Vascular RhoJ Is an Effective and Selective Target for Tumor Angiogenesis and Vascular Disruption

• RhoJ promotes tumor progression by regulating angiogenesis and vessel integrity
• RhoJ blockade disrupts tumor vessels via RhoA-ROCK activation
• RhoJ blockade enhances antiangiogenic and vascular-disrupting therapeutic efficacy
• Tumor-targeted RhoJ inhibition is feasible with EDB-aptide encapsulated siRNA

SummaryCurrent antiangiogenic therapy is limited by its cytostatic nature and systemic side effects. To address these limitations, we have unveiled the role of RhoJ, an endothelial-enriched Rho GTPase, during tumor progression. RhoJ blockade provides a double assault on tumor vessels by both inhibiting tumor angiogenesis and disrupting the preformed tumor vessels through the activation of the RhoA-ROCK (Rho kinase) signaling pathway in tumor endothelial cells, consequently resulting in a functional failure of tumor vasculatures. Moreover, enhanced anticancer effects were observed when RhoJ blockade was employed in concert with a cytotoxic chemotherapeutic agent, angiogenesis-inhibiting agent, or vascular-disrupting agent. These results identify RhoJ blockade as a selective and effective therapeutic strategy for targeting tumor vasculature with minimal side effects.

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