Skip to main content
SpringerLink
Log in

Hedgehog Signaling in Pediatric Brain Tumors

  • Chapter
  • First Online:
Hedgehog signaling activation in human cancer and its clinical implications

  • 512 Accesses

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  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 76:761–775

    PubMed  CAS  Google Scholar 

  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 95:11733–11738

    PubMed  CAS  Google Scholar 

  3. Jacob J, Briscoe J (2003) Gli proteins and the control of spinal-cord patterning. EMBO Rep 4:761–765

    PubMed  CAS  Google Scholar 

  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 121:2537–2547

    PubMed  CAS  Google Scholar 

  5. Chiang C et al (1996) Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383:407–413

    PubMed  CAS  Google Scholar 

  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 75:1417–1430

    PubMed  CAS  Google Scholar 

  7. Hebert JM, Fishell G (2008) The genetics of early telencephalon patterning: some assembly required. Nat Rev Neurosci 9:678–685

    PubMed  CAS  Google Scholar 

  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 81:747–756

    PubMed  CAS  Google Scholar 

  9. Patten I, Placzek M (2000) The role of Sonic hedgehog in neural tube patterning. Cell Mol Life Sci 57:1695–1708

    PubMed  CAS  Google Scholar 

  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 251:320–332

    PubMed  CAS  Google Scholar 

  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 87:661–673

    PubMed  CAS  Google Scholar 

  12. Litingtung Y, Chiang C (2000) Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3. Nat Neurosci 3:979–985

    PubMed  CAS  Google Scholar 

  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 177:30–42

    PubMed  CAS  Google Scholar 

  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 110:247–254

    PubMed  Google Scholar 

  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 107:793–803

    PubMed  Google Scholar 

  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 128:4011–4020

    PubMed  CAS  Google Scholar 

  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 5:103–110

    PubMed  CAS  Google Scholar 

  18. Agarwala S, Sanders TA, Ragsdale CW (2001) Sonic hedgehog control of size and shape in midbrain pattern formation. Science 291:2147–2150

    PubMed  CAS  Google Scholar 

  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 237:1359–1372

    PubMed  Google Scholar 

  20. Koster R, Stick R, Loosli F, Wittbrodt J (1997) Medaka spalt acts as a target gene of hedgehog signaling. Development 124:3147–3156

    PubMed  CAS  Google Scholar 

  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 7:1436–1446

    PubMed  CAS  Google Scholar 

  22. Bayly RD, Ngo M, Aglyamova GV, Agarwala S (2007) Regulation of ventral midbrain patterning by Hedgehog signaling. Development 134:2115–2124

    PubMed  CAS  Google Scholar 

  23. Rallu M et al (2002) Dorsoventral patterning is established in the telencephalon of mutants lacking both Gli3 and Hedgehog signaling. Development 129:4963–4974

    PubMed  CAS  Google Scholar 

  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 125:5079–5089

    PubMed  CAS  Google Scholar 

  25. Tole S, Ragsdale CW, Grove EA (2000) Dorsoventral patterning of the telencephalon is disrupted in the mouse mutant extra-toes(J). Dev Biol 217:254–265

    PubMed  CAS  Google Scholar 

  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 129:4807–4819

    PubMed  CAS  Google Scholar 

  27. Hynes M et al (1995) Induction of midbrain dopaminergic neurons by Sonic hedgehog. Neuron 15:35–44

    PubMed  CAS  Google Scholar 

  28. Joksimovic M et al (2009) Spatiotemporally separable Shh domains in the midbrain define distinct dopaminergic progenitor pools. Proc Natl Acad Sci USA 106:19185–19190

    PubMed  CAS  Google Scholar 

  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 133:1799–1809

    PubMed  CAS  Google Scholar 

  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 135:2093–2103

    PubMed  CAS  Google Scholar 

  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 19:15–26

    PubMed  CAS  Google Scholar 

  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 302:345–355

    PubMed  CAS  Google Scholar 

  33. Arkell R, Beddington RS (1997) BMP-7 influences pattern and growth of the developing hindbrain of mouse embryos. Development 124:1–12

    PubMed  CAS  Google Scholar 

  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 64:476–490

    PubMed  CAS  Google Scholar 

  35. Sotelo C (2004) Cellular and genetic regulation of the development of the cerebellar system. Prog Neurobiol 72:295–339

    PubMed  CAS  Google Scholar 

  36. Vaillant C, Monard D (2009) SHH pathway and cerebellar development. Cerebellum 8:291–301

    PubMed  Google Scholar 

  37. Traiffort E, Angot E, Ruat M (2010) Sonic Hedgehog signaling in the mammalian brain. J Neurochem 113:576–590

    PubMed  CAS  Google Scholar 

  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 270:393–410

    PubMed  CAS  Google Scholar 

  39. Wechsler-Reya RJ, Scott MP (1999) Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 22:103–114

    PubMed  CAS  Google Scholar 

  40. Dahmane N, Ruiz i Altaba A (1999) Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 126:3089–3100

    PubMed  Google Scholar 

  41. Wallace VA (1999) Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol 9:445–448

    PubMed  CAS  Google Scholar 

  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 20:9055–9067

    PubMed  CAS  Google Scholar 

  43. Kenney AM, Cole MD, Rowitch DH (2003) Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development 130:15–28

    PubMed  CAS  Google Scholar 

  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 73:1307–1321

    PubMed  CAS  Google Scholar 

  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 326:1424–1427

    PubMed  CAS  Google Scholar 

  46. Pons S, Trejo JL, Martinez-Morales JR, Marti E (2001) Vitronectin regulates Sonic hedgehog activity during cerebellum development through CREB phosphorylation. Development 128:1481–1492

    PubMed  CAS  Google Scholar 

  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 131:3159–3168

    PubMed  CAS  Google Scholar 

  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 282:37170–37180

    PubMed  CAS  Google Scholar 

  49. Argenti B et al (2005) Hedgehog antagonist REN(KCTD11) regulates proliferation and apoptosis of developing granule cell progenitors. J Neurosci 25:8338–8346

    PubMed  CAS  Google Scholar 

  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 104:2973–2978

    PubMed  CAS  Google Scholar 

  51. Miller B (ed) ((1993) SEER cancer statistics review. National Institutes of Health, Bethesda, MD

    Google Scholar 

  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 17:503–511

    PubMed  CAS  Google Scholar 

  53. Fangusaro J (2009) Pediatric high-grade gliomas and diffuse intrinsic pontine gliomas. J Child Neurol 24:1409–1417

    PubMed  Google Scholar 

  54. Dhall G (2009) Medulloblastoma. J Child Neurol 24:1418–1430

    PubMed  Google Scholar 

  55. Ohgaki H (2009) Epidemiology of brain tumors. Methods Mol Biol 472:323–342

    PubMed  CAS  Google Scholar 

  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 1:14–25

    PubMed  CAS  Google Scholar 

  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 78:199–205

    PubMed  Google Scholar 

  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 100:2246–2252

    PubMed  Google Scholar 

  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 8:1191–1198

    PubMed  CAS  Google Scholar 

  60. Shaw S (2009) Endocrine late effects in survivors of pediatric brain tumors. J Pediatr Oncol Nurs 26:295–302

    PubMed  Google Scholar 

  61. Packer RJ, Rood BR, MacDonald TJ (2003) Medulloblastoma: present concepts of stratification into risk groups. Pediatr Neurosurg 39:60–67

    PubMed  Google Scholar 

  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 50:312–318

    PubMed  Google Scholar 

  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 50:715–717

    PubMed  Google Scholar 

  64. Li MH, Bouffet E, Hawkins CE, Squire JA, Huang A (2005) Molecular genetics of supratentorial primitive neuroectodermal tumors and pineoblastoma. Neurosurg Focus 19:E3

    PubMed  Google Scholar 

  65. Brandes AA et al (2009) Adult neuroectodermal tumors of posterior fossa (medulloblastoma) and of supratentorial sites (stPNET). Crit Rev Oncol Hematol 71:165–179

    PubMed  Google Scholar 

  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 113:145–151

    PubMed  CAS  Google Scholar 

  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 63:413–415

    PubMed  CAS  Google Scholar 

  68. Pietsch T et al (1997) Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res 57:2085–2088

    PubMed  CAS  Google Scholar 

  69. Sarin S, Bernath A (2008) Turcot syndrome (glioma polyposis): a case report. South Med J 101:1273–1274

    PubMed  Google Scholar 

  70. Chang CH, Housepian EM, Herbert C Jr (1969) An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. Radiology 93:1351–1359

    PubMed  CAS  Google Scholar 

  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 17:2127–2136

    PubMed  CAS  Google Scholar 

  72. Packer RJ et al (1994) Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg 81:690–698

    PubMed  CAS  Google Scholar 

  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 22:4881–4887

    PubMed  CAS  Google Scholar 

  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 50:1169–1175

    PubMed  Google Scholar 

  75. Rutkowski S et al (2005) Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352:978–986

    PubMed  CAS  Google Scholar 

  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 19:3470–3476

    PubMed  CAS  Google Scholar 

  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 98:618–624

    PubMed  Google Scholar 

  78. Levy RA, Blaivas M, Muraszko K, Robertson PL (1997) Desmoplastic medulloblastoma: MR findings. AJNR Am J Neuroradiol 18:1364–1366

    PubMed  CAS  Google Scholar 

  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 10:437

    Google Scholar 

  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 103:869–873

    PubMed  Google Scholar 

  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 115:2956–2963

    PubMed  Google Scholar 

  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 16:222–228

    PubMed  CAS  Google Scholar 

  83. Mendrzyk F et al (2006) Isochromosome breakpoints on 17p in medulloblastoma are flanked by different classes of DNA sequence repeats. Genes Chromosomes Cancer 45:401–410

    PubMed  CAS  Google Scholar 

  84. Pfister S, Hartmann C, Korshunov A (2009) Histology and molecular pathology of pediatric brain tumors. J Child Neurol 24:1375–1386

    PubMed  Google Scholar 

  85. Rossi A, Caracciolo V, Russo G, Reiss K, Giordano A (2008) Medulloblastoma: from molecular pathology to therapy. Clin Cancer Res 14:971–976

    PubMed  CAS  Google Scholar 

  86. Rossi MR et al (2006) Array CGH analysis of pediatric medulloblastomas. Genes Chromosomes Cancer 45:290–303

    PubMed  CAS  Google Scholar 

  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 27:1627–1636

    PubMed  Google Scholar 

  88. Thompson MC et al (2006) Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 24:1924–1931

    PubMed  CAS  Google Scholar 

  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 49:295–301

    PubMed  CAS  Google Scholar 

  90. Qualman SJ, Bowen J, Erdman SH (2003) Molecular basis of the brain tumor-polyposis (Turcot) syndrome. Pediatr Dev Pathol 6:574–576

    PubMed  Google Scholar 

  91. Guessous F, Li Y, Abounader R (2008) Signaling pathways in medulloblastoma. J Cell Physiol 217:577–583

    PubMed  CAS  Google Scholar 

  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 23:7951–7957

    PubMed  CAS  Google Scholar 

  93. Lasky JL, Wu H (2005) Notch signaling, brain development, and human disease. Pediatr Res 57:104R–109R

    PubMed  Google Scholar 

  94. Sjolund J, Manetopoulos C, Stockhausen MT, Axelson H (2005) The Notch pathway in cancer: differentiation gone awry. Eur J Cancer 41:2620–2629

    PubMed  Google Scholar 

  95. Crean SJ, Cunningham SJ (1996) Gorlin’s syndrome: main features and recent advances. Br J Hosp Med 56:392–397

    PubMed  CAS  Google Scholar 

  96. Raffel C et al (1997) Sporadic medulloblastomas contain PTCH mutations. Cancer Res 57:842–845

    PubMed  CAS  Google Scholar 

  97. Kim JY et al (2003) Medulloblastoma tumorigenesis diverges from cerebellar granule cell differentiation in patched heterozygous mice. Dev Biol 263:50–66

    PubMed  CAS  Google Scholar 

  98. Xie J et al (1998) Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391:90–92

    PubMed  CAS  Google Scholar 

  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 58:1798–1803

    PubMed  CAS  Google Scholar 

  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 9:1119–1122

    PubMed  CAS  Google Scholar 

  101. Taylor MD et al (2002) Mutations in SUFU predispose to medulloblastoma. Nat Genet 31:306–310

    PubMed  CAS  Google Scholar 

  102. Rieber J et al (2009) Novel oncogene amplifications in tumors from a family with Li–Fraumeni syndrome. Genes Chromosomes Cancer 48:558–568

    PubMed  CAS  Google Scholar 

  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 67:6981–6986

    PubMed  CAS  Google Scholar 

  104. Beauchamp E et al (2009) GLI1 is a direct transcriptional target of EWS–FLI1 oncoprotein. J Biol Chem 284:9074–9082

    PubMed  CAS  Google Scholar 

  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 22:722–727

    PubMed  CAS  Google Scholar 

  106. Dubuc AM et al (2010) The genetics of pediatric brain tumors. Curr Neurol Neurosci Rep 10:215–223

    PubMed  CAS  Google Scholar 

  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 5:198–204

    PubMed  CAS  Google Scholar 

  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 23:2729–2741

    Google Scholar 

  109. Lelievre V et al (2008) Disruption of the PACAP gene promotes medulloblastoma in ptc1 mutant mice. Dev Biol 313:359–370

    PubMed  CAS  Google Scholar 

  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 101:10833–10838

    PubMed  Google Scholar 

  111. Malkin D et al (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233–1238

    PubMed  CAS  Google Scholar 

  112. Goodrich LV, Milenkovic L, Higgins KM, Scott MP (1997) Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277:1109–1113

    PubMed  CAS  Google Scholar 

  113. Wetmore C, Eberhart DE, Curran T (2001) Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res 61:513–516

    PubMed  CAS  Google Scholar 

  114. Stecca B, Ruiz i Altaba A (2009) A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers. EMBO J 28:663–676

    PubMed  CAS  Google Scholar 

  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 124:109–119

    PubMed  CAS  Google Scholar 

  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 68:8788–8795

    PubMed  CAS  Google Scholar 

  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 135:3291–3300

    PubMed  CAS  Google Scholar 

  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 10:89–98

    PubMed  Google Scholar 

  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 17:755–759

    PubMed  CAS  Google Scholar 

  120. Modena P et al (2006) Identification of tumor-specific molecular signatures in intracranial ependymoma and association with clinical characteristics. J Clin Oncol 24:5223–5233

    PubMed  CAS  Google Scholar 

  121. Palm T et al (2009) Expression profiling of ependymomas unravels localization and tumor grade-specific tumorigenesis. Cancer 115:3955–3968

    PubMed  CAS  Google Scholar 

  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 130:5229–5239

    PubMed  CAS  Google Scholar 

  123. Burkhard C et al (2003) A population-based study of the incidence and survival rates in patients with pilocytic astrocytoma. J Neurosurg 98:1170–1174

    PubMed  Google Scholar 

  124. Rush SZ, Abel TW, Valadez JG, Pearson M, Cooper MK (2010) Activation of the Hedgehog pathway in pilocytic astrocytomas. Neuro Oncol 12(8):790–798

    PubMed  CAS  Google Scholar 

  125. Binns W, James LF, Shupe JL, Thacker EJ (1962) Cyclopian-type malformation in lambs. Arch Environ Health 5:106–108

    PubMed  CAS  Google Scholar 

  126. Chen JK, Taipale J, Cooper MK, Beachy PA (2002) Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 16:2743–2748

    PubMed  CAS  Google Scholar 

  127. Stanton BZ, Peng LF (2010) Small-molecule modulators of the Sonic Hedgehog signaling pathway. Mol Biosyst 6:44–54

    PubMed  CAS  Google Scholar 

  128. Romer J, Curran T (2005) Targeting medulloblastoma: small-molecule inhibitors of the Sonic Hedgehog pathway as potential cancer therapeutics. Cancer Res 65:4975–4978

    PubMed  CAS  Google Scholar 

  129. Berman DM et al (2002) Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297:1559–1561

    PubMed  CAS  Google Scholar 

  130. Kumar SK et al (2008) Targeted inhibition of hedgehog signaling by cyclopamine prodrugs for advanced prostate cancer. Bioorg Med Chem 16:2764–2768

    PubMed  CAS  Google Scholar 

  131. Kiselyov AS, Tkachenko SE, Balakin KV, Ivachtchenko AV (2007) Small-molecule modulators of Hh and Wnt signaling pathways. Expert Opin Ther Targets 11:1087–1101

    PubMed  CAS  Google Scholar 

  132. Tremblay MR et al (2009) Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926). J Med Chem 52:4400–4418

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  134. Rubin LL, de Sauvage FJ (2006) Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov 5:1026–1033

    PubMed  CAS  Google Scholar 

  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 39:850–861

    PubMed  CAS  Google Scholar 

  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): CRA9501

    Google Scholar 

  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 13:2072–2086

    PubMed  CAS  Google Scholar 

  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 72:1040–1046

    PubMed  Google Scholar 

  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 40:201–207

    PubMed  CAS  Google Scholar 

  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 277:5548–5555

    PubMed  CAS  Google Scholar 

  141. Yauch RL et al (2009) Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 326:572–574

    PubMed  CAS  Google Scholar 

  142. Vorechovsky I et al (1997) Somatic mutations in the human homologue of Drosophila patched in primitive neuroectodermal tumours. Oncogene 15:361–366

    PubMed  CAS  Google Scholar 

  143. Lee Y et al (2007) Loss of suppressor-of-fused function promotes tumorigenesis. Oncogene 26:6442–6447

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Developmental Biology Program, Children’s Memorial Research Center, Northwestern University, Feinberg School of Medicine and Children’s Memorial Hospital, 2300 Children’s Plaza, 204, Chicago, IL, 60614, USA

    Joon Won Yoon

Authors
  1. Joon Won Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jason Fangusaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philip Iannaccone
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Walterhouse
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joon Won Yoon .

Editor information

Editors and Affiliations

  1. University of Texas Medical Branch, Galveston, 77555, Texas, USA

    Jingwu Xie

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Yoon, J.W., Fangusaro, J., Iannaccone, P., Walterhouse, D. (2011). Hedgehog Signaling in Pediatric Brain Tumors. In: Xie, J. (eds) Hedgehog signaling activation in human cancer and its clinical implications. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-8435-7_8

Download citation

Publish with us

Policies and ethics

Search

Navigation