Comparative mechanisms of cancer cell migration through 3D matrix and physiological microtracks
Comparative mechanisms of cancer cell migration through 3D matrix and physiological microtracks
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DOI：
10.1152/ajpcell.00225.2014
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发表时间：
2015-03-15
影响因子：
5.5
通讯作者：
Reinhart-King, Cynthia A.
中科院分区：
文献类型：
--
作者：
Carey, Shawn P.;Rahman, Aniqua;Reinhart-King, Cynthia A.
肿瘤细胞通过基质细胞外基质（ECM）侵袭是癌症转移的一个关键特征，了解侵袭性迁移的细胞机制对于制定有效的诊断和治疗策略至关重要。由于癌细胞迁移高度适应 ECM 的理化特性，因此以特定环境的方式定义这些迁移机制至关重要。尽管大量的工作已经描述了二维和三维 (3D) 基质环境中癌细胞迁移的特征，但细胞在基质 ECM 内通过天然和细胞衍生的微轨迹移动的迁移程序仍不清楚。我们之前报道了一种图案化 I 型胶原微轨体外模型的开发，该模型能够实现不依赖于基质金属蛋白酶的微轨迁移。在这里，我们表明胶原微轨与天然乳腺基质 ECM 中的通道状间隙非常相似，并检查了微轨迁移背后的细胞外和细胞内机制。细胞-基质机械耦合虽然对于通过 3D 矩阵的迁移至关重要，但对于微轨道迁移来说并不是必需的。相反，细胞骨架动力学，包括肌动蛋白聚合、皮质张力和微管周转，能够通过生理微通道实现持续的、极化的迁移。这些结果表明肿瘤细胞采用特定环境机制进行迁移，并表明选择性靶向细胞骨架动力学，而不是粘附、蛋白水解或细胞牵引力，可以有效抑制癌细胞通过肿瘤基质内预先形成的基质微轨迁移。
Tumor cell invasion through the stromal extracellular matrix (ECM) is a key feature of cancer metastasis, and understanding the cellular mechanisms of invasive migration is critical to the development of effective diagnostic and therapeutic strategies. Since cancer cell migration is highly adaptable to physiochemical properties of the ECM, it is critical to define these migration mechanisms in a context-specific manner. Although extensive work has characterized cancer cell migration in two-and three-dimensional (3D) matrix environments, the migration program employed by cells to move through native and cell-derived microtracks within the stromal ECM remains unclear. We previously reported the development of an in vitro model of patterned type I collagen microtracks that enable matrix metalloproteinase-independent microtrack migration. Here we show that collagen microtracks closely resemble channel-like gaps in native mammary stroma ECM and examine the extracellular and intracellular mechanisms underlying microtrack migration. Cell-matrix mechanocoupling, while critical for migration through 3D matrix, is not necessary for microtrack migration. Instead, cytoskeletal dynamics, including actin polymerization, cortical tension, and microtubule turnover, enable persistent, polarized migration through physiological microtracks. These results indicate that tumor cells employ context-specific mechanisms to migrate and suggest that selective targeting of cytoskeletal dynamics, but not adhesion, proteolysis, or cell traction forces, may effectively inhibit cancer cell migration through preformed matrix microtracks within the tumor stroma.