Abstract
The overexpression of the protein tyrosine kinase, Focal adhesion kinase (FAK), in endothelial cells has implicated its requirement in angiogenesis and tumour growth, but how pericyte FAK regulates tumour angiogenesis is unknown. We show that pericyte FAK regulates tumour growth and angiogenesis in multiple mouse models of melanoma, lung carcinoma and pancreatic B-cell insulinoma and provide evidence that loss of pericyte FAK enhances Gas6-stimulated phosphorylation of the receptor tyrosine kinase, Axl with an upregulation of Cyr61, driving enhanced tumour growth. We further show that pericyte derived Cyr61 instructs tumour cells to elevate expression of the proangiogenic/protumourigenic transmembrane receptor Tissue Factor. Finally, in human melanoma we show that when 50% or more tumour blood vessels are pericyte-FAK negative, melanoma patients are stratified into those with increased tumour size, enhanced blood vessel density and metastasis. Overall our data uncover a previously unknown mechanism of tumour growth by pericytes that is controlled by pericyte FAK.
Highlights
The overexpression of the protein tyrosine kinase, Focal adhesion kinase (FAK), in endothelial cells has implicated its requirement in angiogenesis and tumour growth, but how pericyte FAK regulates tumour angiogenesis is unknown
FAK expression was not affected in endothelial cells or fibroblasts from pdgfrβcre+;fakfl/fl mice but was deleted in pericytes isolated from pdgfrβcre+;fakfl/fl mice, at both protein and RNA levels, with no change in Pdgfrβ RNA levels (Supplementary Fig. 1e, f)
The binding affinity of Axl to Gas[6] has been reported to be significantly higher than for Tyro[323], and p-Tyro[3] levels were increased in FAKKO pericytes (Supplementary Fig. 7b) we focused on pericyte Axl as the major Gas[6] receptor in the enhanced Gas6-stimulated angiogenic responses controlled by pericyte FAK
Summary
The overexpression of the protein tyrosine kinase, Focal adhesion kinase (FAK), in endothelial cells has implicated its requirement in angiogenesis and tumour growth, but how pericyte FAK regulates tumour angiogenesis is unknown. We identify pericyte FAK as a negative regulator of tumour angiogenesis and tumour growth, through its control of Gas6-stimulated Axl activation. We have identified the relationship between pericyte FAK expression on blood vessels and tumour angiogenesis and growth in human melanoma samples. Together, these data highlight an important role for cross-talk between pericytes, ECs and tumour cells, rather than with ECs alone, in the regulation of tumour angiogenesis and growth and place pericyte FAK as an important regulator in this process
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