Regulation of Angiogenesis by Androgen-Responsive Gene EAF2

  • Laura E. Pascal
  • Zhou Wang


Androgens regulate vascular regeneration through the induction of ­angiogenic factors such as VEGF in both normal prostate epithelial cells as well as hormone-responsive cancer cells. Androgen deprivation induces the apoptotic death of androgen-sensitive luminal epithelial or prostate cancer cells. Androgen deprivation also has an impact on the other cell types in the prostate tissue microenvironment including vascular endothelial cells. In animal models, castration results in not only a rapid involution of the prostate but also a reduction in prostatic endothelial cell proliferation, blood flow, and the induction of a hypoxic environment. Hypoxia is a well-known inducer of angiogenesis and neovascularization. Under hypoxic conditions, VHL protein levels decrease and the transcription factor HIF1α is stabilized and transactivates angiogenic factor VEGF. Previous studies have suggested that the tumor suppressor p53 is also induced by hypoxia. Increased p53 expression usually induces cell cycle arrest or apoptosis. However, p53 can also play a role in limiting angiogenesis through the upregulation of anti-angiogenic TSP-1, inhibition of HIF1α, and the transcriptional repression of VEGF. ELL-associated factor 2 (EAF2) was identified as an androgen-responsive tumor suppressor gene that is decreased in prostate cancer and has been shown to regulate p53 target gene TSP-1, to bind and stabilize VHL and to upregulate HIF1α. Interaction of EAF2 and its binding partners p53 and VHL in the regulation of pro-angiogenic HIF1α and anti-angiogenic TSP-1 in the prostate may be critical for maintaining normal tissue homeostasis. Dysregulation of these interacting pathways could lead to increased vascularization and prostate tumorigenesis.


ELL-associated factor 2 Von-Hippel Lindau p53 Thrombospondin 1 Vascular endothelial growth factor Hypoxia inducible factor 1 alpha Prostate cancer Angiogenesis Neovascularization 


  1. 1.
    Weidner N et al (1993) Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 143(2):401–409PubMedGoogle Scholar
  2. 2.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186PubMedCrossRefGoogle Scholar
  3. 3.
    Shojaei F (2012) Anti-angiogenesis therapy in cancer: challenges and future perspectives. Cancer Lett 320:130–137PubMedCrossRefGoogle Scholar
  4. 4.
    Bigler SA, Deering RE, Brawer MK (1993) Comparison of microscopic vascularity in benign and malignant prostate tissue. Hum Pathol 24(2):220–226PubMedCrossRefGoogle Scholar
  5. 5.
    Brawer MK et al (1994) Predictors of pathologic stage in prostatic carcinoma. The role of neovascularity. Cancer 73(3):678–687PubMedCrossRefGoogle Scholar
  6. 6.
    Zetter BR (1998) Angiogenesis and tumor metastasis. Annu Rev Med 49:407–424PubMedCrossRefGoogle Scholar
  7. 7.
    Harper ME et al (1996) Vascular endothelial growth factor (VEGF) expression in prostatic tumours and its relationship to neuroendocrine cells. Br J Cancer 74(6):910–916PubMedCrossRefGoogle Scholar
  8. 8.
    Jackson MW, Bentel JM, Tilley WD (1997) Vascular endothelial growth factor (VEGF) expression in prostate cancer and benign prostatic hyperplasia. J Urol 157(6):2323–2328PubMedCrossRefGoogle Scholar
  9. 9.
    Carnell DM et al (2006) An immunohistochemical assessment of hypoxia in prostate carcinoma using pimonidazole: implications for radioresistance. Int J Radiat Oncol Biol Phys 65(1):91–99PubMedCrossRefGoogle Scholar
  10. 10.
    Vergis R et al (2008) Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer and outcome of radical treatment: a retrospective analysis of two randomised radiotherapy trials and one surgical cohort study. Lancet Oncol 9(4):342–351PubMedCrossRefGoogle Scholar
  11. 11.
    Senger DR et al (1996) Stimulation of endothelial cell migration by vascular permeability factor/vascular endothelial growth factor through cooperative mechanisms involving the alphavbeta3 integrin, osteopontin, and thrombin. Am J Pathol 149(1):293–305PubMedGoogle Scholar
  12. 12.
    Bikfalvi A et al (1991) Interaction of vasculotropin/vascular endothelial cell growth factor with human umbilical vein endothelial cells: binding, internalization, degradation, and biological effects. J Cell Physiol 149(1):50–59PubMedCrossRefGoogle Scholar
  13. 13.
    Senger DR et al (1993) Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer Metastasis Rev 12(3–4):303–324PubMedCrossRefGoogle Scholar
  14. 14.
    Balbay MD et al (1999) Highly metastatic human prostate cancer growing within the prostate of athymic mice overexpresses vascular endothelial growth factor. Clin Cancer Res 5(4):783–789PubMedGoogle Scholar
  15. 15.
    Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2(10):727–739PubMedCrossRefGoogle Scholar
  16. 16.
    Tandle A, Libutti SK (2003) Antiangiogenic therapy: targeting vascular endothelial growth factor and its receptors. Clin Adv Hematol Oncol 1(1):41–48PubMedGoogle Scholar
  17. 17.
    Paez-Ribes M et al (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15(3):220–231PubMedCrossRefGoogle Scholar
  18. 18.
    Ebos JM et al (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15(3):232–239PubMedCrossRefGoogle Scholar
  19. 19.
    Fernando NT et al (2008) Tumor escape from endogenous, extracellular matrix-associated angiogenesis inhibitors by up-regulation of multiple proangiogenic factors. Clin Cancer Res 14(5):1529–1539PubMedCrossRefGoogle Scholar
  20. 20.
    Folkman J (2006) Antiangiogenesis in cancer therapy–endostatin and its mechanisms of action. Exp Cell Res 312(5):594–607PubMedCrossRefGoogle Scholar
  21. 21.
    Hida K et al (2004) Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res 64(22):8249–8255PubMedCrossRefGoogle Scholar
  22. 22.
    Relf M et al (1997) Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res 57(5):963–969PubMedGoogle Scholar
  23. 23.
    Lawler J, Detmar M (2004) Tumor progression: the effects of thrombospondin-1 and −2. Int J Biochem Cell Biol 36(6):1038–1045PubMedCrossRefGoogle Scholar
  24. 24.
    Zabrenetzky V et al (1994) Expression of the extracellular matrix molecule thrombospondin inversely correlates with malignant progression in melanoma, lung and breast carcinoma cell lines. Int J Cancer 59(2):191–195PubMedCrossRefGoogle Scholar
  25. 25.
    Colombel M et al (2005) Androgens repress the expression of the angiogenesis inhibitor thrombospondin-1 in normal and neoplastic prostate. Cancer Res 65(1):300–308PubMedGoogle Scholar
  26. 26.
    Kwak C et al (2002) Thrombospondin-1, vascular endothelial growth factor expression and their relationship with p53 status in prostate cancer and benign prostatic hyperplasia. BJU Int 89(3):303–309PubMedCrossRefGoogle Scholar
  27. 27.
    Mehta R et al (2001) Independent association of angiogenesis index with outcome in prostate cancer. Clin Cancer Res 7(1):81–88PubMedGoogle Scholar
  28. 28.
    Weinstat-Saslow DL et al (1994) Transfection of thrombospondin 1 complementary DNA into a human breast carcinoma cell line reduces primary tumor growth, metastatic potential, and angiogenesis. Cancer Res 54(24):6504–6511PubMedGoogle Scholar
  29. 29.
    Volpert OV, Lawler J, Bouck NP (1998) A human fibrosarcoma inhibits systemic angiogenesis and the growth of experimental metastases via thrombospondin-1. Proc Natl Acad Sci USA 95(11):6343–6348PubMedCrossRefGoogle Scholar
  30. 30.
    Kaygusuz G et al (2007) Microvessel density and regulators of angiogenesis in malignant and nonmalignant prostate tissue. Int Urol Nephrol 39(3):841–850PubMedCrossRefGoogle Scholar
  31. 31.
    Firlej V et al (2011) Thrombospondin-1 triggers cell migration and development of advanced prostate tumors. Cancer Res 71(24):7649–7658PubMedCrossRefGoogle Scholar
  32. 32.
    Sieveking DP et al (2010) A sex-specific role for androgens in angiogenesis. J Exp Med 207(2):345–352PubMedCrossRefGoogle Scholar
  33. 33.
    Franck-Lissbrant I et al (1998) Testosterone stimulates angiogenesis and vascular regrowth in the ventral prostate in castrated adult rats. Endocrinology 139(2):451–456PubMedCrossRefGoogle Scholar
  34. 34.
    Stewart RJ et al (2001) Vascular endothelial growth factor expression and tumor angiogenesis are regulated by androgens in hormone responsive human prostate carcinoma: evidence for androgen dependent destabilization of vascular endothelial growth factor transcripts. J Urol 165(2):688–693PubMedCrossRefGoogle Scholar
  35. 35.
    Gustavsson H, Welen K, Damber JE (2005) Transition of an androgen-dependent human prostate cancer cell line into an androgen-independent subline is associated with increased angiogenesis. Prostate 62(4):364–373PubMedCrossRefGoogle Scholar
  36. 36.
    English HF, Drago JR, Santen RJ (1985) Cellular response to androgen depletion and repletion in the rat ventral prostate: autoradiography and morphometric analysis. Prostate 7(1):41–51PubMedCrossRefGoogle Scholar
  37. 37.
    Lekas E et al (1997) Decrement of blood flow precedes the involution of the ventral prostate in the rat after castration. Urol Res 25(5):309–314PubMedCrossRefGoogle Scholar
  38. 38.
    Shabsigh A et al (1998) Rapid reduction in blood flow to the rat ventral prostate gland after castration: preliminary evidence that androgens influence prostate size by regulating blood flow to the prostate gland and prostatic endothelial cell survival. Prostate 36(3):201–206PubMedCrossRefGoogle Scholar
  39. 39.
    Shabisgh A et al (1999) Early effects of castration on the vascular system of the rat ventral prostate gland. Endocrinology 140(4):1920–1926PubMedCrossRefGoogle Scholar
  40. 40.
    Shabsigh A et al (2001) Biomarker analysis demonstrates a hypoxic environment in the castrated rat ventral prostate gland. J Cell Biochem 81(3):437–444PubMedCrossRefGoogle Scholar
  41. 41.
    Godoy A et al (2011) Androgen deprivation induces rapid involution and recovery of human prostate vasculature. Am J Physiol Endocrinol Metab 300(2):E263–E275PubMedCrossRefGoogle Scholar
  42. 42.
    Folkman J, Hahnfeldt P, Hlatky L (2000) Cancer: looking outside the genome. Nat Rev Mol Cell Biol 1(1):76–79PubMedCrossRefGoogle Scholar
  43. 43.
    Holash J et al (2002) VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA 99(17):11393–11398PubMedCrossRefGoogle Scholar
  44. 44.
    Olsson A et al (2010) Tasquinimod (ABR-215050), a quinoline-3-carboxamide anti-angiogenic agent, modulates the expression of thrombospondin-1 in human prostate tumors. Mol Cancer 9:107PubMedCrossRefGoogle Scholar
  45. 45.
    George D, Moul JW (2012) Emerging treatment options for patients with castration-resistant prostate cancer. Prostate 73:338–349CrossRefGoogle Scholar
  46. 46.
    Simone F et al (2003) ELL-associated factor 2 (EAF2), a functional homolog of EAF1 with alternative ELL binding properties. Blood 101(6):2355–2362PubMedCrossRefGoogle Scholar
  47. 47.
    Xiao W, Jiang F, Wang Z (2006) ELL binding regulates U19/Eaf2 intracellular localization, stability, and transactivation. Prostate 66(1):1–12PubMedCrossRefGoogle Scholar
  48. 48.
    Zhuang F et al (2008) Dynamic intracellular distribution of Eaf2 and its potential involvement in UV-Induced DNA damage response. DNA Cell Biol 27(12):649–656PubMedCrossRefGoogle Scholar
  49. 49.
    Hahn J et al (2007) Apoptosis induction and growth suppression by U19/Eaf2 is mediated through its ELL-binding domain. Prostate 67(2):146–153PubMedCrossRefGoogle Scholar
  50. 50.
    Li M et al (2003) Expression of murine ELL-associated factor 2 (Eaf2) is developmentally regulated. Dev Dyn 228(2):273–280PubMedCrossRefGoogle Scholar
  51. 51.
    Xiao W et al (2003) Suppression of prostate tumor growth by U19, a novel testosterone-regulated apoptosis inducer. Cancer Res 63(15):4698–4704PubMedGoogle Scholar
  52. 52.
    Wang Z et al (1997) Genes regulated by androgen in the rat ventral prostate. Proc Natl Acad Sci USA 94(24):12999–13004PubMedCrossRefGoogle Scholar
  53. 53.
    Xiao W et al (2008) U19/Eaf2 knockout causes lung adenocarcinoma, B-cell lymphoma, hepatocellular carcinoma and prostatic intraepithelial neoplasia. Oncogene 27(11):1536–1544PubMedCrossRefGoogle Scholar
  54. 54.
    O’Malley KJ et al (2009) The expression of androgen-responsive genes is up-regulated in the epithelia of benign prostatic hyperplasia. Prostate 69(16):1716–1723PubMedCrossRefGoogle Scholar
  55. 55.
    Pascal LE et al (2009) Gene expression relationship between prostate cancer cells of Gleason 3, 4 and normal epithelial cells as revealed by cell type-specific transcriptomes. BMC Cancer 9:452PubMedCrossRefGoogle Scholar
  56. 56.
    Pascal LE et al (2011) EAF2 loss enhances angiogenic effects of Von Hippel-Lindau heterozygosity on the murine liver and prostate. Angiogenesis 14(3):331–343PubMedCrossRefGoogle Scholar
  57. 57.
    Cai L et al (2011) Regulation of fertility, survival, and cuticle collagen function by the Caenorhabditis elegans eaf-1 and ell-1 genes. J Biol Chem 286(41):35915–35921PubMedCrossRefGoogle Scholar
  58. 58.
    Xiao W et al (2009) U19/Eaf2 binds to and stabilizes von hippel-lindau protein. Cancer Res 69(6):2599–2606PubMedCrossRefGoogle Scholar
  59. 59.
    Su F et al (2010) Tumor suppressor U19/EAF2 regulates thrombospondin-1 expression via p53. Oncogene 29:421–431PubMedCrossRefGoogle Scholar
  60. 60.
    Zhong H et al (1999) Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59(22):5830–5835PubMedGoogle Scholar
  61. 61.
    Talks KL et al (2000) The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 157(2):411–421PubMedCrossRefGoogle Scholar
  62. 62.
    Salnikow K et al (2000) Hyperinducibility of hypoxia-responsive genes without p53/p21-dependent checkpoint in aggressive prostate cancer. Cancer Res 60(20):5630–5634PubMedGoogle Scholar
  63. 63.
    Roe JS et al (2006) p53 stabilization and transactivation by a von Hippel-Lindau protein. Mol Cell 22(3):395–405PubMedCrossRefGoogle Scholar
  64. 64.
    Zhong H et al (2004) Up-regulation of hypoxia-inducible factor 1alpha is an early event in prostate carcinogenesis. Cancer Detect Prev 28(2):88–93PubMedCrossRefGoogle Scholar
  65. 65.
    Ravi R et al (2000) Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 14(1):34–44PubMedGoogle Scholar
  66. 66.
    Dameron KM et al (1994) Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265(5178):1582–1584PubMedCrossRefGoogle Scholar
  67. 67.
    Nelius T et al (2007) Androgen receptor targets NFkappaB and TSP1 to suppress prostate tumor growth in vivo. Int J Cancer 121(5):999–1008PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  1. 1.Department of UrologyUniversity of PittsburghPittsburghUSA
  2. 2.Prostate and Urologic Cancer ProgramUniversity of Pittsburgh Cancer Institute, University of PittsburghPittsburghUSA
  3. 3.Department of Pharmacology & Chemical BiologyUniversity of PittsburghPittsburghUSA
  4. 4.Shadyside Medical CenterPittsburghUSA

Personalised recommendations