Abstract
The expression of fibroblast growth factor receptor (FGFR)-1 correlates with angiogenesis and is associated with prostate cancer (CaP) progression. To more precisely define the molecular mechanisms whereby FGFR1 causes angiogenesis in the prostate we exploited a transgenic mouse model, JOCK-1, in which activation of a conditional FGFR1 allele in the prostate epithelium caused rapid angiogenesis and progressive hyperplasia. By labeling the vasculature in vivo and applying a novel method to measure the vasculature in three dimensions, we were able to observe a significant increase in vascular volume 1 week after FGFR1 activation. Although vessel volume and branching both continued to increase throughout a 6-week period of FGFR1 activation, importantly, we discovered that continued activation of FGFR1 was not required to maintain the new vasculature. Exploring the molecular mediators of the angiogenic phenotype, we observed consistent upregulation of HIF-1α, vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2), whereas expression of Ang-1 was lost. Further analysis revealed that loss of Ang-1 expression occurred in the basal epithelium, whereas the increase in Ang-2 expression occurred in the luminal epithelium. Reporter assays confirmed that the Ang-2 promoter was regulated by FGFR1 signaling and a small molecule inhibitor of FGFR activity, PD173074, could abrogate this response. These findings establish a method to follow spontaneous angiogenesis in a conditional autochthonous system, implicate the angiopoietins as downstream effectors of FGFR1 activation in vivo, and suggest that therapies targeting FGFR1 could be used to inhibit neovascularization during initiation and progression of CaP.
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Acknowledgements
We thank Matthew Dougherty for advice regarding the volumetric quantitation software, ARIAD Pharmaceuticals (http://www.ariad.com/wt/page/regulation_kits) for providing AP20187, Drs Wayne Klohs and Michael Gieseg at Pfizer for providing PD173074, Deborah Kwok and Caroline Castile for animal husbandry support, Deborah Ng and Kristine Frenk for administrative support and the members of the Greenberg and Spencer laboratories for helpful advice and discussions.
Grant support: National Institutes of Health grant CA64851 (NM Greenberg).
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Winter, S., Acevedo, V., Gangula, R. et al. Conditional activation of FGFR1 in the prostate epithelium induces angiogenesis with concomitant differential regulation of Ang-1 and Ang-2. Oncogene 26, 4897–4907 (2007). https://doi.org/10.1038/sj.onc.1210288
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DOI: https://doi.org/10.1038/sj.onc.1210288
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