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Hedgehog signaling in prostate growth and benign prostate hyperplasia

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Abstract

Hedgehog (Hh) signaling has long been recognized for its role in axial patterning, mesenchymal-epithelial inductive signaling, and growth regulation during fetal development. In many embryonic tissues, Hh functions as a proliferative stimulus. Sonic hedgehog and Indian hedgehog are both expressed by the urothelium of the fetal prostate anlage, where they regulate cell proliferation and differentiation and play a role in prostate ductal budding. Whereas Hh signaling in mouse prostate diminishes during adolescence and is maintained at a low level in the adult, robust Hh signaling is commonly found in the adult human prostate. The reason(s) for robust Hh signaling in the adult human prostate and the actions of Hh signaling on growth and differentiation in the adult are not well understood. However, increased Hh signaling has been associated with prostate cancer and has been shown to accelerate prostate cancer growth. These observations suggest that inappropriate reawakening of this developmental growth signal may play a pivotal role in prostate neoplasia. This review examines the role of Hh signaling during early prostate growth and in its corollary actions during prostate disease, including benign prostate hyperplasia and prostate cancer. The use of Hh inhibitors as a therapeutic modality for androgen-independent treatment of prostate disease is also discussed.

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Referencesand Recommended Reading

  1. Ingham PW, McMahon AP: Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001, 15:3059–3087.

    Article  PubMed  CAS  Google Scholar 

  2. Lin VK, Wang D, Lee IL, et al.: Myosin heavy chain gene expression in normal and hyperplastic human prostate tissue. Prostate 2000, 44:193.

    Article  PubMed  CAS  Google Scholar 

  3. Israeli RS, Powell CT, Corr JG, et al.: Expression of the prostate-specific membrane antigen. Cancer Res 54:1807.

  4. McNeal J: Pathology of benign prostatic hyperplasia: insight into etiology. Urol Clin North Am 1990, 17:477–486.

    PubMed  CAS  Google Scholar 

  5. Lamm MLG, Catbagan WS, Laciak RJ, et al.: Sonic hedgehog activates mesenchymal Gli1 expression during prostate ductal bud formation. Dev Biol 2002, 240:349–366.

    Article  CAS  Google Scholar 

  6. Wang B-E, Shou J, Ross S, et al.: Inhibition of epithelial ductal branching in the prostate by sonic hedgehog is indirectly mediated by stromal cells. J Biol Chem 2002, 278:18506–18613.

    Article  Google Scholar 

  7. Pu Y, Huang L, Prins GS: Sonic hedgehog-patched Gli signaling in the developing rat prostate gland: lobe-specific suppression by neonatal estrogens reduces ductal growth and branching. Dev Biol 2004, 273:257–275.

    Article  PubMed  CAS  Google Scholar 

  8. Barnett DH, Huang HY, Wu XR, et al.: The human prostate expresses sonic hedgehog during fetal development. J Urol 2002, 168:2206–2210.

    Article  PubMed  CAS  Google Scholar 

  9. Podlasek CA, Barnett DH, Clemens JQ, et al.: Prostate development requires sonic hedgehog expressed by the urogenital sinus epithelium. Dev Biol 209:28–39.

  10. Freestone SH, Marker P, Grace OC, et al.: Sonic hedgehog regulates prostatic growth and epithelial differentiation. Dev Biol 2003:264:352–362.

    Article  PubMed  CAS  Google Scholar 

  11. Berman DM, Desai N, Wang X, et al.: Roles for Hedgehog signaling in androgen production and prostate ductal morphogenesis. Dev Biol 2004, 267:387–398.

    Article  PubMed  CAS  Google Scholar 

  12. Doles J, Cook C, Shi X, et al.: Functional compensation in hedgehog signaling during mouse prostate development. Dev Biol 2006, 295:13–25.

    Article  PubMed  CAS  Google Scholar 

  13. Bai CB, Joyner AL: Gli1 can rescue the in vivo function of Gli2. Development 2001, 128:5161–5172.

    PubMed  CAS  Google Scholar 

  14. Barclay WW, Woodruff RD, Hall MC, Cramer SD: A system for studying epithelial-stromal interactions reveals distinct inductive abilities of stromal cells from benign prostatic hyperplasia and prostate cancer. Endocrinology 2005, 146:13–18.

    Article  PubMed  CAS  Google Scholar 

  15. Fan H, Khavari PA: Sonic hedgehog opposes epithelial cell cycle arrest. J Cell Biol 1999, 147:71–76.

    Article  PubMed  CAS  Google Scholar 

  16. Zhang JX, Shaw A, Lipinski R, Gipp J, Bushman W: Lack of demonstrable autocrine hedgehog signaling in human prostate cancer cell lines. J Urol 2006, In press.

  17. Sanchez P, Hernandez AM, Stecca B, et al.: Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proc Natl Acad Sci U S A 2004, 101:12561–12566.

    Article  PubMed  CAS  Google Scholar 

  18. Karhadkar SS, Bova GS, Abdallah N, et al.: Hedgehog signaling in prostate regeneration, neoplasia and metastasis. Nature 2004, 431:707–711.

    Article  PubMed  CAS  Google Scholar 

  19. Sheng T, Li C, Zhang X, et al.: Activation of the hedgehog pathway in advanced prostate cancer. Mol Cancer 2004, 3:29.

    Article  PubMed  CAS  Google Scholar 

  20. Easton DF, Schaid DJ, Whittemore AS, Isaacs WJ: Where are the prostate cancer genes? A summary of eight genome wide searches. Prostate 2003, 57:261–269.

    Article  PubMed  CAS  Google Scholar 

  21. Xu J, Gillanders EM, Isaacs SD, et al.: Genome-wide scan for prostate cancer susceptibility genes in the Johns Hopkins hereditary prostate cancer families. Prostate 2003, 57:320–305.

    Article  PubMed  CAS  Google Scholar 

  22. Kelleher FC, Fennelly D, Rafferty M: Common critical pathways in embryogenesis and cancer. Acta Oncol 2006, 45:375–388.

    Article  PubMed  CAS  Google Scholar 

  23. Fan L, Pepicelli CV, Dibble CC, et al.: Hedgehog signaling promotes prostate xenograft tumor growth. Endocrinology 2004, 145:3961–4970.

    Article  PubMed  CAS  Google Scholar 

  24. Shaw A, Bushman W: Hedgehog signaling in the prostate. J Urol, 2006, In press.

  25. Kyprianou N, Isaacs JT: Activation of programmed cell death in the rat ventral prostate after castration. Endocrinology 1988, 122:552–562.

    Article  PubMed  CAS  Google Scholar 

  26. Isaacs JT, Coffey DS: Etiology and disease process of benign prostate hyperplasia. Prostate Suppl 1989, 2:33–50.

    Article  PubMed  CAS  Google Scholar 

  27. Robinson EJ, Neal DE, Collins AT: Basal cells are progenitors of luminal cells in primary cultures of differentiating human prostatic epithelium. Prostate 1998, 37:149–160.

    Article  PubMed  CAS  Google Scholar 

  28. Hudson DL, O’Hare M, Watt FM, Masters JR: Proliferative heterogeneity in the human prostate: evidence for epithelial stem cells. Lab Invest 2000, 80:1243–1250.

    Article  PubMed  CAS  Google Scholar 

  29. Signoretti S, Loda M: Defining cell lineages in the prostate epithelium. Cell Cycle 2006, 5:138–141.

    PubMed  CAS  Google Scholar 

  30. Collins AT, Berry PA, Hyde C, et al.: Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 2005, 65:10946–10951.

    Article  PubMed  CAS  Google Scholar 

  31. Foster CS, Dodson A, Karavana V, et al.: Prostatic stem cells. J Pathol 2002, 197:551–565.

    Article  PubMed  CAS  Google Scholar 

  32. Tsujimura A, Koikawa Y, Salm S, et al.: Proximal location of mouse prostate epithelial stem cells: a model of prostatic homeostasis. J Cell Biol 2002, 157:1257–1265.

    Article  PubMed  CAS  Google Scholar 

  33. Salm SN, Burger PE, Coetzee S, et al.: TGF-{beta} maintains dormancy of prostatic stem cells in the proximal region of ducts. J Cell Biol 2005, 170:81–90.

    Google Scholar 

  34. Xin L, Lawson DA, Witte ON: The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc Natl Acad Sci U S A 2005, 10:6942–6947.

    Article  CAS  Google Scholar 

  35. Burger PE, Xiong X, Coetzee S, et al.: Sca-1 expression identifies stem cells in the proximal region of prostatic ducts with high capacity to reconstitute prostatic tissue. Proc Natl Acad Sci U S A 2005, 102:7180–7185.

    Article  PubMed  CAS  Google Scholar 

  36. Beachy PA, Karhadkar SS, Berman DM: Tissue repair and stem cell renewal in carcinogenesis. Nature 2004, 432:324–331.

    Article  PubMed  CAS  Google Scholar 

  37. Palma V, Ruiz I, Altaba A: Hedgehog-GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex. Development 2004, 131:337–345.

    Article  PubMed  CAS  Google Scholar 

  38. Machold R, Hayashi S, Rutlin M, et al.: Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 2003, 39:937–950.

    Article  PubMed  CAS  Google Scholar 

  39. Dahmane N, Ruiz I, Altaba A: Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 1999, 126:3089–3100.

    PubMed  Google Scholar 

  40. Ruiz I, Altaba A, Stecca B, Sanchez P: Hedgehog—Gli signaling in brain tumors: stem cells and paradevelopmental programs in cancer. Cancer Lett 2004, 204:145–157.

    Article  CAS  Google Scholar 

  41. Liu S, Dontu G, Mantle ID, et al.: Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 2006, 66:6063–6071.

    Article  PubMed  CAS  Google Scholar 

  42. Hutchin ME, Kariapper MS, Grachtchouk et al.: Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumorigenesis recapitulates the hair growth cycle. Genes Dev 2005, 19:214–223.

    Article  PubMed  CAS  Google Scholar 

  43. Gritli-Linde A, Bei M, Maas R, et al.: Shh signaling within the dental epithelium is necessary for cell proliferation, growth and polarization. Development 2002, 129:5323–5337.

    Article  PubMed  CAS  Google Scholar 

  44. Ramalho-Santos M, Melton DA, McMahon AP: Hedgehog signals regulate multiple aspects of gastrointestinal development. Development 2000, 127:2763–2772.

    PubMed  CAS  Google Scholar 

  45. Hebrok M, Kim SK, St Jacques B, et al.: Regulation of pancreas development by hedgehog signaling. Development 2000, 127:4905–4913.

    PubMed  CAS  Google Scholar 

  46. Kawahira H, Scheel DW, Smith SB, et al.: Hedgehog signaling regulates expansion of pancreatic epithelial cells. Dev Biol 2005, 280:111–121.

    Article  PubMed  CAS  Google Scholar 

  47. Watkins DN, Berman DM, Burkholder SG, et al.: Hedgehog signaling within airway epithelial progenitors and in small-cell lung cancer. Nature 2003, 422:313–317.

    Article  PubMed  CAS  Google Scholar 

  48. Thievessen I, Wolter M, Prior A, et al.: Hedgehog signaling in normal urothelial cells and in urothelial carcinoma cell lines. J Cell Physiol 2005, 203:372–377.

    Article  PubMed  CAS  Google Scholar 

  49. Chen JK, Talpale J, Cooper MK, Beachy PA: Inhibition of hedgehog signaling by direct binding of cyclopamine to smoothened. Genes Dev 2002, 16:2743–2746.

    Article  PubMed  CAS  Google Scholar 

  50. Williams JA, Guicherit OM, Zaharian, et al.: Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions. Proc Natl Acad Sci U S A 2003, 100:4616–4621.

    Article  PubMed  CAS  Google Scholar 

  51. Romer JT, Kimura H, Magdaleno S, et al.: Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/−)p53(−/−) mice. Cancer Cell 2004, 6:229–240.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, University of Wisconsin-Madison, Box 3236, Clinical Science Center-G5, 600 Highland Avenue, Madison, WI, 53792, USA

    Wade Bushman

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  1. Chad M. Vezina
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  2. Wade Bushman
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Correspondence to Wade Bushman.

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Vezina, C.M., Bushman, W. Hedgehog signaling in prostate growth and benign prostate hyperplasia. Curr Urol Rep 8, 275–280 (2007). https://doi.org/10.1007/s11934-007-0073-x

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