title: Endothelial FAK is required for tumour angiogenesis.
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.
authors.affiliation: 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.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Tavora
authors.forename: Silvia
authors.initials: S
authors.lastname: Batista
authors.forename: Louise E
authors.initials: LE
authors.lastname: Reynolds
authors.forename: Shalini
authors.initials: S
authors.lastname: Jadeja
authors.forename: Stephen
authors.initials: S
authors.lastname: Robinson
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Kostourou
authors.forename: Ian
authors.initials: I
authors.lastname: Hart
authors.forename: Marcus
authors.initials: M
authors.lastname: Fruttiger
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
authors.forename: Kairbaan M
authors.initials: KM
authors.lastname: Hodivala-Dilke
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology* / Q000378:metabolism; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A; D051416:Focal Adhesion Protein-Tyrosine Kinases