FAK-heterozygous mice display enhanced tumour angiogenesis
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...
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Veröffentlicht in: | Nature communications 2013-06, Vol.4 (1), p.2020-2020, Article 2020 |
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Zusammenfassung: | 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.
Focal adhesion kinase (FAK) regulates angiogenesis and FAK inhibitors are currently developed as anticancer drugs. Here Kostourou and colleagues show that genetic FAK heterozygosity or low doses of a pharmacological FAK inhibitor unexpectedly increase angiogenesis and tumour growth
in vitro
and
in vivo
. |
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ISSN: | 2041-1723 2041-1723 |
DOI: | 10.1038/ncomms3020 |