Physical confinement alters tumor cell adhesion and migration phenotypes
Physical confinement alters tumor cell adhesion and migration phenotypes
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DOI：
10.1096/fj.12-211441
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发表时间：
2012-10-01
期刊：
影响因子：
4.8
通讯作者：
Konstantopoulos, Konstantinos
中科院分区：
文献类型：
--
作者：
Balzer, Eric M.;Tong, Ziqiu;Konstantopoulos, Konstantinos
平面表面上的细胞迁移是由肌动蛋白突起、整合素介导的粘附和肌球蛋白介导的收缩的循环驱动的;然而，这种机制可能无法准确描述三维（3D）空间中的运动。通过将细胞置于限制性的3D环境中，我们证明了物理限制构成了改变细胞形态并抑制人乳腺癌（MDA-MB-231）间充质运动的生物物理刺激。背腹极性，应力纤维，和局灶性粘连明显减弱的限制。肌球蛋白、Rho/ROCK或β 1-整联蛋白的抑制剂不会损害通过3 μ m宽通道的迁移（限制），尽管这些治疗会抑制50 μ m宽通道中的运动（非限制迁移）>= 50%。引人注目的是，即使F-肌动蛋白被破坏，受限的迁移仍然存在，但在很大程度上取决于微管（MT）动力学。干扰MT聚合/解聚导致受限制的细胞经历频繁的方向变化，从而相对于载体对照降低平均净位移>= 80%。活细胞EB 1-GFP成像显示，限制重定向MT聚合朝向前沿，其中MT在细胞前沿的推进过程中持续影响。这些结果表明，物理限制可以诱导细胞骨架的改变，减少依赖的迁移细胞的粘附收缩力耦合。这种机制可以解释为什么整合素在3D环境中迁移期间可以表现出减少或改变的功能。Balzer，E. M.，唐，Z.保罗角D、洪，W.- C.的方法，斯特罗卡湾M.，Boggs，A. E、马丁，S。美国，Konstantopoulos，K.物理限制改变肿瘤细胞粘附和迁移表型。FASEB J.26，4045-4056（2012）。www.fasebj.org
Cell migration on planar surfaces is driven by cycles of actin protrusion, integrin-mediated adhesion, and myosin-mediated contraction; however, this mechanism may not accurately describe movement in 3-dimensional (3D) space. By subjecting cells to restrictive 3D environments, we demonstrate that physical confinement constitutes a biophysical stimulus that alters cell morphology and suppresses mesenchymal motility in human breast carcinoma (MDA-MB-231). Dorsoventral polarity, stress fibers, and focal adhesions are markedly attenuated by confinement. Inhibitors of myosin, Rho/ROCK, or beta 1-integrins do not impair migration through 3-mu m-wide channels (confinement), even though these treatments repress motility in 50-mu m-wide channels (unconfined migration) by >= 50%. Strikingly, confined migration persists even when F-actin is disrupted, but depends largely on microtubule (MT) dynamics. Interfering with MT polymerization/depolymerization causes confined cells to undergo frequent directional changes, thereby reducing the average net displacement by >= 80% relative to vehicle controls. Live-cell EB1-GFP imaging reveals that confinement redirects MT polymerization toward the leading edge, where MTs continuously impact during advancement of the cell front. These results demonstrate that physical confinement can induce cytoskeletal alterations that reduce the dependence of migrating cells on adhesion-contraction force coupling. This mechanism may explain why integrins can exhibit reduced or altered function during migration in 3D environments.-Balzer, E. M., Tong, Z., Paul, C. D., Hung, W.-C., Stroka, K. M., Boggs, A. E., Martin, S. S., Konstantopoulos, K. Physical confinement alters tumor cell adhesion and migration phenotypes. FASEB J. 26, 4045-4056 (2012). www.fasebj.org