Abstract
Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays a fundamental role in integrin and growth factor mediated signalling and is an important player in cell migration and proliferation, processes vital for angiogenesis. However, the role of FAK in adult pathological angiogenesis is unknown. We have generated endothelial-specific tamoxifen-inducible FAK knockout mice by crossing FAK-floxed (FAKfl/fl) mice with the platelet derived growth factor b (Pdgfb)-iCreER mice. Tamoxifen-treatment of Pdgfb-iCreER;FAKfl/fl mice results in FAK deletion in adult endothelial cells (ECs) without any adverse effects. Importantly however, endothelial FAK-deletion in adult mice inhibited tumour growth and reduced tumour angiogenesis. Furthermore, in in vivo angiogenic assays FAK deletion impairs vascular endothelial growth factor (VEGF)-induced neovascularization. In addition, in vitro deletion of FAK in ECs resulted in reduced VEGF-stimulated Akt phosphorylation and correlating reduced cellular proliferation as well as increased cell death. Our data suggest that FAK is required for adult pathological angiogenesis and validates FAK as a possible target for anti-angiogenic therapies.
Highlights
Angiogenesis, the formation of new blood vessels from preexisting vessels, contributes to several pathological conditions including cancer (Carmeliet, 2003; Hicklin & Ellis, 2005)
Our study suggests that this role for focal adhesion kinase (FAK) extends to at least vascular endothelial growth factor (VEGF)- and basic fibroblast growth factor (bFGF)-dependent angiogenic responses
We have evidence that the basis of the angiogenic defect in the platelet derived growth factor b (Pdgfb)-iCreER;FAKfl/fl mice likely involves the effect of endothelial FAK deletion inhibiting endothelial cells (ECs) directional migration and proliferation both in vivo and in vitro
Summary
Angiogenesis, the formation of new blood vessels from preexisting vessels, contributes to several pathological conditions including cancer (Carmeliet, 2003; Hicklin & Ellis, 2005). The coordinated downstream signalling via endothelial growth factor receptors (1) Adhesion and Angiogenesis Laboratory, Centre of Tumour Biology, Institute of Cancer and Cancer Research UK Clinical Centre, Barts & The London, Queen Mary’s School of Medicine & Dentistry, John Vane Science Centre, Charterhouse Square, London, UK. One molecule that is common to both signalling pathways is the ubiquitously expressed tyrosine kinase, focal adhesion kinase (FAK) (Mitra et al, 2005). The convergence of these pathways on FAK suggests that this molecule is likely to be important during blood vessel development in the growing tumour
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