Cancer Research. 2008 Jun 1;68(11):4296-302.
Twist is required for thrombin-induced tumor angiogenesis and growth.
Hu L, Roth JM, Brooks P, Ibrahim S, Karpatkin S.
Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.
Significance:
The Twist transcription factor is a master regulator of embryonic morphogenesis and necessary for proper cell migration and tissue reorganization during embryogenesis. Thrombin enhances the malignant phenotype by inducing tumor growth, migration, invasion and metastasis.
Our finding that Thrombin upregulates Twist in 5 different tumor cell lines and that Twist is required for thrombin-induced tumor angiogenesis, growth and metastasis, supports the role of Twist as a master regulator in tumorigenesis as well as embryogenesis.
Abstract:
Twist, a master regulator of embryonic morphogenesis, induces functions that are also required for tumor invasion and metastasis. Because thrombin contributes to the malignant phenotype by up-regulating tumor metastasis, we examined its effect on Twist in five different tumor cell lines and two different endothelial cell lines. Thrombin up-regulated Twist mRNA and protein in all seven cell lines. Down-regulation of Twist in B16F10 tumor cell lines led to a approximately 3-fold decrease in tumor growth on a chorioallantoic membrane assay and approximately 2-fold decrease in syngeneic mice. Angiogenesis was decreased approximately 45% and 36%, respectively.
The effect of Twist on angiogenesis was further examined and compared with the effect of thrombin. In studies using a Twist-inducible plasmid, several identical vascular growth factors and receptors were up-regulated approximately 2- to 3-fold in tumor cells as well as human umbilical vascular endothelial cells by both Twist as well as thrombin (vascular endothelial growth factor, KDR, Ang-2, matrix metalloproteinase 1, GRO-alpha, and CD31). Thrombin-induced endothelial cell chemotaxis and Matrigel endothelial cell tubule formation were similarly regulated by Twist.
Thus, thrombin up-regulates Twist, which is required for thrombin-induced angiogenesis as measured by endothelial cell migration, Matrigel tubule formation, and tumor angiogenesis.
PMID: 18519689
