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Conditional ROCK activation in vivo induces tumor cell dissemination and angiogenesis
Daniel R Croft1, Erik Sahai, Georgia Mavria
1Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
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.
Insights
Increased Rho-kinase (ROCK) signaling drives tumor invasion and angiogenesis. Inhibiting ROCK may offer a therapeutic strategy against metastatic cancers with elevated Rho GTPases.
Area of Science:
- Oncology
- Cell Biology
- Molecular Medicine
Background:
- Tumor progression to invasive and metastatic forms involves significant cell morphologic changes regulated by Rho GTPases.
- Elevated RhoA, RhoC, and their effector proteins ROCK I and ROCK II are frequently observed in human cancers, correlating with invasive phenotypes.
Purpose of the Study:
- To investigate the role of ROCK signaling in solid tumor progression, specifically invasion and angiogenesis.
- To determine if increased ROCK signaling is sufficient to promote tumor cell dissemination and vascularization.
Main Methods:
- Development of a conditionally activated ROCK II construct (ROCK:ER) by fusing the kinase domain to the estrogen receptor hormone-binding domain.
- Culturing ROCK:ER-expressing colon carcinoma cells and growing them as tumors in immunocompromised nude mice.
- Activation of ROCK:ER signaling to observe effects on tumor morphology, invasion, and vascularization.
Main Results:
- ROCK:ER activation led to aggressive tumor cell dissemination into the surrounding stroma, demonstrating ROCK's sufficiency in promoting invasion.
- Tumors with activated ROCK:ER exhibited increased vascularization, indicating a role for ROCK in tumor angiogenesis.
- ROCK:ER activation induced epithelial cell morphologic changes and altered protein distribution (ezrin, adherens junctions, ECM-binding proteins), facilitating motility.
Conclusions:
- Increased ROCK signaling is sufficient to drive tumor cell invasion and angiogenesis.
- ROCK inhibitors show potential as antimetastatic and antiangiogenic agents for cancers with elevated Rho GTPase pathway activity.
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