Novel therapeutic targets for the regulation of tumor angiogenesis and lymphangiogenesis

Abstract

RhoJ is a small GTPase known to be highly expressed in endothelial cells (EC). To date, the exact role of RhoJ in various angiogenic stimuli has not been fully defined. This study aims to evaluate the role of RhoJ in tumor angiogenesis and progression and to seek therapeutic applicability for cancer therapy. RhoJ is involved in EC migration and EC tube formation; it negatively modulates the RhoA-ROCK-Myosin signal pathway. In addition, like other Rho GTPases, RhoJ is important in the maintenance of endothelial paracellular integrity. The activity of RhoJ is dynamically regu-lated by VEGF-A/VEGFR2 signaling, indicating that RhoJ takes an active part in VEGF-driven angiogenesis. In the murine solid tumor model, the expression of RhoJ is regulated in a specific spatiotemporal manner, in which most expression is restricted in the tumor vessels of early stage and growing vascular fronts. RhoJ is indispensable in the formation and net-working of tumor neovessels, and tumor growth and metastasis is significantly suppressed when RhoJ is deficient. Moreover, RhoJ knockout induces tumor vascular disruption and in-creased leakage of the plasma component and blood into the tumor interstitium, which even-tually gives rise to the shutdown of tumor vascular flow. A concurrent blockade of RhoJ and VEGF-A/VEGFR-2 signaling further potentiates the efficacy of RhoJ knockout, which may prevents alternative Rho GTPases from VEGF-mediated activation. To explore the clinical possibility of RhoJ blockade as a cancer therapeutic, the current study applied a novel in vivo siRNA delivery system using aptide. RhoJ siRNA incorporated into EDB-aptide conjugated PEG-liposome complex displayed prominent anti-angiogenic effects against solid tumors. In conclusion, RhoJ plays a critical role during tumor progression through the regulation of angiogenesis and vascular integrity, making it a promising target for anti-angiogenic and vascular disrupting therapy.