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

Oncogene volume 26, pages 4897–4907 (2007)Cite this article

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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References

  • American Cancer Society (2006). Cancer Facts and Figures 2006. American Cancer Society: Atlanta, GA.

  • Bergers G, Benjamin LE . (2003). Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3: 401–410.

    Article  CAS  PubMed  Google Scholar 

  • Bicknell R, Harris AL . (2004). Novel angiogenic signaling pathways and vascular targets. Annu Rev Pharmacol Toxicol 44: 219–238.

    Article  CAS  PubMed  Google Scholar 

  • Bikfalvi A, Klein S, Pintucci G, Rifkin DB . (1997). Biological roles of fibroblast growth factor-2. Endocr Rev 18: 26–45.

    CAS  PubMed  Google Scholar 

  • Dery MA, Michaud MD, Richard DE . (2005). Hypoxia-inducible factor 1: regulation by hypoxic and non-hypoxic activators. Int J Biochem Cell Biol 37: 535–540.

    Article  CAS  PubMed  Google Scholar 

  • Doll JA, Reiher FK, Crawford SE, Pins MR, Campbell SC, Bouck NP . (2001). Thrombospondin-1, vascular endothelial growth factor and fibroblast growth factor-2 are key functional regulators of angiogenesis in the prostate. Prostate 49: 293–305.

    Article  CAS  PubMed  Google Scholar 

  • Dorkin TJ, Robinson MC, Marsh C, Neal DE, Leung HY . (1999). aFGF immunoreactivity in prostate cancer and its co-localization with bFGF and FGF8. J Pathol 189: 564–569.

    Article  CAS  PubMed  Google Scholar 

  • Foley KP, Leonard MW, Engel JD . (1993). Quantitation of RNA using the polymerase chain reaction. Trends Genet 9: 380–385.

    Article  CAS  PubMed  Google Scholar 

  • Folkman J . (1971). Tumor angiogenesis: therapeutic implications. N Engl J Med 285: 1182–1186.

    Article  CAS  PubMed  Google Scholar 

  • Folkman J, Hanahan D . (1991). Switch to the angiogenic phenotype during tumorigenesis. Princess Takamatsu Symp 22: 339–347.

    CAS  PubMed  Google Scholar 

  • Folkman J, Shing Y . (1992). Angiogenesis. J Biol Chem 267: 10931–10934.

    CAS  PubMed  Google Scholar 

  • Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD et al. (1996). Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16: 4604–4613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Foster BA, Kaplan PJ, Greenberg NM . (1999). Characterization of the FGF axis and identification of a novel FGFR1iiic isoform during prostate cancer progression in the TRAMP model. Prostate Cancer Prostatic Dis 2: 76–82.

    Article  CAS  PubMed  Google Scholar 

  • Freeman KW, Welm BE, Gangula RD, Rosen JM, Ittmann M, Greenberg NM et al. (2003). Inducible prostate intraepithelial neoplasia with reversible hyperplasia in conditional FGFR1-expressing mice. Cancer Res 63: 8256–8263.

    CAS  PubMed  Google Scholar 

  • Giri D, Ropiquet F, Ittmann M . (1999). Alterations in expression of basic fibroblast growth factor (FGF) 2 and its receptor FGFR-1 in human prostate cancer. Clin Cancer Res 5: 1063–1071.

    CAS  PubMed  Google Scholar 

  • Gnanapragasam VJ, Robinson MC, Marsh C, Robson CN, Hamdy FC, Leung HY . (2003). FGF8 isoform b expression in human prostate cancer. Br J Cancer 88: 1432–1438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greenberg NM, DeMayo F, Finegold MJ, Medina D, Tilley WD, Aspinall JO et al. (1995). Prostate cancer in a transgenic mouse. Proc Natl Acad Sci USA 92: 3439–3443.

    Article  CAS  PubMed  Google Scholar 

  • Greenberg NM, DeMayo FJ, Sheppard PC, Barrios R, Lebovitz R, Finegold M et al. (1994). The rat probasin gene promoter directs hormonally and developmentally regulated expression of a heterologous gene specifically to the prostate in transgenic mice. Mol Endocrinol 8: 230–239.

    CAS  PubMed  Google Scholar 

  • Hayward SW, Baskin LS, Haughney PC, Cunha AR, Foster BA, Dahiya R et al. (1996). Epithelial development in the rat ventral prostate, anterior prostate and seminal vesicle. Acta Anat (Basel) 155: 81–93.

    Article  CAS  Google Scholar 

  • Hobbs S, Jitrapakdee S, Wallace JC . (1998). Development of a bicistronic vector driven by the human polypeptide chain elongation factor 1alpha promoter for creation of stable mammalian cell lines that express very high levels of recombinant proteins. Biochem Biophys Res Commun 252: 368–372.

    Article  CAS  PubMed  Google Scholar 

  • Huss WJ, Barrios RJ, Foster BA, Greenberg NM . (2003). Differential expression of specific FGF ligand and receptor isoforms during angiogenesis associated with prostate cancer progression. Prostate 54: 8–16.

    Article  PubMed  Google Scholar 

  • Javerzat S, Auguste P, Bikfalvi A . (2002). The role of fibroblast growth factors in vascular development. Trends Mol Med 8: 483–489.

    Article  CAS  PubMed  Google Scholar 

  • Jin C, Wang F, Wu X, Yu C, Luo Y, McKeehan WL . (2004). Directionally specific paracrine communication mediated by epithelial FGF9 to stromal FGFR3 in two-compartment premalignant prostate tumors. Cancer Res 64: 4555–4562.

    Article  CAS  PubMed  Google Scholar 

  • Kim I, Kim JH, Ryu YS, Jung SH, Nah JJ, Koh GY . (2000). Characterization and expression of a novel alternatively spliced human angiopoietin-2. J Biol Chem 275: 18550–18556.

    Article  CAS  PubMed  Google Scholar 

  • Kwabi-Addo B, Ozen M, Ittmann M . (2004). The role of fibroblast growth factors and their receptors in prostate cancer. Endocr Relat Cancer 11: 709–724.

    Article  CAS  PubMed  Google Scholar 

  • Lind AJ, Wikstrom P, Granfors T, Egevad L, Stattin P, Bergh A . (2005). Angiopoietin 2 expression is related to histological grade, vascular density, metastases, and outcome in prostate cancer. Prostate 62: 394–399.

    Article  PubMed  Google Scholar 

  • Livak KJ, Schmittgen TD . (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25: 402–408.

    Article  CAS  Google Scholar 

  • Mohammadi M, Froum S, Hamby JM, Schroeder MC, Panek RL, Lu GH et al. (1998). Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J 17: 5896–5904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakamura T, Mochizuki Y, Kanetake H, Kanda S . (2001). Signals via FGF receptor 2 regulate migration of endothelial cells. Biochem Biophys Res Commun 289: 801–806.

    Article  CAS  PubMed  Google Scholar 

  • Tait CR, Jones PF . (2004). Angiopoietins in tumours: the angiogenic switch. J Pathol 204: 1–10.

    Article  CAS  PubMed  Google Scholar 

  • Thomson AA . (2001). Role of androgens and fibroblast growth factors in prostatic development. Reproduction 121: 187–195.

    Article  CAS  PubMed  Google Scholar 

  • Wang F, McKeehan K, Yu C, Ittmann M, McKeehan WL . (2004). Chronic activity of ectopic type 1 fibroblast growth factor receptor tyrosine kinase in prostate epithelium results in hyperplasia accompanied by intraepithelial neoplasia. Prostate 58: 1–12.

    Article  CAS  PubMed  Google Scholar 

  • Wang GL, Semenza GL . (1995). Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 270: 1230–1237.

    Article  CAS  PubMed  Google Scholar 

  • Wang S, Garcia AJ, Wu M, Lawson DA, Witte ON, Wu H . (2006). Pten deletion leads to the expansion of a prostatic stem/progenitor cell subpopulation and tumor initiation. Proc Natl Acad Sci USA 103: 1480–1485.

    Article  CAS  PubMed  Google Scholar 

  • Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J . (1993). Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 143: 401–409.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Weidner N, Semple JP, Welch WR, Folkman J . (1991). Tumor angiogenesis and metastasis – correlation in invasive breast carcinoma. N Engl J Med 324: 1–8.

    Article  CAS  PubMed  Google Scholar 

  • Welm BE, Freeman KW, Chen M, Contreras A, Spencer DM, Rosen JM . (2002). Inducible dimerization of FGFR1: development of a mouse model to analyze progressive transformation of the mammary gland. J Cell Biol 157: 703–714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Winter SF, Cooper AB, Greenberg NM . (2003). Models of metastatic prostate cancer: a transgenic perspective. Prostate Cancer Prostatic Dis 6: 204–211.

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Thomas TZ, Kasper S, Matusik RJ . (2000). A small composite probasin promoter confers high levels of prostate-specific gene expression through regulation by androgens and glucocorticoids in vitro and in vivo. Endocrinology 141: 4698–4710.

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Yang N, Park JW, Katsaros D, Fracchioli S, Cao G et al. (2003). Tumor-derived vascular endothelial growth factor up-regulates angiopoietin-2 in host endothelium and destabilizes host vasculature, supporting angiogenesis in ovarian cancer. Cancer Res 63: 3403–3412.

    CAS  PubMed  Google Scholar 

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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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Author notes

  1. K W Freeman

    Present address: 3Current address: Department of Genetics, Harvard Medical School, Harvard University, Boston, MA, USA.,

Authors and Affiliations

  1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    S F Winter & N M Greenberg

  2. Department of Immunology, Baylor College of Medicine, Houston, TX, USA

    V D Acevedo, R D Gangula, K W Freeman & D M Spencer

Authors
  1. S F Winter
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  2. V D Acevedo
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Correspondence to N M Greenberg.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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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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