Conditional ROCK Activation In vivo Induces Tumor Cell Dissemination and Angiogenesis
Open Access
- 15 December 2004
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 64 (24) , 8994-9001
- https://doi.org/10.1158/0008-5472.can-04-2052
Abstract
Progression of tumors to invasive and metastatic forms requires that tumor cells undergo dramatic morphologic changes, a process regulated by Rho GTPases. Elevated expression of RhoA and RhoC, as well as the Rho effector proteins ROCK I and ROCK II, are commonly observed in human cancers and are often associated with more invasive and metastatic phenotypes. To examine how ROCK contributes to the progression of solid tumors, we established a conditionally activated form of ROCK II by fusing the kinase domain to the estrogen receptor hormone-binding domain (ROCK:ER). ROCK:ER-expressing colon carcinoma cells grown as tumors in immunocompromised nude mice organized into discrete clusters surrounding blood vessels. However, ROCK:ER activation resulted in the aggressive dissemination of tumor cells into the surrounding stroma, indicating that increased ROCK signaling is sufficient to promote invasion from solid tumors. In addition, tumors in which ROCK:ER was activated were more highly vascularized, indicating that ROCK contributes to tumor angiogenesis. ROCK:ER activation resulted in changes to epithelial morphology and organization that facilitated motility in vitro, likely by inducing the redistribution of proteins such as ezrin, as well as adherens junction and extracellular matrix-binding proteins. These results suggest that ROCK inhibitors would be useful antimetastatic and antiangiogenic chemotherapeutic agents in tumors associated with elevated RhoA, RhoC, ROCK I, or ROCK II expression.Keywords
This publication has 47 references indexed in Scilit:
- RAS and RHO GTPases in G1-phase cell-cycle regulationNature Reviews Molecular Cell Biology, 2004
- Expression of seven main Rho family members in gastric carcinomaBiochemical and Biophysical Research Communications, 2004
- Phosphoinositide binding and phosphorylation act sequentially in the activation mechanism of ezrinThe Journal of cell biology, 2004
- Sticky BusinessCell, 2003
- ROCK and Dia have opposing effects on adherens junctions downstream of RhoNature Cell Biology, 2002
- RHO–GTPases and cancerNature Reviews Cancer, 2002
- Specificity and mechanism of action of some commonly used protein kinase inhibitorsBiochemical Journal, 2000
- Rho-Kinase Inhibitor Retards Migration and in Vivo Dissemination of Human Prostate Cancer CellsBiochemical and Biophysical Research Communications, 2000
- Activation of ERM proteins in vivo by Rho involves phosphatidyl-inositol 4-phosphate 5-kinase and not ROCK kinasesCurrent Biology, 1999
- Rho-Kinase Phosphorylates COOH-terminal Threonines of Ezrin/Radixin/Moesin (ERM) Proteins and Regulates Their Head-to-Tail AssociationThe Journal of cell biology, 1998