Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis.
Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis.
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DOI：
10.1083/jcb.200209006
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发表时间：
2003-01-20
期刊：
影响因子：
--
通讯作者：
Friedl P
中科院分区：
文献类型：
--
作者：
Wolf K;Mazo I;Leung H;Engelke K;von Andrian UH;Deryugina EI;Strongin AY;Bröcker EB;Friedl P
侵袭性肿瘤的体外和体内扩散涉及ECM屏障的蛋白降解。然而，这一过程只能通过基于蛋白酶抑制剂的治疗而不完全减弱，这表明存在迁移补偿策略。在三维胶原基质中，纺锤形蛋白水解力强的HT1080纤维肉瘤和β-MB-231癌细胞表现出结构性的间叶型运动，包括Mt1整合素和基质金属蛋白酶在纤维结合部位的共同聚集和管状蛋白降解轨迹的产生。然而，几乎完全抑制MMPs、丝氨酸蛋白酶、组织蛋白和其他蛋白酶，诱导了近乎不减的迁移速率向球形形态的转变。持续的蛋白酶非依赖性迁移是由灵活的阿米巴样形状变化引起的，即在没有基质降解的情况下，通过预先存在的基质间隙推进挤压和形成收缩环，伴随而来的是成簇的β1整合素和纤维结合部位的MT1-MMPs的丢失，以及肌动蛋白细胞骨架的弥漫性皮质分布。通过活体多光子显微镜监测，证实了注射到小鼠真皮中的HT-1080细胞获得了不依赖于蛋白酶的阿米巴播散。综上所述，从蛋白水解性间充质向非蛋白水解性阿米巴运动的转变突出了细胞迁移的超分子可塑性机制，并进一步代表了肿瘤细胞在取消细胞周蛋白分解后的一种可能的逃逸机制。
Invasive tumor dissemination in vitro and in vivo involves the proteolytic degradation of ECM barriers. This process, however, is only incompletely attenuated by protease inhibitor–based treatment, suggesting the existence of migratory compensation strategies. In three-dimensional collagen matrices, spindle-shaped proteolytically potent HT-1080 fibrosarcoma and MDA-MB-231 carcinoma cells exhibited a constitutive mesenchymal-type movement including the coclustering of β1 integrins and MT1–matrix metalloproteinase (MMP) at fiber bindings sites and the generation of tube-like proteolytic degradation tracks. Near-total inhibition of MMPs, serine proteases, cathepsins, and other proteases, however, induced a conversion toward spherical morphology at near undiminished migration rates. Sustained protease-independent migration resulted from a flexible amoeba-like shape change, i.e., propulsive squeezing through preexisting matrix gaps and formation of constriction rings in the absence of matrix degradation, concomitant loss of clustered β1 integrins and MT1-MMP from fiber binding sites, and a diffuse cortical distribution of the actin cytoskeleton. Acquisition of protease-independent amoeboid dissemination was confirmed for HT-1080 cells injected into the mouse dermis monitored by intravital multiphoton microscopy. In conclusion, the transition from proteolytic mesenchymal toward nonproteolytic amoeboid movement highlights a supramolecular plasticity mechanism in cell migration and further represents a putative escape mechanism in tumor cell dissemination after abrogation of pericellular proteolysis.
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影响因子：
64.5
作者：
Hiraoka, N;Allen, E;Weiss, SJ
通讯作者：
Weiss, SJ
影响因子：
7.5
作者：
BIRKEDALHANSEN, H
通讯作者：
BIRKEDALHANSEN, H
影响因子：
64.5
作者：
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影响因子：
32.4
作者：
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通讯作者：
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影响因子：
4.8
作者：
AIMES, RT;QUIGLEY, JP
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QUIGLEY, JP