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.

Neuron-Derived Neurotrophic Factor Ameliorates Adverse Cardiac Remodeling After Experimental Myocardial Infarction

“…[26][27][28] Recently, we reported that NDNF enhances the phosphorylation of Akt and its downstream molecule eNOS, and capillary formation in ischemic skeletal muscle of mice. 5 We also demonstrated that NDNF promotes network formation of endothelial cells through its ability to stimulate the phosphorylation of Akt and eNOS.…”

PF573,228 inhibits vascular tumor cell growth, migration as well as angiogenesis, induces apoptosis and abrogates PRAS40 and S6RP phosphorylation

“…This, in turn, leads to increased (18,19). In addition, FAK-induced cell migration has been associated with the development of various neoplasms (2,20). Thus, the blocking of FAK is a plausible target for therapeutic inhibition of cell motility, and perhaps of angiogenesis, since endothelial cell migration is crucial during the angiogenic process.…”

“…Focal adhesion kinase is required for tumor angiogenesis (20,21). Therefore, FAK may be an important target in the abrogation of tumor angiogenesis, especially in the context of problematic vascular tumors such as infantile hemangiomas (IH) and hemangioendotheliomas.…”

Focal adhesion kinase

“…In both settings it is apparent that endothelial FAK is an important mediator of VEGF-induced neovascularization. 20,21 Taken together, these findings provide strong rationale for targeting FAK to simultaneously counter tumor metastasis and angiogenesis. To this end, there has been a surge in the discovery and preclinical development of agents directed against FAK.…”

“…20,21 To explore the relationship between ovarian cancer cell FAK and pFAK expression and the tumor vasculature, we stained the specimens for CD31 and quantified microvessel density (MVD). The median MVD was 21.6 vessels/high power field (range, 8.6-38.3 vessels/high power field).…”