A20
Roles of Rho GTPases in tumour angiogenesis and vessel establishment
Sabu Abraham1, Margaret Yeo1, Christopher J Marshall1, Georgia Mavria2
1The Institute of Cancer Research, London, UK, 2Leeds Institute of Molecular Medicine, St James University Hospital, UK
Angiogenesis is necessary for tumour growth and metastasis. During new blood vessel formation, endothelial cells undergo complex morphological changes such as spreading and extension of protrusions during migration, and cell contraction during assembly. Because these morphological changes are dependent on the actin cytoskeleton we are studying the roles of the Rho family of small GTPases and their regulators. We have performed screens in a 3D co-culture system of endothelial cells and fibroblasts and have found roles for less well characterised members of the family such as RhoG and RhoC, and for the atypical members Rnd1 and RhoBTB2. RhoG is required for endothelial cell migration, whereas RhoC controls MLC2 phosphorylation and actomyosin contractility. Surprisingly our studies have shown that inhibition of the Rho effector ROCK does not inhibit but promotes angiogenesis in tissue culture and in tumours in vivo. In established and quiescent tubes VE-cadherin signals to ROCK and MLC2 phosphorylation to suppress sprouting and promote quiescence. ROCK inhibition results in increased VEGFR2 phosphorylation and sprouting that is reversed by inhibition of VEGFR2 and Rac1.
