Activation of Hedgehog Signaling in Human Cancer

  • Jingwu XieEmail author
  • Ervin Epstein


Hedgehog gene was first described in Drosophila in 1980 by Nobel laureates Drs. E. Wieschaus and C. Nusslein-Volhard. Over the past three decades, the hedgehog pathway has been shown to be a major regulator for cell differentiation, tissue polarity, cell proliferation, stem cell maintenance, and carcinogenesis. The first link of Hh signaling to human cancer was established in 1996 through studies of a rare familiar disease, Gorlin syndrome. Follow-up studies from many laboratories reveal activation of this pathway in a range of human cancer types, including basal cell carcinomas (BCCs), medulloblastomas, leukemia, gastrointestinal, lung, ovarian, breast, and prostate cancers. Targeted inhibition of Hh signaling is now believed to be effective in treatment and prevention of human cancer. Even more exciting is the discovery and synthesis of a variety of specific inhibitors for this pathway. In this review, we summarize major advances in our understanding of Hh signaling activation in human cancer, useful mouse models for studying Hh-mediated carcinogenesis, the roles of Hh signaling in tumor initiation, promotion, tumor metastasis, and cancer stem cell maintenance as well as antagonists for Hh signaling and their clinical implications.


Hedgehog Smoothened PTCH1 Cancer Basal cell carcinomas Signal transduction Clinical trials and animal model 



Current research in my laboratory is supported by grants from the National Cancer Institute CA94160 and Wells Center for Pediatric Research.


  1. 1.
    Nusslein-Volhard C, Wieschaus E (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287:795–801PubMedGoogle Scholar
  2. 2.
    Krauss S, Concordet JP, Ingham PW (1993) A functionally conserved homolog of the Drosophila segment polarity gene hh is expressed in tissues with polarizing activity in zebrafish embryos. Cell 75:1431–1444PubMedGoogle Scholar
  3. 3.
    Echelard Y et al (1993) Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75:1417–1430PubMedGoogle Scholar
  4. 4.
    Riddle RD, Johnson RL, Laufer E, Tabin C (1993) Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75:1401–1416PubMedGoogle Scholar
  5. 5.
    Chang DT et al (1994) Products, genetic linkage and limb patterning activity of a murine hedgehog gene. Development 120:3339–3353PubMedGoogle Scholar
  6. 6.
    Roelink H et al (1994) Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord. Cell 76:761–775PubMedGoogle Scholar
  7. 7.
    Epstein EH (2008) Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer 8:743–754PubMedGoogle Scholar
  8. 8.
    Xie J (2005) Hedgehog signaling in prostate cancer. Future Oncol 1:331–338PubMedGoogle Scholar
  9. 9.
    Xie J (2008) Hedgehog signaling pathway: development of antagonists for cancer therapy. Curr Oncol Rep 10:107–113PubMedGoogle Scholar
  10. 10.
    Xie J (2008) Molecular biology of basal and squamous cell carcinomas. Adv Exp Med Biol 624:241–251PubMedGoogle Scholar
  11. 11.
    Jiang J, Hui CC (2008) Hedgehog signaling in development and cancer. Dev Cell 15:801–812PubMedGoogle Scholar
  12. 12.
    Ingham PW, Placzek M (2006) Orchestrating ontogenesis: variations on a theme by sonic hedgehog. Nat Rev Genet 7:841–850PubMedGoogle Scholar
  13. 13.
    Sasaki H, Hui C, Nakafuku M, Kondoh H (1997) A binding site for Gli proteins is essential for HNF-3beta floor plate enhancer activity in transgenics and can respond to Shh in vitro. Development 124:1313–1322PubMedGoogle Scholar
  14. 14.
    Kinzler KW, Vogelstein B (1990) The GLI gene encodes a nuclear protein which binds specific sequences in the human genome. Mol Cell Biol 10:634–642PubMedGoogle Scholar
  15. 15.
    McMahon AP, Ingham PW, Tabin CJ (2003) Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol 53:1–114PubMedGoogle Scholar
  16. 16.
    Ingham PW, McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15:3059–3087, doi:10.1101/gad.938601PubMedGoogle Scholar
  17. 17.
    Taipale J, Beachy PA (2001) The Hedgehog and Wnt signalling pathways in cancer. Nature 411:349–354PubMedGoogle Scholar
  18. 18.
    Lee JJ et al (1994) Autoproteolysis in hedgehog protein biogenesis. Science 266:1528–1537PubMedGoogle Scholar
  19. 19.
    Porter JA, Young KE, Beachy PA (1996) Cholesterol modification of hedgehog signaling proteins in animal development. Science 274:255–259PubMedGoogle Scholar
  20. 20.
    Porter JA et al (1995) The product of hedgehog autoproteolytic cleavage active in local and long-range signalling. Nature 374:363–366PubMedGoogle Scholar
  21. 21.
    Buglino JA, Resh MD (2008) Hhat is a palmitoylacyltransferase with specificity for N-palmitoylation of Sonic Hedgehog. J Biol Chem 283:22076–22088PubMedGoogle Scholar
  22. 22.
    Kawakami T et al (2002) Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling. Development 129:5753–5765PubMedGoogle Scholar
  23. 23.
    Ma Y et al (2002) Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell 111:63–75, doi:S0092867402009777 [pii]PubMedGoogle Scholar
  24. 24.
    Caspary T et al (2002) Mouse dispatched homolog1 is required for long-range, but not juxtacrine, Hh signaling. Curr Biol 12:1628–1632, doi:S0960982202011478 [pii]PubMedGoogle Scholar
  25. 25.
    Dierker T, Dreier R, Petersen A, Bordych C, Grobe K (2009) Heparan sulfate-modulated, metalloprotease-mediated sonic hedgehog release from producing cells. J Biol Chem 284:8013–8022PubMedGoogle Scholar
  26. 26.
    Beckett K, Franch-Marro X, Vincent JP (2008) Glypican-mediated endocytosis of Hedgehog has opposite effects in flies and mice. Trends Cell Biol 18:360–363PubMedGoogle Scholar
  27. 27.
    Lum L et al (2003) Identification of Hedgehog pathway components by RNAi in Drosophila cultured cells. Science 299:2039–2045PubMedGoogle Scholar
  28. 28.
    Baena-Lopez LA, Rodriguez I, Baonza A (2008) The tumor suppressor genes dachsous and fat modulate different signalling pathways by regulating dally and dally-like. Proc Natl Acad Sci USA 105:9645–9650PubMedGoogle Scholar
  29. 29.
    Toyoda H, Kinoshita-Toyoda A, Fox B, Selleck SB (2000) Structural analysis of glycosaminoglycans in animals bearing mutations in sugarless, sulfateless, and tout-velu. Drosophila homologues of vertebrate genes encoding glycosaminoglycan biosynthetic enzymes. J Biol Chem 275:21856–21861PubMedGoogle Scholar
  30. 30.
    Bellaiche Y, The I, Perrimon N (1998) Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion. Nature 394:85–88PubMedGoogle Scholar
  31. 31.
    Koziel L, Kunath M, Kelly OG, Vortkamp A (2004) Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev Cell 6:801–813PubMedGoogle Scholar
  32. 32.
    Stone DM et al (1996) The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 384:129–134PubMedGoogle Scholar
  33. 33.
    Taipale J, Cooper MK, Maiti T, Beachy PA (2002) Patched acts catalytically to suppress the activity of Smoothened. Nature 418:892–897PubMedGoogle Scholar
  34. 34.
    Chuang PT, McMahon AP (1999) Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 397:617–621PubMedGoogle Scholar
  35. 35.
    Martinelli DC, Fan CM (2007) Gas1 extends the range of Hedgehog action by facilitating its signaling. Genes Dev 21:1231–1243PubMedGoogle Scholar
  36. 36.
    Seppala M et al (2007) Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog. J Clin Invest 117:1575–1584PubMedGoogle Scholar
  37. 37.
    Allen BL, Tenzen T, McMahon AP (2007) The Hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development. Genes Dev 21:1244–1257PubMedGoogle Scholar
  38. 38.
    Okada A et al (2006) Boc is a receptor for sonic hedgehog in the guidance of commissural axons. Nature 444:369–373PubMedGoogle Scholar
  39. 39.
    Tenzen T et al (2006) The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev Cell 10:647–656PubMedGoogle Scholar
  40. 40.
    Zhang W, Kang JS, Cole F, Yi MJ, Krauss RS (2006) Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Dev Cell 10:657–665PubMedGoogle Scholar
  41. 41.
    Yao S, Lum L, Beachy P (2006) The ihog cell-surface proteins bind Hedgehog and mediate pathway activation. Cell 125:343–357PubMedGoogle Scholar
  42. 42.
    Capurro MI et al (2008) Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding. Dev Cell 14:700–711PubMedGoogle Scholar
  43. 43.
    Yavari A et al (2010) Role of lipid metabolism in smoothened derepression in hedgehog signaling. Dev Cell 19:54–65PubMedGoogle Scholar
  44. 44.
    Khaliullina H et al (2009) Patched regulates Smoothened trafficking using lipoprotein-derived lipids. Development 136:4111–4121PubMedGoogle Scholar
  45. 45.
    Callejo A, Culi J, Guerrero I (2008) Patched, the receptor of Hedgehog, is a lipoprotein receptor. Proc Natl Acad Sci USA 105:912–917PubMedGoogle Scholar
  46. 46.
    Bijlsma MF et al (2006) Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion. PLoS Biol 4:e232PubMedGoogle Scholar
  47. 47.
    Philipp M et al (2008) Smoothened signaling in vertebrates is facilitated by a G protein-coupled receptor kinase. Mol Biol Cell 19:5478–5489PubMedGoogle Scholar
  48. 48.
    Ogden SK et al (2008) G protein Galphai functions immediately downstream of Smoothened in Hedgehog signalling. Nature 456:967–970PubMedGoogle Scholar
  49. 49.
    Molnar C, Holguin H, Mayor F Jr, Ruiz-Gomez A, de Celis JF (2007) The G protein-coupled receptor regulatory kinase GPRK2 participates in Hedgehog signaling in Drosophila. Proc Natl Acad Sci USA 104:7963–7968PubMedGoogle Scholar
  50. 50.
    Riobo NA, Saucy B, Dilizio C, Manning DR (2006) Activation of heterotrimeric G proteins by Smoothened. Proc Natl Acad Sci USA 103:12607–12612PubMedGoogle Scholar
  51. 51.
    Jia J, Tong C, Wang B, Luo L, Jiang J (2004) Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I. Nature 432:1045–1050PubMedGoogle Scholar
  52. 52.
    Zhang C, Williams EH, Guo Y, Lum L, Beachy PA (2004) Extensive phosphorylation of Smoothened in Hedgehog pathway activation. Proc Natl Acad Sci USA 101:17900–17907PubMedGoogle Scholar
  53. 53.
    Zhao Y, Tong C, Jiang J (2007) Hedgehog regulates smoothened activity by inducing a conformational switch. Nature 450:252–258PubMedGoogle Scholar
  54. 54.
    Corbit KC et al (2005) Vertebrate Smoothened functions at the primary cilium. Nature 437:1018–1021PubMedGoogle Scholar
  55. 55.
    Huangfu D et al (2003) Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426:83–87PubMedGoogle Scholar
  56. 56.
    May SR et al (2005) Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Dev Biol 287:378–389PubMedGoogle Scholar
  57. 57.
    Huangfu D, Anderson KV (2005) Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci USA 102:11325–11330PubMedGoogle Scholar
  58. 58.
    Zhang Q, Davenport JR, Croyle MJ, Haycraft CJ, Yoder BK (2005) Disruption of IFT results in both exocrine and endocrine abnormalities in the pancreas of Tg737(orpk) mutant mice. Lab Invest 85:45–64PubMedGoogle Scholar
  59. 59.
    Hoover AN et al (2008) C2cd3 is required for cilia formation and Hedgehog signaling in mouse. Development 135:4049–4058PubMedGoogle Scholar
  60. 60.
    Scholey JM, Anderson KV (2006) Intraflagellar transport and cilium-based signaling. Cell 125:439–442PubMedGoogle Scholar
  61. 61.
    Cortellino S et al (2009) Defective ciliogenesis, embryonic lethality and severe impairment of the Sonic Hedgehog pathway caused by inactivation of the mouse complex A intraflagellar transport gene Ift122/Wdr10, partially overlapping with the DNA repair gene Med1/Mbd4. Dev Biol 325:225–237PubMedGoogle Scholar
  62. 62.
    Haycraft CJ et al (2005) Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet 1:e53PubMedGoogle Scholar
  63. 63.
    Wang Y, Zhou Z, Walsh CT, McMahon AP (2009) Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation. Proc Natl Acad Sci USA 106:2623–2628PubMedGoogle Scholar
  64. 64.
    Wilson CW, Chen MH, Chuang PT (2009) Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary cilium. PLoS ONE 4:e5182PubMedGoogle Scholar
  65. 65.
    Rohatgi R, Milenkovic L, Corcoran RB, Scott MP (2009) Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation process. Proc Natl Acad Sci USA 106:3196–3201PubMedGoogle Scholar
  66. 66.
    Han YG et al (2009) Dual and opposing roles of primary cilia in medulloblastoma development. Nat Med 15:1062–1065PubMedGoogle Scholar
  67. 67.
    Wong SY et al (2009) Primary cilia can both mediate and suppress Hedgehog pathway-dependent tumorigenesis. Nat Med 15:1055–1061PubMedGoogle Scholar
  68. 68.
    Kovacs JJ et al (2008) Beta-arrestin-mediated localization of smoothened to the primary cilium. Science 320:1777–1781PubMedGoogle Scholar
  69. 69.
    Chen MH et al (2009) Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved. Genes Dev 23:1910–1928PubMedGoogle Scholar
  70. 70.
    Jia J et al (2009) Suppressor of fused inhibits mammalian Hedgehog signaling in the absence of cilia. Dev Biol 330:452–460PubMedGoogle Scholar
  71. 71.
    Cheung HO et al (2009) The kinesin protein Kif7 is a critical regulator of Gli transcription factors in mammalian hedgehog signaling. Sci Signal 2:ra29PubMedGoogle Scholar
  72. 72.
    Endoh-Yamagami S et al (2009) The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development. Curr Biol 19:1320–1326PubMedGoogle Scholar
  73. 73.
    Wilson CW et al (2009) Fused has evolved divergent roles in vertebrate Hedgehog signalling and motile ciliogenesis. Nature 459:98–102PubMedGoogle Scholar
  74. 74.
    Merchant M et al (2005) Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus. Mol Cell Biol 25:7054–7068PubMedGoogle Scholar
  75. 75.
    Chen MH, Gao N, Kawakami T, Chuang PT (2005) Mice deficient in the fused homolog do not exhibit phenotypes indicative of perturbed hedgehog signaling during embryonic development. Mol Cell Biol 25:7042–7053PubMedGoogle Scholar
  76. 76.
    Eggenschwiler JT, Espinoza E, Anderson KV (2001) Rab23 is an essential negative regulator of the mouse Sonic hedgehog signalling pathway. Nature 412:194–198PubMedGoogle Scholar
  77. 77.
    Reiter JF, Skarnes WC (2006) Tectonic, a novel regulator of the Hedgehog pathway required for both activation and inhibition. Genes Dev 20:22–27PubMedGoogle Scholar
  78. 78.
    Varjosalo M et al (2008) Application of active and kinase-deficient kinome collection for identification of kinases regulating hedgehog signaling. Cell 133:537–548PubMedGoogle Scholar
  79. 79.
    Evangelista M et al (2008) Kinome siRNA screen identifies regulators of ciliogenesis and hedgehog signal transduction. Sci Signal 1:ra7PubMedGoogle Scholar
  80. 80.
    Svard J et al (2006) Genetic elimination of suppressor of fused reveals an essential repressor function in the Mammalian hedgehog signaling pathway. Dev Cell 10:187–197PubMedGoogle Scholar
  81. 81.
    Aszterbaum M et al (1999) Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice. Nat Med 5:1285–1291PubMedGoogle Scholar
  82. 82.
    Hahn H et al (1998) Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome. Nat Med 4:619–622PubMedGoogle Scholar
  83. 83.
    Goodrich LV, Milenkovic L, Higgins KM, Scott MP (1997) Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277:1109–1113PubMedGoogle Scholar
  84. 84.
    Barnfield PC, Zhang X, Thanabalasingham V, Yoshida M, Hui CC (2005) Negative regulation of Gli1 and Gli2 activator function by Suppressor of fused through multiple mechanisms. Differentiation 73:397–405PubMedGoogle Scholar
  85. 85.
    Kise Y, Morinaka A, Teglund S, Miki H (2009) Sufu recruits GSK3beta for efficient ­processing of Gli3. Biochem Biophys Res Commun 387:569–574PubMedGoogle Scholar
  86. 86.
    Yue S, Chen Y, Cheng SY (2009) Hedgehog signaling promotes the degradation of tumor suppressor Sufu through the ubiquitin-proteasome pathway. Oncogene 28:492–499PubMedGoogle Scholar
  87. 87.
    Kinzler KW, Ruppert JM, Bigner SH, Vogelstein B (1988) The GLI gene is a member of the Kruppel family of zinc finger proteins. Nature 332:371–374PubMedGoogle Scholar
  88. 88.
    Ruppert JM et al (1988) The GLI-Kruppel family of human genes. Mol Cell Biol 8:3104–3113PubMedGoogle Scholar
  89. 89.
    Sheng T, Chi S, Zhang X, Xie J (2006) Regulation of Gli1 localization by the cAMP/protein kinase A signaling axis through a site near the nuclear localization signal. J Biol Chem 281:9–12PubMedGoogle Scholar
  90. 90.
    Kogerman P et al (1999) Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1. Nat Cell Biol 1:312–319PubMedGoogle Scholar
  91. 91.
    Stecca B et al (2007) Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci USA 104:5895–5900PubMedGoogle Scholar
  92. 92.
    Pan Y, Bai CB, Joyner AL, Wang B (2006) Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol Cell Biol 26:3365–3377PubMedGoogle Scholar
  93. 93.
    Huntzicker EG et al (2006) Dual degradation signals control Gli protein stability and tumor formation. Genes Dev 20:276–281PubMedGoogle Scholar
  94. 94.
    Wang B, Li Y (2006) Evidence for the direct involvement of βTrCP in Gli3 protein processing. Proc Natl Acad Sci USA 103:33–38PubMedGoogle Scholar
  95. 95.
    Di Marcotullio L et al (2006) Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch-dependent ubiquitination. Nat Cell Biol 8:1415–1423PubMedGoogle Scholar
  96. 96.
    Jiang J (2006) Regulation of Hh/Gli signaling by dual ubiquitin pathways. Cell Cycle 5:2457–2463PubMedGoogle Scholar
  97. 97.
    Canettieri G et al (2010) Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation. Nat Cell Biol 12:132–142PubMedGoogle Scholar
  98. 98.
    Huangfu D, Anderson KV (2006) Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development 133:3–14PubMedGoogle Scholar
  99. 99.
    Cheng SY, Bishop JM (2002) Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex. Proc Natl Acad Sci USA 99:5442–5447PubMedGoogle Scholar
  100. 100.
    Hahn H et al (1996) Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85:841–851PubMedGoogle Scholar
  101. 101.
    Johnson RL et al (1996) Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272:1668–1671PubMedGoogle Scholar
  102. 102.
    Epstein E Jr (2001) Genetic determinants of basal cell carcinoma risk. Med Pediatr Oncol 36:555–558PubMedGoogle Scholar
  103. 103.
    Aszterbaum M, Beech J, Epstein EH Jr (1999) Ultraviolet radiation mutagenesis of hedgehog pathway genes in basal cell carcinomas. J Investig Dermatol Symp Proc 4:41–45PubMedGoogle Scholar
  104. 104.
    Xie J et al (1998) Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391:90–92PubMedGoogle Scholar
  105. 105.
    Lam CW et al (1999) A frequent activated smoothened mutation in sporadic basal cell carcinomas. Oncogene 18:833–836PubMedGoogle Scholar
  106. 106.
    Reifenberger J et al (2005) Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol 152:43–51PubMedGoogle Scholar
  107. 107.
    Reifenberger J et al (1998) Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res 58:1798–1803PubMedGoogle Scholar
  108. 108.
    Couve-Privat S, Bouadjar B, Avril MF, Sarasin A, Daya-Grosjean L (2002) Significantly high levels of ultraviolet-specific mutations in the smoothened gene in basal cell carcinomas from DNA repair-deficient xeroderma pigmentosum patients. Cancer Res 62:7186–7189PubMedGoogle Scholar
  109. 109.
    Xie J et al (2001) A role of PDGFRalpha in basal cell carcinoma proliferation. Proc Natl Acad Sci USA 98:9255–9259PubMedGoogle Scholar
  110. 110.
    Athar M et al (2004) Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis. Cancer Res 64:7545–7552PubMedGoogle Scholar
  111. 111.
    Berman DM et al (2003) Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425:846–851PubMedGoogle Scholar
  112. 112.
    Watkins DN et al (2003) Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 422:313–317PubMedGoogle Scholar
  113. 113.
    Wang DH et al (2010) Aberrant epithelial-mesenchymal Hedgehog signaling characterizes Barrett’s metaplasia. Gastroenterology 138:1810–1822PubMedGoogle Scholar
  114. 114.
    Bailey JM, Mohr AM, Hollingsworth MA (2009) Sonic hedgehog paracrine signaling regulates metastasis and lymphangiogenesis in pancreatic cancer. Oncogene 28:3513–3525PubMedGoogle Scholar
  115. 115.
    Feldmann G et al (2008) An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer. Mol Cancer Ther 7:2725–2735PubMedGoogle Scholar
  116. 116.
    Thayer SP et al (2003) Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425:851–856PubMedGoogle Scholar
  117. 117.
    Pasca di Magliano M et al (2006) Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev 20:3161–3173PubMedGoogle Scholar
  118. 118.
    Nolan-Stevaux O et al (2009) GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev 23:24–36PubMedGoogle Scholar
  119. 119.
    Fan L et al (2004) Hedgehog signaling promotes prostate xenograft tumor growth. Endocrinology 145:3961–3970PubMedGoogle Scholar
  120. 120.
    Karhadkar SS et al (2004) Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431:707–712PubMedGoogle Scholar
  121. 121.
    Sanchez P et al (2004) Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proc Natl Acad Sci USA 101:12561–12566PubMedGoogle Scholar
  122. 122.
    Sheng T et al (2004) Activation of the hedgehog pathway in advanced prostate cancer. Mol Cancer 3:29PubMedGoogle Scholar
  123. 123.
    He J et al (2006) Suppressing Wnt signaling by the hedgehog pathway through sFRP-1. J Biol Chem 281:35598–35602PubMedGoogle Scholar
  124. 124.
    Ehtesham M et al (2007) Ligand-dependent activation of the hedgehog pathway in glioma progenitor cells. Oncogene 26(39):5752–5761PubMedGoogle Scholar
  125. 125.
    Bhattacharya R et al (2008) Role of hedgehog signaling in ovarian cancer. Clin Cancer Res 14:7659–7666PubMedGoogle Scholar
  126. 126.
    Fiaschi M, Rozell B, Bergstrom A, Toftgard R (2009) Development of mammary tumors by conditional expression of GLI1. Cancer Res 69:4810–4817PubMedGoogle Scholar
  127. 127.
    Kasper M, Jaks V, Fiaschi M, Toftgard R (2009) Hedgehog signalling in breast cancer. Carcinogenesis 30:903–911PubMedGoogle Scholar
  128. 128.
    Liao X et al (2009) Aberrant activation of hedgehog signaling pathway in ovarian cancers: effect on prognosis, cell invasion and differentiation. Carcinogenesis 30:131–140PubMedGoogle Scholar
  129. 129.
    Lindemann RK (2008) Stroma-initiated hedgehog signaling takes center stage in B-cell lymphoma. Cancer Res 68:961–964PubMedGoogle Scholar
  130. 130.
    Dierks C et al (2008) Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 14:238–249PubMedGoogle Scholar
  131. 131.
    Zhao C et al (2009) Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458:776–779PubMedGoogle Scholar
  132. 132.
    Read TA et al (2009) Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma. Cancer Cell 15:135–147PubMedGoogle Scholar
  133. 133.
    Hofmann I et al (2009) Hedgehog signaling is dispensable for adult murine hematopoietic stem cell function and hematopoiesis. Cell Stem Cell 4:559–567PubMedGoogle Scholar
  134. 134.
    Gao J et al (2009) Hedgehog signaling is dispensable for adult hematopoietic stem cell ­function. Cell Stem Cell 4:548–558PubMedGoogle Scholar
  135. 135.
    Siggins SL et al (2009) The Hedgehog receptor Patched1 regulates myeloid and lymphoid progenitors by distinct cell-extrinsic mechanisms. Blood 114:995–1004PubMedGoogle Scholar
  136. 136.
    Merchant A, Joseph G, Wang Q, Brennan S, Matsui W (2010) Gli1 regulates the proliferation and differentiation of HSCs and myeloid progenitors. Blood 115:2391–2396PubMedGoogle Scholar
  137. 137.
    Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111PubMedGoogle Scholar
  138. 138.
    Sims-Mourtada J et al (2006) Hedgehog: an attribute to tumor regrowth after chemoradiotherapy and a target to improve radiation response. Clin Cancer Res 12:6565–6572PubMedGoogle Scholar
  139. 139.
    Olive KP et al (2009) Inhibition of hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324:1457–1461PubMedGoogle Scholar
  140. 140.
    Yoshikawa R et al (2008) Hedgehog signal activation in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy. Br J Cancer 98:1670–1674PubMedGoogle Scholar
  141. 141.
    Huang S et al (2006) Activation of the hedgehog pathway in human hepatocellular carcinomas. Carcinogenesis 27:1334–1340PubMedGoogle Scholar
  142. 142.
    Lee Y, Kawagoe R, Sasai K, Li Y, Russell HR, Curran T, McKinnon PJ (2007) Loss of suppressor-of-fused function promotes tumorigenesis. Oncogene. 2007 Sep 27;26(44):6442–7. Epub 2007 Apr 23.Google Scholar
  143. 143.
    Kubo M et al (2004) Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer. Cancer Res 64:6071–6074PubMedGoogle Scholar
  144. 144.
    Mancuso M et al (2004) Basal cell carcinoma and its development: insights from radiation-induced tumors in Ptch1-deficient mice. Cancer Res 64:934–941PubMedGoogle Scholar
  145. 145.
    Ellis T et al (2003) Patched 1 conditional null allele in mice. Genesis 36:158–161PubMedGoogle Scholar
  146. 146.
    Adolphe C, Hetherington R, Ellis T, Wainwright B (2006) Patched1 functions as a gatekeeper by promoting cell cycle progression. Cancer Res 66:2081–2088PubMedGoogle Scholar
  147. 147.
    Grachtchouk V et al (2003) The magnitude of hedgehog signaling activity defines skin tumor phenotype. EMBO J 22:2741–2751, doi:10.1093/emboj/cdg271PubMedGoogle Scholar
  148. 148.
    Mao J et al (2006) A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. Cancer Res 66:10171–10178PubMedGoogle Scholar
  149. 149.
    Grachtchouk M et al (2000) Basal cell carcinomas in mice overexpressing Gli2 in skin. Nat Genet 24:216–217, doi:10.1038/73417PubMedGoogle Scholar
  150. 150.
    Nilsson M et al (2000) Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proc Natl Acad Sci USA 97:3438–3443PubMedGoogle Scholar
  151. 151.
    Oro AE et al (1997) Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 276:817–821PubMedGoogle Scholar
  152. 152.
    Romer JT et al (2004) Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/−)p53(−/−) mice. Cancer Cell 6:229–240PubMedGoogle Scholar
  153. 153.
    Nieuwenhuis E et al (2006) Mice with a targeted mutation of patched2 are viable but develop alopecia and epidermal hyperplasia. Mol Cell Biol 26:6609–6622PubMedGoogle Scholar
  154. 154.
    Lee Y et al (2006) Patched2 modulates tumorigenesis in patched1 heterozygous mice. Cancer Res 66:6964–6971PubMedGoogle Scholar
  155. 155.
    Lee Y et al (2007) Loss of suppressor-of-fused function promotes tumorigenesis. Oncogene 26:6442–6447PubMedGoogle Scholar
  156. 156.
    Svard J, Rozell B, Toftgard R, Teglund S (2009) Tumor suppressor gene co-operativity in compound Patched1 and suppressor of fused heterozygous mutant mice. Mol Carcinog 48:408–419PubMedGoogle Scholar
  157. 157.
    Hallahan AR et al (2004) The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Res 64:7794–7800PubMedGoogle Scholar
  158. 158.
    Schuller U et al (2008) Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell 14:123–134PubMedGoogle Scholar
  159. 159.
    Yang ZJ et al (2008) Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell 14:135–145PubMedGoogle Scholar
  160. 160.
    Ward RJ et al (2009) Multipotent CD15+ cancer stem cells in patched-1-deficient mouse medulloblastoma. Cancer Res 69:4682–4690PubMedGoogle Scholar
  161. 161.
    Feldmann G et al (2007) Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res 67:2187–2196PubMedGoogle Scholar
  162. 162.
    Tian H et al (2009) Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci USA 106:4254–4259PubMedGoogle Scholar
  163. 163.
    Teglund S, Toftgard R (2010) Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim Biophys Acta 1805:181–208PubMedGoogle Scholar
  164. 164.
    Yang L, Xie G, Fan Q, Xie J (2010) Activation of the hedgehog-signaling pathway in human cancer and the clinical implications. Oncogene 29:469–481PubMedGoogle Scholar
  165. 165.
    Chen JK, Taipale J, Cooper MK, Beachy PA (2002) Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 16:2743–2748PubMedGoogle Scholar
  166. 166.
    Yauch RL et al (2008) A paracrine requirement for hedgehog signalling in cancer. Nature 455:406–410PubMedGoogle Scholar
  167. 167.
    Sanchez P, Ruiz i Altaba A (2005) In vivo inhibition of endogenous brain tumors through systemic interference of Hedgehog signaling in mice. Mech Dev 122:223–230PubMedGoogle Scholar
  168. 168.
    Berman DM et al (2002) Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297:1559–1561PubMedGoogle Scholar
  169. 169.
    Tremblay MR et al (2009) Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926). J Med Chem 52:4400–4418PubMedGoogle Scholar
  170. 170.
    Xie J, Garrossian M (2009) Cyclopamine tartrate salt and uses thereof. US Patent WO 2009099625 20090813.Google Scholar
  171. 171.
    Von Hoff DD et al (2009) Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 361:1164–1172Google Scholar
  172. 172.
    Hyman JM et al (2009) Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade. Proc Natl Acad Sci USA 106:14132–14137PubMedGoogle Scholar
  173. 173.
    Rudin CM et al (2009) Treatment of medulloblastoma with Hedgehog pathway inhibitor GDC-0449. N Engl J Med 361(12):1173–1178PubMedGoogle Scholar
  174. 174.
    So PL, Fujimoto MA, Epstein EH Jr (2008) Pharmacologic retinoid signaling and physiologic retinoic acid receptor signaling inhibit basal cell carcinoma tumorigenesis. Mol Cancer Ther 7:1275–1284PubMedGoogle Scholar
  175. 175.
    Kim J et al (2010) Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell 17:388–399PubMedGoogle Scholar
  176. 176.
    Slusarz A et al (2010) Common botanical compounds inhibit the hedgehog signaling pathway in prostate cancer. Cancer Res 70:3382–3390PubMedGoogle Scholar
  177. 177.
    Liu H, Gu D, Xie J (2011) Clinical implications of hedgehog signaling pathway inhibitors. Chin J Cancer 30(1):13–26.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Wells Center for Pediatric ResearchIndiana University School of MedicineIndianapolisUSA

Personalised recommendations