Cancer cell migration: integrated roles of matrix mechanics and transforming potential.
Cancer cell migration: integrated roles of matrix mechanics and transforming potential.
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DOI：
10.1371/journal.pone.0020355
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Zaman MH
中科院分区：
文献类型：
--
作者：
Baker EL;Srivastava J;Yu D;Bonnecaze RT;Zaman MH
在阐明乳腺癌进展的分子机制方面已经取得了重大进展;然而，对相关的细胞生物物理特征知之甚少。为此，我们使用延时共聚焦显微镜来研究乳腺上皮细胞（MEC）癌症进展系列中细胞运动性、三维（3D）基质刚度、基质结构和转化潜力之间的相互作用。我们使用了一个充分表征的乳腺癌进展模型，其中人源MCF 10A MEC过表达ErbB 2、14-3-3 β或ErbB 2和14-3-3 β两者，空载体作为对照。细胞运动性测定显示，当在二维（2D）基质上培养时，单独过表达ErbB 2的MEC表现出显著高的迁移速度，而单独过表达14-3-3 β 1最抑制在2D基质上的迁移（与未转化的MEC相比）。我们的研究结果还表明，14-3-3 ErbB 2蛋白和ErbB 2蛋白的共过表达促进了细胞在3D基质中的迁移能力，这反映在细胞迁移速度上。此外，足够硬度的3D基质可显著阻碍部分转化细胞的迁移能力，但增加的3D基质硬度对共过表达ErbB 2和14-3-3 β的完全转化细胞所表现出的侵袭性迁移行为的影响较小。最后，本研究表明，对于具有部分或全部转化潜力的MEC，单独过表达ErbB 2的MEC显示出细胞迁移速度对基质结构的最大敏感性，而单独过表达14-3-3 β的MEC显示出对基质结构的最小敏感性。鉴于目前的乳腺癌机械生物学的知识，这些研究结果总体上表明，细胞运动是由一个复杂的相互作用之间的矩阵力学和转化潜力。
Significant progress has been achieved toward elucidating the molecular mechanisms that underlie breast cancer progression; yet, much less is known about the associated cellular biophysical traits. To this end, we use time-lapsed confocal microscopy to investigate the interplay among cell motility, three-dimensional (3D) matrix stiffness, matrix architecture, and transforming potential in a mammary epithelial cell (MEC) cancer progression series. We use a well characterized breast cancer progression model where human-derived MCF10A MECs overexpress either ErbB2, 14-3-3ζ, or both ErbB2 and 14-3-3ζ, with empty vector as a control. Cell motility assays showed that MECs overexpressing ErbB2 alone exhibited notably high migration speeds when cultured atop two-dimensional (2D) matrices, while overexpression of 14-3-3ζ alone most suppressed migration atop 2D matrices (as compared to non-transformed MECs). Our results also suggest that co-overexpression of the 14-3-3ζ and ErbB2 proteins facilitates cell migratory capacity in 3D matrices, as reflected in cell migration speed. Additionally, 3D matrices of sufficient stiffness can significantly hinder the migratory ability of partially transformed cells, but increased 3D matrix stiffness has a lesser effect on the aggressive migratory behavior exhibited by fully transformed cells that co-overexpress both ErbB2 and 14-3-3ζ. Finally, this study shows that for MECs possessing partial or full transforming potential, those overexpressing ErbB2 alone show the greatest sensitivity of cell migration speed to matrix architecture, while those overexpressing 14-3-3ζ alone exhibit the least sensitivity to matrix architecture. Given the current knowledge of breast cancer mechanobiology, these findings overall suggest that cell motility is governed by a complex interplay between matrix mechanics and transforming potential.