Abstract
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is overexpressed in many cancer types and in vivo studies have shown that vascular endothelial cell FAK expression and FAK-phosphorylation at tyrosine (Y) 397, and subsequently FAK-Y861, are important in tumour angiogenesis. Pericytes also play a vital role in regulating tumour blood vessel stabilisation, but the specific involvement of pericyte FAK-Y397 and FAK-Y861 phosphorylation in tumour blood vessels is unknown. Using PdgfrβCre + ;FAKWT/WT, PdgfrβCre + ;FAKY397F/Y397F and PdgfrβCre + ;FAKY861F/Y861F mice, our data demonstrate that Lewis lung carcinoma tumour growth, tumour blood vessel density, blood vessel perfusion and pericyte coverage were affected only in late stage tumours in PdgfrβCre + ;FAKY861F/Y861F but not PdgfrβCre + ;FAKY397F/Y397F mice. Further examination indicates a dual role for pericyte FAK-Y861 phosphorylation in the regulation of tumour vessel regression and also in the control of pericyte derived signals that influence apoptosis in cancer cells. Overall this study identifies the role of pericyte FAK-Y861 in the regulation of tumour vessel regression and tumour growth control and that non-phosphorylatable FAK-Y861F in pericytes reduces tumour growth and blood vessel density.
Highlights
Angiogenesis is a complex biological process that involves multiple cell types, crosstalk between these cells and responses to different stimuli [1–3]
Pericytes isolated from PdgfrβCre + ;FAKWT/WT, PdgfrβCre + ;FAKY861F/Y861F and PdgfrβCre + ;FAKY397F/Y397F mice confirmed the presence of the myc-tag indicating chicken Focal adhesion kinase (FAK)-knockin and normal levels of total FAK (Supplementary Fig. 1c)
Our data demonstrate that FAK-Y861F pericytes decrease tumour burden, at least in part, by directly affecting tumour cell apoptosis, and call for further consideration of the role of tumour pericytes in the direct control of tumour growth, in addition to their effects on vessel stabilisation
Summary
Angiogenesis is a complex biological process that involves multiple cell types, crosstalk between these cells and responses to different stimuli [1–3]. Interactions between pericytes and endothelial cells play important roles in angiogenesis. Pericyte recruitment to newly forming blood vessels is thought to promote neovessel stabilisation and is an essential step in neovascularisation [4, 5]. Failure to recruit pericytes to blood vessels can affect vascular remodelling, vessel regression and vessel leakage [1, 2, 6]. This has led to pericyte-targeted therapies being developed and a better understanding of the role of pericytes in tumour angiogenesis [7, 8].
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