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Role of Sonic Hedgehog (Shh) Signaling in Bladder Cancer Stemness and Tumorigenesis

  • Regenerative Medicine (A Atala, Section Editor)
  • Published:
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Abstract

Sonic hedgehog (Shh) signaling pathway has emerged as a critical component of bladder development, cancer initiation, and progression. While the role of Shh signaling in bladder development is well documented, its role in bladder cancer progression is uncertain. Additionally, epithelial-to-mesenchymal transition (EMT) has been identified to promote bladder cancer progression in the initial stages and also contribute to drug resistance in the later stage and ultimately metastasis. We speculate that epithelial-to-mesenchymal transitions (EMT) and Shh fuel the carcinogenesis process. This review presents the most recent studies focusing on the role of Shh signaling in bladder cancer progression

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. American Cancer Society; 2015.

  2. Malkowicz S-B, Van Poppel H, Mickisch G, et al. Muscle invasive urothelial carcinoma of the bladder. Urology. 2007;69:3–16.

    Article  PubMed  Google Scholar 

  3. Wu X-R. Urothelial tumorigenesis: a tale of divergent pathways. Nat Rev Cancer. 2005;5:713–25.

    Article  CAS  PubMed  Google Scholar 

  4. Clark M-F, Dick J-E, Dirks P-B, et al. Cancer stem cells-perspective on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 2006;66:9339–44.

    Article  Google Scholar 

  5. Dancik G-M, Owens C-R, Iczkowski K-A, Theodorescu D. A cell of origin gene signature indicates human bladder cancer has distinct cellular progenitors. Stem Cells. 2014;32:974–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Al-Hajj M, Wicha M-S, Hernandez B, Morrison S-J, Clarke M-F. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100:3983–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Singh S-K, Hawkins C, Clarke I-D, Squire J-A, Bayani J, Hide T, et al. Identification of human brain tumor initiating cells. Nature. 2004;432:396–401.

    Article  CAS  PubMed  Google Scholar 

  8. Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 2008;15:504–14.

    Article  CAS  PubMed  Google Scholar 

  9. Collins A-T, Berry P-A, Hyde C, Stower M-J, Maitland N-J. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005;65:10946–51.

    Article  CAS  PubMed  Google Scholar 

  10. Hermann P-C, Huber S-L, Herrier T, Aicher A, Ellwart J-W, Guba M, et al. Distinct population of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1:313–23.

    Article  CAS  PubMed  Google Scholar 

  11. Mani S-A, Guo W, Liao M-J, Eaton E-N, Ayyanan A, Zhou A-Y, et al. The epithelial-to-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Volkmer J-P, Sahoo D, Chin R-K, Ho P-L, Tang C, Kurtova A, et al. Three differentiation states risk-stratify bladder cancer into distinct subtypes. Proc Natl Acad Sci U S A. 2012;109:2078–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Bentivegna A, Conconi D, Panzeri E, Sala E, Bovo G, Vigano P, et al. Biological heterogeneity of putative bladder cancer stem-like cell population from human bladder transitional cell carcinoma. Cancer Sci. 2010;101:416–24.

    Article  CAS  PubMed  Google Scholar 

  14. Tran M-N, Jinesh G-G, McConkey D-J, Kamat A-M. Bladder cancer stem cells. Curr Stem Cell Res Therapy. 2010;5:387–95.

    Article  CAS  Google Scholar 

  15. Chan K-S, Espinosa I, Chao M, Wong D, Ailes L, Diehn M, et al. Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc Natl Acad Sci U S A. 2009;106:14016–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Kasper S. Identification, characterization, and biological relevance of prostate cancer stem cells from clinical specimens. Urol Oncol. 2009;27:301–3.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Santisteban M, Reiman J-M, Asiedu M-K, Behrens M-D, Nassar A, Kalli K-R, et al. Immune-induced epithelial-to-mesenchymal transition in vivo generates breast cancer stem cells. Cancer Res. 2009;69:2887–95.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Hay E-D. An overview of epithelia-mesenchymal transformation. Acta Anat (Basel). 1995;154:8–20.

    Article  CAS  Google Scholar 

  19. Nollet F, Kools P, van Roy F. Phylogenetic analysis of the cadherin superfamily allows identification of six major subfamilies besides several solitary members. J Mol Biol. 2000;299:551–72.

    Article  CAS  PubMed  Google Scholar 

  20. Rangel M-C, Karasawa H, Castro N-P, Nagaoka T, Salomon D-S, Bianco C. Role of Cripto-1 during epithelial-to-mesenchymal transition in development and cancer. Am J Pathol. 2012;180:2188–200.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Radisky D-C. Epithelial-mesenchymal transition. J Cell Sci. 2005;118:4325–6.

    Article  CAS  PubMed  Google Scholar 

  22. Chaffer C-L, Breman J-P, Slavin J-L, Blick T, Thompson E-W, Williams E-D. Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Res. 2006;66:11271–8.

    Article  CAS  PubMed  Google Scholar 

  23. Islam S-S, Mokhtari R-B, Yaser E-H, Azadi M-A, Alauddin M, Yeger H, et al. TGF-β1 induces EMT reprograming of porcine bladder urothelial cells in collagen producing fibroblast-like cells in Smad2/Smad3-dependent manner. J Cell Commun Signal. 2013. doi:10.1007/s11523-015-0386-5. This manuscript described how the porcine bladder urothelial cells transformed to mesenchymal cells and contribute bladder fibrosis. They showed TGF-beta1 may contributes to bladder fibrosis through Smad2/Smad3 dependent manner.

    PubMed Central  PubMed  Google Scholar 

  24. Huang T-T, Wang H, Kingsley E-A, Risbridger G-P, Russel P-J. Molecular profiling of bladder cancer: involvement of TGF-β pathway in bladder cancer progression. Cancer Lett. 2008;265:27–38.

    Article  Google Scholar 

  25. Ingham P-W, McMahon A-P. Hedgehog signaling in animal development. Genes Dev. 2001;15:3059–87.

    Article  CAS  PubMed  Google Scholar 

  26. Gonnissen A, Isebaert HK. Hedgehog signaling in prostate cancer and its therapeutic implication. Int J Mol Sci. 2013;14:13979–4007.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Muller J-M, Chevrier L, Cochard S, Meunier A-C, Chadeneau C. Hedgehog, Notch and Wnt developmental pathways as target for anti-cancer drugs. Drug Discov Today Disease Mech. 2007;4:285–91.

    Article  Google Scholar 

  28. Maugeri-Sacca M, Zeuner A, De Maria R. Therapeutic-targeting of cancer stem cells. Front Oncol. 2011;1:10.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev. 2008;22:2454–72.

    Article  CAS  PubMed  Google Scholar 

  30. Corbit K-C, Aanstad P, Singla V, Norman A-R, Stainler D-Y, Reiter J-F. Vertebrate smoothened functions at the primary cilium. Nature. 2005;437:1018–21.

    Article  CAS  PubMed  Google Scholar 

  31. Han L, Shi S, Gong T, Zhang Z, Sun X. Cancer stem cells: therapeutic implication and prospectives in cancer therapy. Acta Pharmaceutica Sinica B. 2013;3:65–75.

    Article  Google Scholar 

  32. Jiang J, Hui C-C. Hedgehog signaling in development and cancer. Dev Cell. 2008;15:801–12.

    Article  CAS  PubMed  Google Scholar 

  33. Elisabeth H-V, Davis O-W, Philip M-I. The Sonic hedgehog-patched-Gli pathway in human development and disease. Am J Hum Genet. 2000;67:1047–54.

    Article  Google Scholar 

  34. Cheng W, Yeung C-K, Ng Y-K, Zhang J-R, Hui C-C, Kim P-C. Sonic hedgehog mediator Gli2 regulates bladder mesenchymal patterning. J Urol. 2008;180:1543–50.

    Article  CAS  PubMed  Google Scholar 

  35. Sgiroyanagi Y, Liu B, Cao M, Agras K, Li J, Hseieh M-H, et al. Urothelial sonic hedgehog signaling plays an important role in bladder amooth formation. Differentiation. 2007;75:968–77.

    Article  Google Scholar 

  36. DeSouza K-R, Saha M, Carpenter A-R, Scott M, McHugh K-M. Analysis of the sonic hedgehog signaling pathway in normal and abnormal bladder development. PLoS ONE. 2013. doi:10.1371/journal.pone.0053675.

    Google Scholar 

  37. Zhu G, Zhao H-E, Wu D, Zhang L, Li L, He D, et al. Sonic hedgehog signaling in normal human bladder development. J Urol. 2013;189:e222.

    Article  Google Scholar 

  38. Doles J, Cook C, Shi X, Valosky J, Lipinski R, Bushman W. Functional compensation in hedgehog signaling during mouse prostate development. Dev Biol. 2006;295:13–25.

    Article  CAS  PubMed  Google Scholar 

  39. Haraguchi R, Motoyama J, Sasaki H, Satoh Y, Miyagawa S, Nakagata N, et al. Molecular analysis of coordinated bladder and urinogenital organ formation by hedgehog signaling. Development. 2007;134:525–33.

    Article  CAS  PubMed  Google Scholar 

  40. Haraguchi R, Ro M, Hui C, Motoyama J, Makino S, Shiroishi T, et al. Unique functions of sonic hedgehog signaling during external genetalia development. Development. 2001;128:4241–50.

    CAS  PubMed  Google Scholar 

  41. Castelino R-C, Barwick B-G, Schniederjan M, Buss M-C, Becher O, Hambardzumyan D, et al. Heterozygosity of Pten promotes tumorigenesis in a mouse model medulloblastoma. PLoS ONE. 2010;5:p10849.

    Article  Google Scholar 

  42. Takebe N, Harris P-J, Warren R-Q, Ivy S-P. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog signaling pathways. Nat Rev Clin Oncol. 2011;8:97–106.

    Article  CAS  PubMed  Google Scholar 

  43. Dennler S, Andre J, Alexaki I, Li A, Magnaldo T, ten Dijke P, et al. Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res. 2007;67:6981–6.

    Article  CAS  PubMed  Google Scholar 

  44. Islam S-S, Mokhtari R-B, Kumar S, Maalouf J, Arab S, Yeger H, et al. Spatio-temporal distribution of Smads and role of Smads/TGF-beta/BMP-4 in the regulation of mouse bladder organogenesis. PLoS ONE. 2013. doi:10.1371/journal.pone.oo61340.

    Google Scholar 

  45. Mauviel A. Transforming growth factor-beta: a key mediator of fibrosis. Methods Mol Med. 2005;117:69–80.

    CAS  PubMed  Google Scholar 

  46. Al-Hajj M, Clarke M-F. Self-renewal and solid tumor stem cells. Proc Natl Acad Sci U S A. 2004;23:7274–82.

    CAS  Google Scholar 

  47. Islam S-S, Mokhtari R-B, Noman A-S, Uddin M, Rahman M-Z, Azadi M-A, et al. Sonic hedgehog (Shh) signaling promotes tumorigenicity and stemness voa activation of epithelial-to-mesenchymal transition (EMT) in bladder cancer. Mol Carcinogenesis. 2015. doi:10.1002/mc.22300. This manuscript elegantly showed how TGF-beta activate Shh and activated Shh contributes to bladder cancer migration, invasion and metastatic features as well as bladder cancer cells stemness.

    Google Scholar 

  48. She J-J, Zhang P-G, Wang Z-M, Gan W-M, Che X-M. Identification of of side population cells from bladder cancer cells by DyeCle Violet staining. Cancer Biol Ther. 2008;7:1663–8.

    Article  CAS  PubMed  Google Scholar 

  49. Ning Z-F, Huang Y-Z, Lin T-X, Zhou Y-X, Jiang C, Xu K-W, et al. Subpopulation of stem-like cells in side in side populztion cells from the human bladder transitional cell cancer cell line T24. J Int Med Res. 2009;37:621–30.

    Article  CAS  PubMed  Google Scholar 

  50. Ji P, Diederichs S, Wang W, Boing S, Metzgar R, Schneider P-M, et al. MALAT-1, a novel non-coding RNA and thymosin beta4 predict metastasis and survival in early stage non-small cell lung cancer. Oncogene. 2003;22:8031–41.

    Article  PubMed  Google Scholar 

  51. Ying L, Chen Q, Wang Y, Zhou Z, Huang Y, Qui F. Upregulation of MALAT-1 contributes to bladder cancer migration by inducing epithelial-to-mesenchymal transition. Mol Biosyst. 2012;8:2289–94.

    Article  CAS  PubMed  Google Scholar 

  52. Fan Y, Shen B, Tan M, Mu X, Qin Y, Zhang F, et al. TGF-β-induced upregulation of malat1 promotes bladder cancer metastasisby associating with suz12. Clin Cancer Res. 2014;20:1–11.

    Article  CAS  Google Scholar 

  53. Mao L et al. A critical role of sonic hedgehog signaling in maintaining the tumorigenicity of neuroblastoma cells. Cancer Sci. 2009;100:1848–55.

    Article  CAS  PubMed  Google Scholar 

  54. Liu S, Dontu G, Mantle I-D, Patel S, Ahn N-S, Jackson K-W, et al. Hedgehog signaling and Bmi1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 2006;66:6063–71.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Moraes R-C, Zhang X, Harrington N, Fung J-Y, Wu M-F, Hilsenbeck S-G, et al. Constitutive activation of smoothened (SMO) in mammary gland of transgenic mice leads to increased proliferation, altered differentiation and ductal dysplasia. Development. 2007;134:1231–42.

    Article  CAS  PubMed  Google Scholar 

  56. Shin K, Lim A, Zhao C, Sahoo D, Pan Y, Splekerkoetter E, et al. Hedhehog signaling restrain bladder cancer progression by eliciting stromal production of urothelial differentiation factors. Cancer Cell. 2014;13:521–33. This study described how Shh signaling initiate bladder cancer at the beginning and lost at the later stage of bladder cancer progression.

    Article  Google Scholar 

  57. Fei D-L, Sanchez-Mejias A, Wang Z, Flaveny C, Long J et al. hedgehog signaling regulates bladder cancer growth and tumorigenicity. Cancer Res 2012;72. doi: 10.1158/0008-5472.CAN-11-4123.

  58. Berman D-M, Karhadkar S-S, Hallahan A-R, et al. Medullublastoma growth inhibition by hedgehog pathway blockade. Science 200;297:1559-1561.

  59. Chen J-K, Taipale J, Cooper M-K, Beachy P-A. Inhibition of hedgehog signaling by direct binding of cyclopamine to smoothened. Genes Dev. 2002;16:2743–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Developmental and Stem Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada

    Islam S. Syed, Akbari Pedram & Walid A. Farhat

  2. Cancer Biology and Experimental Therapeutic Section, Division of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia

    Islam S. Syed

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Correspondence to Walid A. Farhat.

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Islam S Syed, Akbari Pedram, and Walid A Farhat each declare no potential conflicts of interest.

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Syed, I.S., Pedram, A. & Farhat, W.A. Role of Sonic Hedgehog (Shh) Signaling in Bladder Cancer Stemness and Tumorigenesis. Curr Urol Rep 17, 11 (2016). https://doi.org/10.1007/s11934-015-0568-9

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