Wolf Katarina, Mazo Irina, Leung Harry, Engelke Katharina, von Andrian Ulrich H, Deryugina Elena I, Strongin Alex Y, Bröcker Eva-B, Friedl Peter
Department of Dermatology, University of Würzburg, 97080 Würzburg, Germany.
J Cell Biol. 2003 Jan 20;160(2):267-77. doi: 10.1083/jcb.200209006. Epub 2003 Jan 13.
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 beta 1 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 beta 1 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.
侵袭性肿瘤在体外和体内的扩散涉及细胞外基质（ECM）屏障的蛋白水解降解。然而，基于蛋白酶抑制剂的治疗只能部分减弱这一过程，这表明存在迁移补偿策略。在三维胶原基质中，具有蛋白水解活性的梭形HT - 1080纤维肉瘤细胞和MDA - MB - 231癌细胞表现出一种组成型间充质样运动，包括β1整合素和MT1 - 基质金属蛋白酶（MMP）在纤维结合位点的共聚集以及管状蛋白水解降解轨迹的形成。然而，对MMPs、丝氨酸蛋白酶、组织蛋白酶和其他蛋白酶的近乎完全抑制，在迁移速率几乎未降低的情况下诱导细胞向球形形态转变。持续的非蛋白酶依赖性迁移源于灵活的变形虫样形状变化，即通过预先存在的基质间隙进行推进挤压并在无基质降解的情况下形成收缩环，同时β1整合素和MT1 - MMP从纤维结合位点聚集丢失，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，将HT - 1080细胞注射到小鼠真皮中证实了其获得非蛋白酶依赖性变形虫样扩散。总之，从蛋白水解性间充质运动向非蛋白水解性变形虫样运动的转变突出了细胞迁移中的一种超分子可塑性机制，并且进一步代表了在细胞周围蛋白水解被消除后肿瘤细胞扩散中的一种假定逃逸机制。
