dc.description.abstract | Tumour angiogenesis is a hallmark of cancer. Focal adhesion kinase
(FAK) is a non-receptor tyrosine kinase involved in endothelial cells (ECs)
survival, proliferation and migration. FAK has several tyrosine phosphorylation
sites thought to be involved in FAK function but the requirement of
phosphorylation of these residues in vivo is unknown. We have generated mice
where endogenous FAK is deleted simultaneously with the expression of nonphosphorylatable
FAK-Y397F or FAK-Y861F mutated or wild type forms of FAK
in adult endothelium in order to test this.
My data show that EC-FAK-Y397FKI mice present with decreased tumour
angiogenesis (in sygeneic B16F0, CMT19T and LLC) but impaired B16F0 and
CMT19T tumour growth only, with increased tumour hypoxia. FAK-Y397F
tumour endothelium is not perfusion, leakage or vascular maturation defective.
This mutation affects VEGF-, PlGF- and bFGF-driven angiogenesis in vivo and
VEGF+Ang2 administration is able to partially rescue this phenotype ex vivo.
In contrast, endothelial FAK-Y861F mutation leads to an initial delay in
B16F0 tumour angiogenesis, that subsequently resolves, and does not affect
B16F0 tumour growth. LLC and CMT19T tumour growth and angiogenesis are
not affected by the endothelial FAK-Y861F mutation; neither are tumour blood
vessel perfusion, leakage, vascular maturation or tumour hypoxia. VEGF-, PlGFand
bFGF-driven angiogenesis in vivo and ex vivo was not affected by the
endothelial FAK-Y861F mutation, whereas increased in vivo angiogenesis was
triggered by Ang2 administration.
Lastly, to understand whether cytokine profiles that might affect
angiocrine signalling are affected differentially in FAK-Y397F vs FAK-Y861F
endothelial cells, I show that CCL1 and CCL2 are increased in FAK-Y397F but IL-
13, IL-1F3, CCL4, IL-1F1, CCL2 and others are increased in FAK-Y861F
endothelial cells.
Overall my data indicates that endothelial-specific FAK mutations on two
phosphorylation sites has different effects on tumour angiogenesis, tumour
growth, growth factor stimulated angiogenesis in vivo and ex-vivo and cytokine
production. | en_US |