FAK-heterozygous mice display enhanced tumour angiogenesis

• DOI: 10.1038/ncomms3020
• Publication Date: 2013-06-25T15:08:06Z
• Authors: 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; Kairbaan Hodivala...
• Keywords: Talin; 0301 basic medicine; 570; GROWTH-FACTOR; Heterozygote; Cell Survival; 610; Cell Separation; In Vitro Techniques; Article; Mice; 03 medical and health sciences; Subcutaneous Tissue; Neoplasms; Animals; TYROSINE-861; CANCER-CELLS; PHOSPHORYLATION; Neovascularization; Cell Proliferation; Pathologic; 0303 health sciences; Science & Technology; Neovascularization, Pathologic; Endothelial Cells; ADENOCARCINOMA; FOCAL-ADHESION KINASE; ENDOTHELIAL-CELLS; Immunohistochemistry; Vinculin; Tumor Burden; Multidisciplinary Sciences; TUBE FORMATION; Focal Adhesion Kinase 1; SURVIVAL; Science & Technology - Other Topics; Mutant Proteins; Paxillin; Proto-Oncogene Proteins c-akt; SRC; Signal Transduction

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.