Visualizing extravasation dynamics of metastatic tumor cells.
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.
Department of Pathology and Moores Cancer Center, University of California, San Diego, 9500 Gilman Drive, MC0612, La Jolla, CA 92093, USA.
Konstantin
K
Stoletov
Hisashi
H
Kato
Erin
E
Zardouzian
Jonathan
J
Kelber
Jing
J
Yang
Sanford
S
Shattil
Richard
R
Klemke
D000818:Animals; D030801:Animals, Genetically Modified; D045744:Cell Line, Tumor / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D022081:Cell Surface Extensions / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000033:anatomy & histology / Q000502:physiology; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051879:Twist-Related Protein 1 / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D015027:Zebrafish; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
D019012:Integrin beta1; D051879:Twist-Related Protein 1; D042461:Vascular Endothelial Growth Factor A; D054460:rho-Associated Kinases