Conditional activation of FGFR1 in the prostate epithelium induces angiogenesis with concomitant differential regulation of Ang-1 and Ang-2.

摘要: The expression of fibroblast growth factor receptor (FGFR)-1 correlates with angiogenesis and is associated prostate cancer (CaP) progression. To more precisely define the molecular mechanisms whereby FGFR1 causes in we exploited a transgenic mouse model, JOCK-1, which activation conditional allele epithelium caused rapid progressive hyperplasia. By labeling vasculature vivo applying novel method to measure three dimensions, were able observe significant increase vascular volume 1 week after activation. Although vessel branching both continued throughout 6-week period activation, importantly, discovered that was not required maintain new vasculature. Exploring mediators angiogenic phenotype, observed consistent upregulation HIF-1α, endothelial (VEGF) angiopoietin 2 (Ang-2), whereas Ang-1 lost. Further analysis revealed loss occurred basal epithelium, Ang-2 luminal epithelium. Reporter assays confirmed promoter regulated by signaling small molecule inhibitor FGFR activity, PD173074, could abrogate this response. These findings establish follow spontaneous autochthonous system, implicate angiopoietins as downstream effectors vivo, suggest therapies targeting be used inhibit neovascularization during initiation progression CaP.