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Hedgehog Signaling in Pediatric Brain Tumors

  • Joon Won Yoon
  • Jason Fangusaro
  • Philip Iannaccone
  • David Walterhouse
Chapter

Abstract

Dysregulation of the Sonic hedgehog (SHH) signal transduction ­pathway is observed in a variety of developmental disorders of the central nervous system and in some brain tumors. During development, SHH signaling contributes to establishing a dorso-ventral axis within the neural tube, proliferation of cells in the region of the developing brain and ultimately brain growth, establishing inter-brain boundaries, and establishing regional specificity within the brain. SHH signaling contributes to the development of the cerebellum through paracrine signaling from Purkinje cells to cerebellar granule precursors (CGP) and promotes CGP proliferation. It is believed that mutations in components of the pathway cause constitutive pathway activation in CGPs, which contributes to the development of some medulloblastomas. Medulloblastoma is the most common malignant pediatric brain tumor. Current therapy includes a combination of surgery, chemotherapy, and radiotherapy. Inhibition of the Hedgehog signaling pathway or genes and pathways that modulate Hedgehog signaling represent a novel strategy to possibly improve outcomes with less toxicity for some patients with medulloblastoma and potentially other pediatric brain tumors. Hedgehog pathway inhibitors are being developed and early phase clinical trials are underway. Optimal efficacy with these agents may require combinations with agents targeting other pathways and genes that play roles in CGP development and in modulating Hedgehog signaling in medulloblastoma.

Keywords

Sonic hedgehog Central nervous system Cerebellum Pediatric brain tumors Medulloblastoma Hedgehog inhibitors 

References

  1. 1.
    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
  2. 2.
    Teillet MA, Lapointe F, Le Douarin NM (1998) The relationships between notochord and floor plate in vertebrate development revisited. Proc Natl Acad Sci USA 95:11733–11738PubMedGoogle Scholar
  3. 3.
    Jacob J, Briscoe J (2003) Gli proteins and the control of spinal-cord patterning. EMBO Rep 4:761–765PubMedGoogle Scholar
  4. 4.
    Marti E, Takada R, Bumcrot DA, Sasaki H, McMahon AP (1995) Distribution of Sonic hedgehog peptides in the developing chick and mouse embryo. Development 121:2537–2547PubMedGoogle Scholar
  5. 5.
    Chiang C et al (1996) Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383:407–413PubMedGoogle Scholar
  6. 6.
    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
  7. 7.
    Hebert JM, Fishell G (2008) The genetics of early telencephalon patterning: some assembly required. Nat Rev Neurosci 9:678–685PubMedGoogle Scholar
  8. 8.
    Ericson J et al (1995) Sonic hedgehog induces the differentiation of ventral forebrain neurons: a common signal for ventral patterning within the neural tube. Cell 81:747–756PubMedGoogle Scholar
  9. 9.
    Patten I, Placzek M (2000) The role of Sonic hedgehog in neural tube patterning. Cell Mol Life Sci 57:1695–1708PubMedGoogle Scholar
  10. 10.
    Aoto K, Nishimura T, Eto K, Motoyama J (2002) Mouse GLI3 regulates Fgf8 expression and apoptosis in the developing neural tube, face, and limb bud. Dev Biol 251:320–332PubMedGoogle Scholar
  11. 11.
    Ericson J, Morton S, Kawakami A, Roelink H, Jessell TM (1996) Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity. Cell 87:661–673PubMedGoogle Scholar
  12. 12.
    Litingtung Y, Chiang C (2000) Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3. Nat Neurosci 3:979–985PubMedGoogle Scholar
  13. 13.
    Pringle NP et al (1996) Determination of neuroepithelial cell fate: induction of the oligodendrocyte lineage by ventral midline cells and sonic hedgehog. Dev Biol 177:30–42PubMedGoogle Scholar
  14. 14.
    van Straaten HW, Thors F, Wiertz-Hoessels L, Hekking J, Drukker J (1985) Effect of a notochordal implant on the early morphogenesis of the neural tube and neuroblasts: histometrical and histological results. Dev Biol 110:247–254PubMedGoogle Scholar
  15. 15.
    van Straaten HW, Hekking JW, Beursgens JP, Terwindt-Rouwenhorst E, Drukker J (1989) Effect of the notochord on proliferation and differentiation in the neural tube of the chick embryo. Development 107:793–803PubMedGoogle Scholar
  16. 16.
    Charrier JB, Lapointe F, Le Douarin NM, Teillet MA (2001) Anti-apoptotic role of Sonic hedgehog protein at the early stages of nervous system organogenesis. Development 128:4011–4020PubMedGoogle Scholar
  17. 17.
    Britto J, Tannahill D, Keynes R (2002) A critical role for sonic hedgehog signaling in the early expansion of the developing brain. Nat Neurosci 5:103–110PubMedGoogle Scholar
  18. 18.
    Agarwala S, Sanders TA, Ragsdale CW (2001) Sonic hedgehog control of size and shape in midbrain pattern formation. Science 291:2147–2150PubMedGoogle Scholar
  19. 19.
    Fogel JL, Chiang C, Huang X, Agarwala S (2008) Ventral specification and perturbed boundary formation in the mouse midbrain in the absence of Hedgehog signaling. Dev Dyn 237:1359–1372PubMedGoogle Scholar
  20. 20.
    Koster R, Stick R, Loosli F, Wittbrodt J (1997) Medaka spalt acts as a target gene of hedgehog signaling. Development 124:3147–3156PubMedGoogle Scholar
  21. 21.
    Strahle U, Blader P, Henrique D, Ingham PW (1993) Axial, a zebrafish gene expressed along the developing body axis, shows altered expression in cyclops mutant embryos. Genes Dev 7:1436–1446PubMedGoogle Scholar
  22. 22.
    Bayly RD, Ngo M, Aglyamova GV, Agarwala S (2007) Regulation of ventral midbrain patterning by Hedgehog signaling. Development 134:2115–2124PubMedGoogle Scholar
  23. 23.
    Rallu M et al (2002) Dorsoventral patterning is established in the telencephalon of mutants lacking both Gli3 and Hedgehog signaling. Development 129:4963–4974PubMedGoogle Scholar
  24. 24.
    Kohtz JD, Baker DP, Corte G, Fishell G (1998) Regionalization within the mammalian telencephalon is mediated by changes in responsiveness to Sonic Hedgehog. Development 125:5079–5089PubMedGoogle Scholar
  25. 25.
    Tole S, Ragsdale CW, Grove EA (2000) Dorsoventral patterning of the telencephalon is disrupted in the mouse mutant extra-toes(J). Dev Biol 217:254–265PubMedGoogle Scholar
  26. 26.
    Ishibashi M, McMahon AP (2002) A sonic hedgehog-dependent signaling relay regulates growth of diencephalic and mesencephalic primordia in the early mouse embryo. Development 129:4807–4819PubMedGoogle Scholar
  27. 27.
    Hynes M et al (1995) Induction of midbrain dopaminergic neurons by Sonic hedgehog. Neuron 15:35–44PubMedGoogle Scholar
  28. 28.
    Joksimovic M et al (2009) Spatiotemporally separable Shh domains in the midbrain define distinct dopaminergic progenitor pools. Proc Natl Acad Sci USA 106:19185–19190PubMedGoogle Scholar
  29. 29.
    Blaess S, Corrales JD, Joyner AL (2006) Sonic hedgehog regulates Gli activator and repressor functions with spatial and temporal precision in the mid/hindbrain region. Development 133:1799–1809PubMedGoogle Scholar
  30. 30.
    Blaess S, Stephen D, Joyner AL (2008) Gli3 coordinates three-dimensional patterning and growth of the tectum and cerebellum by integrating Shh and Fgf8 signaling. Development 135:2093–2103PubMedGoogle Scholar
  31. 31.
    Hynes M et al (1997) Control of cell pattern in the neural tube by the zinc finger transcription factor and oncogene Gli-1. Neuron 19:15–26PubMedGoogle Scholar
  32. 32.
    Lebel M, Mo R, Shimamura K, Hui CC (2007) Gli2 and Gli3 play distinct roles in the dorsoventral patterning of the mouse hindbrain. Dev Biol 302:345–355PubMedGoogle Scholar
  33. 33.
    Arkell R, Beddington RS (1997) BMP-7 influences pattern and growth of the developing hindbrain of mouse embryos. Development 124:1–12PubMedGoogle Scholar
  34. 34.
    Stecca B, Ruiz i Altaba A (2005) Brain as a paradigm of organ growth: hedgehog–Gli signaling in neural stem cells and brain tumors. J Neurobiol 64:476–490PubMedGoogle Scholar
  35. 35.
    Sotelo C (2004) Cellular and genetic regulation of the development of the cerebellar system. Prog Neurobiol 72:295–339PubMedGoogle Scholar
  36. 36.
    Vaillant C, Monard D (2009) SHH pathway and cerebellar development. Cerebellum 8:291–301PubMedGoogle Scholar
  37. 37.
    Traiffort E, Angot E, Ruat M (2010) Sonic Hedgehog signaling in the mammalian brain. J Neurochem 113:576–590PubMedGoogle Scholar
  38. 38.
    Lewis PM, Gritli-Linde A, Smeyne R, Kottmann A, McMahon AP (2004) Sonic hedgehog signaling is required for expansion of granule neuron precursors and patterning of the mouse cerebellum. Dev Biol 270:393–410PubMedGoogle Scholar
  39. 39.
    Wechsler-Reya RJ, Scott MP (1999) Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 22:103–114PubMedGoogle Scholar
  40. 40.
    Dahmane N, Ruiz i Altaba A (1999) Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 126:3089–3100PubMedGoogle Scholar
  41. 41.
    Wallace VA (1999) Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol 9:445–448PubMedGoogle Scholar
  42. 42.
    Kenney AM, Rowitch DH (2000) Sonic hedgehog promotes G(1) cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol Cell Biol 20:9055–9067PubMedGoogle Scholar
  43. 43.
    Kenney AM, Cole MD, Rowitch DH (2003) Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development 130:15–28PubMedGoogle Scholar
  44. 44.
    Jarman AP, Grau Y, Jan LY, Jan YN (1993) Atonal is a proneural gene that directs chordotonal organ formation in the Drosophila peripheral nervous system. Cell 73:1307–1321PubMedGoogle Scholar
  45. 45.
    Flora A, Klisch TJ, Schuster G, Zoghbi HY, Zoghbi HY (2009) Deletion of Atoh1 disrupts Sonic Hedgehog signaling in the developing cerebellum and prevents medulloblastoma. Science 326:1424–1427PubMedGoogle Scholar
  46. 46.
    Pons S, Trejo JL, Martinez-Morales JR, Marti E (2001) Vitronectin regulates Sonic hedgehog activity during cerebellum development through CREB phosphorylation. Development 128:1481–1492PubMedGoogle Scholar
  47. 47.
    Rios I, Alvarez-Rodriguez R, Marti E, Pons S (2004) Bmp2 antagonizes sonic hedgehog-mediated proliferation of cerebellar granule neurones through Smad5 signalling. Development 131:3159–3168PubMedGoogle Scholar
  48. 48.
    Alvarez-Rodriguez R, Barzi M, Berenguer J, Pons S (2007) Bone morphogenetic protein 2 opposes Shh-mediated proliferation in cerebellar granule cells through a TIEG-1-based regulation of Nmyc. J Biol Chem 282:37170–37180PubMedGoogle Scholar
  49. 49.
    Argenti B et al (2005) Hedgehog antagonist REN(KCTD11) regulates proliferation and apoptosis of developing granule cell progenitors. J Neurosci 25:8338–8346PubMedGoogle Scholar
  50. 50.
    Fogarty MP, Emmenegger BA, Grasfeder LL, Oliver TG, Wechsler-Reya RJ (2007) Fibroblast growth factor blocks Sonic hedgehog signaling in neuronal precursors and tumor cells. Proc Natl Acad Sci USA 104:2973–2978PubMedGoogle Scholar
  51. 51.
    Miller B (ed) ((1993) SEER cancer statistics review. National Institutes of Health, Bethesda, MDGoogle Scholar
  52. 52.
    Rickert CH, Paulus W (2001) Epidemiology of central nervous system tumors in childhood and adolescence based on the new WHO classification. Childs Nerv Syst 17:503–511PubMedGoogle Scholar
  53. 53.
    Fangusaro J (2009) Pediatric high-grade gliomas and diffuse intrinsic pontine gliomas. J Child Neurol 24:1409–1417PubMedGoogle Scholar
  54. 54.
    Dhall G (2009) Medulloblastoma. J Child Neurol 24:1418–1430PubMedGoogle Scholar
  55. 55.
    Ohgaki H (2009) Epidemiology of brain tumors. Methods Mol Biol 472:323–342PubMedGoogle Scholar
  56. 56.
    Surawicz TS et al (1999) Descriptive epidemiology of primary brain and CNS tumors: results from the Central Brain Tumor Registry of the United States, 1990–1994. Neuro Oncol 1:14–25PubMedGoogle Scholar
  57. 57.
    Benesch M et al (2006) Late sequela after treatment of childhood low-grade gliomas: a retrospective analysis of 69 long-term survivors treated between 1983 and 2003. J Neurooncol 78:199–205PubMedGoogle Scholar
  58. 58.
    Broniscer A et al (2004) Second neoplasms in pediatric patients with primary central nervous system tumors: the St. Jude Children’s Research Hospital experience. Cancer 100:2246–2252PubMedGoogle Scholar
  59. 59.
    Kretschmar CS, Warren MP, Lavally BL, Dyer S, Tarbell NJ (1990) Ototoxicity of preradiation cisplatin for children with central nervous system tumors. J Clin Oncol 8:1191–1198PubMedGoogle Scholar
  60. 60.
    Shaw S (2009) Endocrine late effects in survivors of pediatric brain tumors. J Pediatr Oncol Nurs 26:295–302PubMedGoogle Scholar
  61. 61.
    Packer RJ, Rood BR, MacDonald TJ (2003) Medulloblastoma: present concepts of stratification into risk groups. Pediatr Neurosurg 39:60–67PubMedGoogle Scholar
  62. 62.
    Fangusaro J et al (2008) Intensive chemotherapy followed by consolidative myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) in young children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNETs): report of the Head Start I and II experience. Pediatr Blood Cancer 50:312–318PubMedGoogle Scholar
  63. 63.
    Fangusaro JR et al (2008) Brainstem primitive neuroectodermal tumors (bstPNET): results of treatment with intensive induction chemotherapy followed by consolidative chemotherapy with autologous hematopoietic cell rescue. Pediatr Blood Cancer 50:715–717PubMedGoogle Scholar
  64. 64.
    Li MH, Bouffet E, Hawkins CE, Squire JA, Huang A (2005) Molecular genetics of supratentorial primitive neuroectodermal tumors and pineoblastoma. Neurosurg Focus 19:E3PubMedGoogle Scholar
  65. 65.
    Brandes AA et al (2009) Adult neuroectodermal tumors of posterior fossa (medulloblastoma) and of supratentorial sites (stPNET). Crit Rev Oncol Hematol 71:165–179PubMedGoogle Scholar
  66. 66.
    Guran S, Tunca Y, Imirzalioglu N (1999) Hereditary TP53 codon 292 and somatic P16INK4A codon 94 mutations in a Li–Fraumeni syndrome family. Cancer Genet Cytogenet 113:145–151PubMedGoogle Scholar
  67. 67.
    Mathur MN, Thompson JF, O’Brien CJ, Davidson TI, McCarthy WH (1993) Naevoid basal cell carcinoma (Gorlin’s) syndrome. Aust N Z J Surg 63:413–415PubMedGoogle Scholar
  68. 68.
    Pietsch T et al (1997) Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res 57:2085–2088PubMedGoogle Scholar
  69. 69.
    Sarin S, Bernath A (2008) Turcot syndrome (glioma polyposis): a case report. South Med J 101:1273–1274PubMedGoogle Scholar
  70. 70.
    Chang CH, Housepian EM, Herbert C Jr (1969) An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. Radiology 93:1351–1359PubMedGoogle Scholar
  71. 71.
    Packer RJ et al (1999) Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: a Children’s Cancer Group Study. J Clin Oncol 17:2127–2136PubMedGoogle Scholar
  72. 72.
    Packer RJ et al (1994) Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg 81:690–698PubMedGoogle Scholar
  73. 73.
    Chi SN et al (2004) Feasibility and response to induction chemotherapy intensified with high-dose methotrexate for young children with newly diagnosed high-risk disseminated medulloblastoma. J Clin Oncol 22:4881–4887PubMedGoogle Scholar
  74. 74.
    Dhall G et al (2008) Outcome of children less than three years old at diagnosis with non-metastatic medulloblastoma treated with chemotherapy on the “Head Start” I and II protocols. Pediatr Blood Cancer 50:1169–1175PubMedGoogle Scholar
  75. 75.
    Rutkowski S et al (2005) Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352:978–986PubMedGoogle Scholar
  76. 76.
    Ris MD, Packer R, Goldwein J, Jones-Wallace D, Boyett JM (2001) Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children’s Cancer Group study. J Clin Oncol 19:3470–3476PubMedGoogle Scholar
  77. 77.
    Amlashi SF, Riffaud L, Brassier G, Morandi X (2003) Nevoid basal cell carcinoma syndrome: relation with desmoplastic medulloblastoma in infancy. A population-based study and review of the literature. Cancer 98:618–624PubMedGoogle Scholar
  78. 78.
    Levy RA, Blaivas M, Muraszko K, Robertson PL (1997) Desmoplastic medulloblastoma: MR findings. AJNR Am J Neuroradiol 18:1364–1366PubMedGoogle Scholar
  79. 79.
    Rutkowski S, Van Hoff K, Emser A, Garre M, Walker D, Grundy R, Dhall G, Finlay J, Grill J (2008) Prognostic factors and survival of young children with medulloblastoma: an international meta-analysis. Nuerooncology 10:437Google Scholar
  80. 80.
    Beutler D et al (2005) Three-year recurrence-free survival in a patient with recurrent medulloblastoma after resection, high-dose chemotherapy, and intrathecal Yttrium-90-labeled DOTA0-d-Phe1-Tyr3-octreotide radiopeptide brachytherapy. Cancer 103:869–873PubMedGoogle Scholar
  81. 81.
    Butturini AM et al (2009) High-dose chemotherapy and autologous hematopoietic progenitor cell rescue in children with recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors: the impact of prior radiotherapy on outcome. Cancer 115:2956–2963PubMedGoogle Scholar
  82. 82.
    Dunkel IJ et al (1998) High-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue for patients with recurrent medulloblastoma. Children’s Cancer Group. J Clin Oncol 16:222–228PubMedGoogle Scholar
  83. 83.
    Mendrzyk F et al (2006) Isochromosome breakpoints on 17p in medulloblastoma are flanked by different classes of DNA sequence repeats. Genes Chromosomes Cancer 45:401–410PubMedGoogle Scholar
  84. 84.
    Pfister S, Hartmann C, Korshunov A (2009) Histology and molecular pathology of pediatric brain tumors. J Child Neurol 24:1375–1386PubMedGoogle Scholar
  85. 85.
    Rossi A, Caracciolo V, Russo G, Reiss K, Giordano A (2008) Medulloblastoma: from molecular pathology to therapy. Clin Cancer Res 14:971–976PubMedGoogle Scholar
  86. 86.
    Rossi MR et al (2006) Array CGH analysis of pediatric medulloblastomas. Genes Chromosomes Cancer 45:290–303PubMedGoogle Scholar
  87. 87.
    Pfister S et al (2009) Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci. J Clin Oncol 27:1627–1636PubMedGoogle Scholar
  88. 88.
    Thompson MC et al (2006) Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 24:1924–1931PubMedGoogle Scholar
  89. 89.
    McLaughlin MR, Gollin SM, Lese CM, Albright AL (1998) Medulloblastoma and glioblastoma multiforme in a patient with Turcot syndrome: a case report. Surg Neurol 49:295–301PubMedGoogle Scholar
  90. 90.
    Qualman SJ, Bowen J, Erdman SH (2003) Molecular basis of the brain tumor-polyposis (Turcot) syndrome. Pediatr Dev Pathol 6:574–576PubMedGoogle Scholar
  91. 91.
    Guessous F, Li Y, Abounader R (2008) Signaling pathways in medulloblastoma. J Cell Physiol 217:577–583PubMedGoogle Scholar
  92. 92.
    Ellison DW et al (2005) Beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children’s Cancer Study Group Brain Tumour Committee. J Clin Oncol 23:7951–7957PubMedGoogle Scholar
  93. 93.
    Lasky JL, Wu H (2005) Notch signaling, brain development, and human disease. Pediatr Res 57:104R–109RPubMedGoogle Scholar
  94. 94.
    Sjolund J, Manetopoulos C, Stockhausen MT, Axelson H (2005) The Notch pathway in cancer: differentiation gone awry. Eur J Cancer 41:2620–2629PubMedGoogle Scholar
  95. 95.
    Crean SJ, Cunningham SJ (1996) Gorlin’s syndrome: main features and recent advances. Br J Hosp Med 56:392–397PubMedGoogle Scholar
  96. 96.
    Raffel C et al (1997) Sporadic medulloblastomas contain PTCH mutations. Cancer Res 57:842–845PubMedGoogle Scholar
  97. 97.
    Kim JY et al (2003) Medulloblastoma tumorigenesis diverges from cerebellar granule cell differentiation in patched heterozygous mice. Dev Biol 263:50–66PubMedGoogle Scholar
  98. 98.
    Xie J et al (1998) Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391:90–92PubMedGoogle Scholar
  99. 99.
    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
  100. 100.
    Ding Q et al (1999) Mouse suppressor of fused is a negative regulator of sonic hedgehog signaling and alters the subcellular distribution of Gli1. Curr Biol 9:1119–1122PubMedGoogle Scholar
  101. 101.
    Taylor MD et al (2002) Mutations in SUFU predispose to medulloblastoma. Nat Genet 31:306–310PubMedGoogle Scholar
  102. 102.
    Rieber J et al (2009) Novel oncogene amplifications in tumors from a family with Li–Fraumeni syndrome. Genes Chromosomes Cancer 48:558–568PubMedGoogle Scholar
  103. 103.
    Dennler S et al (2007) 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 67:6981–6986PubMedGoogle Scholar
  104. 104.
    Beauchamp E et al (2009) GLI1 is a direct transcriptional target of EWS–FLI1 oncoprotein. J Biol Chem 284:9074–9082PubMedGoogle Scholar
  105. 105.
    Zhao H, Ayrault O, Zindy F, Kim JH, Roussel MF (2008) Post-transcriptional down-regulation of Atoh1/Math1 by bone morphogenic proteins suppresses medulloblastoma development. Genes Dev 22:722–727PubMedGoogle Scholar
  106. 106.
    Dubuc AM et al (2010) The genetics of pediatric brain tumors. Curr Neurol Neurosci Rep 10:215–223PubMedGoogle Scholar
  107. 107.
    Rao G, Pedone CA, Coffin CM, Holland EC, Fults DW (2003) c-Myc enhances sonic hedgehog-induced medulloblastoma formation from nestin-expressing neural progenitors in mice. Neoplasia 5:198–204PubMedGoogle Scholar
  108. 108.
    Fernandez LA et al (2009) YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes Dev 23:2729–2741Google Scholar
  109. 109.
    Lelievre V et al (2008) Disruption of the PACAP gene promotes medulloblastoma in ptc1 mutant mice. Dev Biol 313:359–370PubMedGoogle Scholar
  110. 110.
    Di Marcotullio L et al (2004) REN(KCTD11) is a suppressor of Hedgehog signaling and is deleted in human medulloblastoma. Proc Natl Acad Sci USA 101:10833–10838PubMedGoogle Scholar
  111. 111.
    Malkin D et al (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233–1238PubMedGoogle Scholar
  112. 112.
    Goodrich LV, Milenkovic L, Higgins KM, Scott MP (1997) Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277:1109–1113PubMedGoogle Scholar
  113. 113.
    Wetmore C, Eberhart DE, Curran T (2001) Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res 61:513–516PubMedGoogle Scholar
  114. 114.
    Stecca B, Ruiz i Altaba A (2009) A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers. EMBO J 28:663–676PubMedGoogle Scholar
  115. 115.
    Yoon JW, Gilbertson R, Iannaccone S, Iannaccone P, Walterhouse D (2009) Defining a role for Sonic hedgehog pathway activation in desmoplastic medulloblastoma by identifying GLI1 target genes. Int J Cancer 124:109–119PubMedGoogle Scholar
  116. 116.
    Corcoran RB, Bachar Raveh T, Barakat MT, Lee EY, Scott MP (2008) Insulin-like growth factor 2 is required for progression to advanced medulloblastoma in patched1 heterozygous mice. Cancer Res 68:8788–8795PubMedGoogle Scholar
  117. 117.
    Parathath SR, Mainwaring LA, Fernandez LA, Campbell DO, Kenney AM (2008) Insulin receptor substrate 1 is an effector of sonic hedgehog mitogenic signaling in cerebellar neural precursors. Development 135:3291–3300PubMedGoogle Scholar
  118. 118.
    De Smaele E et al (2008) An integrated approach identifies Nhlh1 and Insm1 as Sonic Hedgehog-regulated genes in developing cerebellum and medulloblastoma. Neoplasia 10:89–98PubMedGoogle Scholar
  119. 119.
    Musani V et al (2006) Mutation in exon 7 of PTCH deregulates SHH/PTCH/SMO signaling: possible linkage to WNT. Int J Mol Med 17:755–759PubMedGoogle Scholar
  120. 120.
    Modena P et al (2006) Identification of tumor-specific molecular signatures in intracranial ependymoma and association with clinical characteristics. J Clin Oncol 24:5223–5233PubMedGoogle Scholar
  121. 121.
    Palm T et al (2009) Expression profiling of ependymomas unravels localization and tumor grade-specific tumorigenesis. Cancer 115:3955–3968PubMedGoogle Scholar
  122. 122.
    Fu W, Baker NE (2003) Deciphering synergistic and redundant roles of Hedgehog. Decapentaplegic and Delta that drive the wave of differentiation in Drosophila eye development. Development 130:5229–5239PubMedGoogle Scholar
  123. 123.
    Burkhard C et al (2003) A population-based study of the incidence and survival rates in patients with pilocytic astrocytoma. J Neurosurg 98:1170–1174PubMedGoogle Scholar
  124. 124.
    Rush SZ, Abel TW, Valadez JG, Pearson M, Cooper MK (2010) Activation of the Hedgehog pathway in pilocytic astrocytomas. Neuro Oncol 12(8):790–798PubMedGoogle Scholar
  125. 125.
    Binns W, James LF, Shupe JL, Thacker EJ (1962) Cyclopian-type malformation in lambs. Arch Environ Health 5:106–108PubMedGoogle Scholar
  126. 126.
    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
  127. 127.
    Stanton BZ, Peng LF (2010) Small-molecule modulators of the Sonic Hedgehog signaling pathway. Mol Biosyst 6:44–54PubMedGoogle Scholar
  128. 128.
    Romer J, Curran T (2005) Targeting medulloblastoma: small-molecule inhibitors of the Sonic Hedgehog pathway as potential cancer therapeutics. Cancer Res 65:4975–4978PubMedGoogle Scholar
  129. 129.
    Berman DM et al (2002) Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297:1559–1561PubMedGoogle Scholar
  130. 130.
    Kumar SK et al (2008) Targeted inhibition of hedgehog signaling by cyclopamine prodrugs for advanced prostate cancer. Bioorg Med Chem 16:2764–2768PubMedGoogle Scholar
  131. 131.
    Kiselyov AS, Tkachenko SE, Balakin KV, Ivachtchenko AV (2007) Small-molecule modulators of Hh and Wnt signaling pathways. Expert Opin Ther Targets 11:1087–1101PubMedGoogle Scholar
  132. 132.
    Tremblay MR et al (2009) Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926). J Med Chem 52:4400–4418PubMedGoogle Scholar
  133. 133.
    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
  134. 134.
    Rubin LL, de Sauvage FJ (2006) Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov 5:1026–1033PubMedGoogle Scholar
  135. 135.
    Wong H et al (2009) Preclinical assessment of the absorption, distribution, metabolism and excretion of GDC-0449 (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide), an orally bioavailable systemic Hedgehog signalling pathway inhibitor. Xenobiotica 39:850–861PubMedGoogle Scholar
  136. 136.
    Gajjar AJ, Stewart C, Ellison DW, Curran T, Phillips P, Goldman G, Packer R, Kun LE, Boyett JM, Gilbertson RJ (2010) A phase I pharmacokinetic trial of sonic hedgehog (SHH) antagonist GDC-0449 in pediatric patients with recurrent or refractory medulloblastoma: a Pediatric Brain Tumor Consortium study (PBTC 25). J Clin Oncol 28 (Suppl. 18): CRA9501Google Scholar
  137. 137.
    St-Jacques B, Hammerschmidt M, McMahon AP (1999) Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev 13:2072–2086PubMedGoogle Scholar
  138. 138.
    Hellemans J et al (2003) Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips. Am J Hum Genet 72:1040–1046PubMedGoogle Scholar
  139. 139.
    Mortier GR, Kramer PP, Giedion A, Beemer FA (2003) Acrocapitofemoral dysplasia: an autosomal recessive skeletal dysplasia with cone shaped epiphyses in the hands and hips. J Med Genet 40:201–207PubMedGoogle Scholar
  140. 140.
    Yoon JW et al (2002) Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. J Biol Chem 277:5548–5555PubMedGoogle Scholar
  141. 141.
    Yauch RL et al (2009) Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 326:572–574PubMedGoogle Scholar
  142. 142.
    Vorechovsky I et al (1997) Somatic mutations in the human homologue of Drosophila patched in primitive neuroectodermal tumours. Oncogene 15:361–366PubMedGoogle Scholar
  143. 143.
    Lee Y et al (2007) Loss of suppressor-of-fused function promotes tumorigenesis. Oncogene 26:6442–6447PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Joon Won Yoon
    • 1
  • Jason Fangusaro
  • Philip Iannaccone
  • David Walterhouse
  1. 1.Department of Pediatrics, Developmental Biology Program, Children’s Memorial Research CenterNorthwestern University, Feinberg School of Medicine and Children’s Memorial HospitalChicagoUSA

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