BioMEMS Resource Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
Integr Biol (Camb). 2009 Sep;1(8-9):506-12. doi: 10.1039/b908595e. Epub 2009 Jul 16.
When cancer cells spread away from the primary tumor, they often follow the trajectories of lymphatic vessels, nerves, white matter tracts, or other heterogeneous structures in tissues. To better understand this form of guided cell migration we designed a series of microfluidic devices that mechanically constrain migrating cancer cells inside microchannels with cross-section comparable to cell size. We observed unexpectedly fast and persistent movement in one direction for several hours of cancer cells of different types. The persistent motility occurs spontaneously, in the absence of external gradients, suggesting the presence of intrinsic mechanisms driving cancer cell motility that are induced in conditions of mechanical confinement. To probe the mechanisms responsible for this behavior, we exposed cancer cells inside channels to drugs targeting the microtubules, and measured a significant reduction in the average migration speed. Surprisingly, a small number of cells appeared not to be affected by the treatment and displayed fast and persistent migration, comparable to the untreated cells. The new matrix-free, 3D-confined motility assay replicates critical interactions that cancer cells would normally have inside tissues, is compatible with high-content, high-throughput analysis of cellular motility at single cell level, and could provide useful insights into the biology of cancer cell migratory phenotype.
当癌细胞从原发性肿瘤扩散时，它们通常会沿着淋巴管、神经、白质束或组织内的其他异质结构的轨迹扩散。为了更好地理解这种形式的细胞迁移，我们设计了一系列微流控装置，这些装置在与细胞大小相当的横截面的微通道内机械地限制迁移的癌细胞。我们观察到不同类型的癌细胞在数小时内出乎意料地快速和持续地朝一个方向移动。这种持续的运动是自发发生的，没有外部梯度，这表明存在内在的机制驱动癌细胞的运动，这些机制是在机械约束的条件下被诱导产生的。为了探究导致这种行为的机制，我们将通道内的癌细胞暴露于针对微管的药物中，发现癌细胞的平均迁移速度显著降低。令人惊讶的是，少数细胞似乎不受药物的影响，表现出快速和持续的迁移，与未处理的细胞相当。这种新的无基质、3D 约束的运动检测方法复制了癌细胞在组织内通常会发生的关键相互作用，与单细胞水平的细胞运动高通量、高内涵分析兼容，可能为癌症细胞迁移表型的生物学提供有用的见解。
