Department of Pathology and Moores Cancer Center, University of California, San Diego, 9500 Gilman Drive, MC0612, La Jolla, CA 92093, USA.
J Cell Sci. 2010 Jul 1;123(Pt 13):2332-41. doi: 10.1242/jcs.069443. Epub 2010 Jun 8.
Little is known about how metastatic cancer cells arrest in small capillaries and traverse the vascular wall during extravasation in vivo. Using real-time intravital imaging of human tumor cells transplanted into transparent zebrafish, we show here that extravasation of cancer cells is a highly dynamic process that involves the modulation of tumor cell adhesion to the endothelium and intravascular cell migration along the luminal surface of the vascular wall. Tumor cells do not damage or induce vascular leak at the site of extravasation, but rather induce local vessel remodeling characterized by clustering of endothelial cells and cell-cell junctions. Intravascular locomotion of tumor cells is independent of the direction of blood flow and requires beta1-integrin-mediated adhesion to the blood-vessel wall. Interestingly, the expression of the pro-metastatic gene Twist in tumor cells increases their intravascular migration and extravasation through the vessel wall. However, in this case, Twist expression causes the tumor cells to switch to a beta1-integrin-independent mode of extravasation that is associated with the formation of large dynamic rounded membrane protrusions. Our results demonstrate that extravasation of tumor cells is a highly dynamic process influenced by metastatic genes that target adhesion and intravascular migration of tumor cells, and induce endothelial remodeling.
关于转移性癌细胞如何在体内渗出过程中在小毛细血管中停滞并穿过血管壁，目前知之甚少。通过对移植到透明斑马鱼体内的人类肿瘤细胞进行实时活体成像，我们在此表明，癌细胞的渗出是一个高度动态的过程，涉及肿瘤细胞与内皮细胞的黏附的调节以及沿血管壁腔面的血管内细胞迁移。癌细胞在渗出部位不会损伤或引起血管渗漏，而是诱导局部血管重塑，表现为内皮细胞和成细胞连接的聚集。肿瘤细胞的血管内运动不依赖于血流方向，并且需要β1 整合素介导的与血管壁的黏附。有趣的是，肿瘤细胞中促转移基因 Twist 的表达增加了它们通过血管壁的血管内迁移和渗出。然而，在这种情况下，Twist 的表达使肿瘤细胞切换到与形成大的动态圆形膜突起相关的β1 整合素非依赖性渗出模式。我们的结果表明，肿瘤细胞的渗出是一个高度动态的过程，受转移性基因的影响，这些基因靶向肿瘤细胞的黏附和血管内迁移，并诱导内皮重塑。
