N.N. Blokhin National Medical Research Center of Oncology, Moscow, 115478, Russia.
Department of Biology and A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow, 119992, Russia.
Biol Cell. 2019 Oct;111(10):245-261. doi: 10.1111/boc.201800078. Epub 2019 Aug 22.
Metastatic disease is caused by the ability of cancer cells to reach distant organs and form secondary lesions at new locations. Dissemination of cancer cells depends on their migration plasticity - an ability to switch between motility modes driven by distinct molecular machineries. One of such switches is mesenchymal-to-amoeboid transition. Although mesenchymal migration of individual cells requires Arp2/3-dependent actin polymerisation, amoeboid migration is characterised by a high level of actomyosin contractility and often involves the formation of membrane blebs. The acquisition of amoeboid motility by mesenchymal cells is often associated with enhanced metastasis.
We studied the ability of mesenchymal HT1080 fibrosarcoma cells to switch to amoeboid motility. We induced the transition from lamellipodium-rich to blebbing phenotype either by down-regulating the Arp2/3 complex, pharmacologically or by RNAi, or by decreasing substrate adhesiveness. Each of these treatments induced blebbing in a subset of fibrosarcoma cells, but not in normal subcutaneous fibroblasts. A significant fraction of HT1080 cells that switched to blebbing behaviour exhibited stem cell-like features, such as expression of the stem cell marker CD133, an increased efflux of Hoechst-33342 and positive staining for Oct4, Sox2 and Nanog. Furthermore, the isolated CD133+ cells demonstrated an increased ability to switch to bleb-rich amoeboid phenotype both under inhibitor's treatment and in 3D collagen gels.
Together, our data show a significant correlation between the increased ability of cells to switch between migration modes and their stem-like features, suggesting that migration plasticity is an additional property of stem-like population of fibrosarcoma cells. This combination of features could facilitate both dissemination of these cells to distant locations, and their establishment self-renewal in a new microenvironment, as required for metastasis formation.
These data suggest that migration plasticity is a new feature of cancer stem-like cells that can significantly facilitate their dissemination to a secondary location by allowing them to adapt quickly to challenging microenvironments. Moreover, it complements their resistance to apoptosis and self-renewal potential, thus enabling them not only to disseminate efficiently, but also to survive and colonise new niches.
转移性疾病是由癌细胞到达远处器官并在新位置形成继发性病变的能力引起的。癌细胞的扩散取决于它们的迁移可塑性——一种能够在由不同分子机制驱动的运动模式之间切换的能力。这种转变之一是间质到阿米巴样的转变。虽然单个细胞的间质迁移需要 Arp2/3 依赖性肌动蛋白聚合，但阿米巴样迁移的特点是肌动球蛋白收缩力高，并且经常涉及膜泡的形成。间质细胞获得阿米巴样运动能力通常与增强的转移有关。
我们研究了间质 HT1080 纤维肉瘤细胞向阿米巴样运动的能力。我们通过下调 Arp2/3 复合物、药理学或 RNAi ，或通过降低底物粘附性，从富含片状伪足的表型诱导到泡状表型的转变。这些处理中的每一种都在纤维肉瘤细胞的亚群中诱导泡状，但在正常皮下成纤维细胞中没有。相当一部分切换到泡状行为的 HT1080 细胞表现出干细胞样特征，例如干细胞标记物 CD133 的表达、Hoechst-33342 的流出增加以及 Oct4、Sox2 和 Nanog 的阳性染色。此外，分离的 CD133+细胞在抑制剂处理和 3D 胶原凝胶中均显示出向富含泡状的阿米巴样表型转变的能力增强。
总之，我们的数据显示细胞在运动模式之间切换的能力与它们的干细胞样特征之间存在显著相关性，表明迁移可塑性是纤维肉瘤细胞干细胞样群体的另一个特性。这种特征组合可以促进这些细胞向远处位置的扩散，以及它们在新微环境中自我更新的建立，这是形成转移所必需的。
这些数据表明，迁移可塑性是癌症干细胞样细胞的一个新特征，它可以通过使它们能够快速适应具有挑战性的微环境，显著促进它们向继发性位置的扩散。此外，它补充了它们对细胞凋亡的抗性和自我更新的潜力，从而使它们不仅能够有效地扩散，而且能够存活并在新的生态位中定植。
