This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hu, L. Articles by Karpatkin, S. Search for Related Content PubMed PubMed Citation Articles by Hu, L. Articles by Karpatkin, S.

Twist Is Required for Thrombin-Induced Tumor Angiogenesis and Growth

Departments of ¹ Medicine, ² Radiation Oncology, and ³ Pathology, New York University School of Medicine, New York, New York

Requests for reprints: Simon Karpatkin, New York University School of Medicine, 550 First Avenue, New York, NY 10016. Phone: 212-263-5609; Fax: 212-263-0695; E-mail: Simon.Karpatkin{at}med.nyu.edu.

Key Words: Thrombin • Twist • tumor • endothelial cell • angiogenesis

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 3-fold decrease in tumor growth on a chorioallantoic membrane assay and 2-fold decrease in syngeneic mice. Angiogenesis was decreased 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 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-, 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. [Cancer Res 2008;68(11):4296–302]