力来观察这些狭窄的通道能够让细胞产生逆着支架方向的牵引力。

Kumar解释说，“既然是只有一条路可走，细胞会不浪费它们的能量来寻找其他的迁移途径。”

这可能是一种在生理上有着重要作用的机制，这是因为恶性脑瘤倾向于沿着组织界面和受限的空间，如血管和神经束，最快速地浸润组织。(生物谷 Bioon.com)

doi: 10.1073/pnas.1118073109
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Independent regulation of tumor cell migration by matrix stiffness and confinement

Amit Pathak and Sanjay Kumar

Tumor invasion and metastasis are strongly regulated by biophysical interactions between tumor cells and the extracellular matrix (ECM). While the influence of ECM stiffness on cell migration, adhesion, and contractility has been extensively studied in 2D culture, extension of this concept to 3D cultures that more closely resemble tissue has proven challenging, because perturbations that change matrix stiffness often concurrently change cellular confinement. This coupling is particularly problematic given that matrix-imposed steric barriers can regulate invasion speed independent of mechanics. Here we introduce a matrix platform based on microfabrication of channels of defined wall stiffness and geometry that allows independent variation of ECM stiffness and channel width. For a given ECM stiffness, cells confined to narrow channels surprisingly migrate faster than cells in wide channels or on unconstrained 2D surfaces, which we attribute to increased polarization of cell-ECM traction forces. Confinement also enables cells to migrate increasingly rapidly as ECM stiffness rises, in contrast with the biphasic relationship observed on unconfined ECMs. Inhibition of nonmuscle myosin II dissipates this traction polarization and renders the relationship between migration speed and ECM stiffness comparatively insensitive to matrix confinement. We test these hypotheses in silico by devising a multiscale mathematical model that relates cellular force generation to ECM stiffness and geometry, which we show is capable of recapitulating key experimental trends. These studies represent a paradigm for investigating matrix regulation of invasion and demonstrate that matrix confinement alters the relationship between cell migration speed and ECM stiffness.