FAK-heterozygous mice display enhanced tumour angiogenesis

Vassiliki Kostourou (), Tanguy Lechertier, Louise E. Reynolds, Delphine M. Lees, Marianne Baker, Dylan T. Jones, Bernardo Tavora, Antoine R. Ramjaun, Graeme M. Birdsey, Stephen D. Robinson, Maddy Parsons, Anna M. Randi, Ian R. Hart and Kairbaan Hodivala-Dilke
Additional contact information
Vassiliki Kostourou: Vascular Adhesion Laboratory, BSRC Alexander Fleming, 34 Fleming Street, Vari
Tanguy Lechertier: Centre for Tumour Biology, Barts Cancer Institute—a CR-UK Centre of Excellence, John Vane Science Centre, Queen Mary University of London, Charterhouse Square
Louise E. Reynolds: Centre for Tumour Biology, Barts Cancer Institute—a CR-UK Centre of Excellence, John Vane Science Centre, Queen Mary University of London, Charterhouse Square
Delphine M. Lees: Centre for Tumour Biology, Barts Cancer Institute—a CR-UK Centre of Excellence, John Vane Science Centre, Queen Mary University of London, Charterhouse Square
Marianne Baker: Centre for Tumour Biology, Barts Cancer Institute—a CR-UK Centre of Excellence, John Vane Science Centre, Queen Mary University of London, Charterhouse Square
Dylan T. Jones: Centre for Tumour Biology, Barts Cancer Institute—a CR-UK Centre of Excellence, John Vane Science Centre, Queen Mary University of London, Charterhouse Square
Bernardo Tavora: Centre for Tumour Biology, Barts Cancer Institute—a CR-UK Centre of Excellence, John Vane Science Centre, Queen Mary University of London, Charterhouse Square
Antoine R. Ramjaun: Centre for Tumour Biology, Barts Cancer Institute—a CR-UK Centre of Excellence, John Vane Science Centre, Queen Mary University of London, Charterhouse Square
Graeme M. Birdsey: Faculty of Medicine, Imperial College London, NHLI Cardiovascular Sciences, Hammersmith Hospital, Du Cane Road
Stephen D. Robinson: Centre for Tumour Biology, Barts Cancer Institute—a CR-UK Centre of Excellence, John Vane Science Centre, Queen Mary University of London, Charterhouse Square
Maddy Parsons: New Hunts House, Kings College London
Anna M. Randi: Faculty of Medicine, Imperial College London, NHLI Cardiovascular Sciences, Hammersmith Hospital, Du Cane Road
Ian R. Hart: Centre for Tumour Biology, Barts Cancer Institute—a CR-UK Centre of Excellence, John Vane Science Centre, Queen Mary University of London, Charterhouse Square
Kairbaan Hodivala-Dilke: Centre for Tumour Biology, Barts Cancer Institute—a CR-UK Centre of Excellence, John Vane Science Centre, Queen Mary University of London, Charterhouse Square

Nature Communications, 2013, vol. 4, issue 1, 1-11

Abstract: Abstract Genetic ablation of endothelial focal adhesion kinase (FAK) can inhibit pathological angiogenesis, suggesting that loss of endothelial FAK is sufficient to reduce neovascularization. Here we show that reduced stromal FAK expression in FAK-heterozygous mice unexpectedly enhances both B16F0 and CMT19T tumour growth and angiogenesis. We further demonstrate that cell proliferation and microvessel sprouting, but not migration, are increased in serum-stimulated FAK-heterozygous endothelial cells. FAK-heterozygous endothelial cells display an imbalance in FAK phosphorylation at pY397 and pY861 without changes in Pyk2 or Erk1/2 activity. By contrast, serum-stimulated phosphorylation of Akt is enhanced in FAK-heterozygous endothelial cells and these cells are more sensitive to Akt inhibition. Additionally, low doses of a pharmacological FAK inhibitor, although too low to affect FAK autophosphorylation in vitro, can enhance angiogenesis ex vivo and tumour growth in vivo. Our results highlight a potential novel role for FAK as a nonlinear, dose-dependent regulator of angiogenesis where heterozygous levels of FAK enhance angiogenesis.

Date: 2013
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DOI: 10.1038/ncomms3020

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