1932

Abstract

Neuroblastoma is a developmental tumor of young children arising from the embryonic sympathoadrenal lineage of the neural crest. Neuroblastoma is the primary cause of death from pediatric cancer for children between the ages of one and five years and accounts for ∼13% of all pediatric cancer mortality. Its clinical impact and unique biology have made this aggressive malignancy the focus of a large concerted translational research effort. New insights into tumor biology are driving the development of new classification schemas. Novel targeted therapeutic approaches include small-molecule inhibitors as well as epigenetic, noncoding-RNA, and cell-based immunologic therapies. In this review, recent insights regarding the pathogenesis and biology of neuroblastoma are placed in context with the current understanding of tumor biology and tumor/host interactions. Systematic classification of patients coupled with therapeutic advances point to a future of improved clinical outcomes for this biologically distinct and highly aggressive pediatric malignancy.

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2015-01-14
2024-03-28
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Literature Cited

  1. 1. CDC. U.S. Cancer Statistics Working Group 2013. United States Cancer Statistics: 1999–2010 incidence and mortality web-based report. US Dep. Health Hum. Serv., Cent. Disease Control Prev. and Natl. Cancer Inst.
  2. London WB, Castleberry RP, Matthay KK. 2.  et al. 2005. Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children's Oncology Group. J. Clin. Oncol. 23:6459–65 [Google Scholar]
  3. Monclair T, Brodeur GM, Ambros PF. 3.  et al. 2009. The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J. Clin. Oncol. 27:298–303 [Google Scholar]
  4. Park JR, Bagatell R, London WB. 4.  et al. 2013. Children's Oncology Group's 2013 blueprint for research: neuroblastoma. Pediatr. Blood Cancer 60:985–93 [Google Scholar]
  5. Yu AL.5.  2014. Update on outcome for high-risk neuroblastoma treated on a randomized trial of chimeric anti-gd2 antibody (ch14.18) + GM-CSF/IL2 in first response: a Children's Oncology Group study. Presented at Advances in Neuroblastoma Res. Conf. (ANR2014), Cologne [Google Scholar]
  6. Betters E, Liu Y, Kjaeldgaard A. 6.  et al. 2010. Analysis of early human neural crest development. Dev. Biol. 344:578–92 [Google Scholar]
  7. Fredlund E, Ringner M, Maris JM, Pahlman S. 7.  2008. High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma. Proc. Natl. Acad. Sci. USA 105:14094–99 [Google Scholar]
  8. Takahashi Y, Sipp D, Enomoto H. 8.  2013. Tissue interactions in neural crest cell development and disease. Science 341:860–63 [Google Scholar]
  9. Hall BK.9.  2000. The neural crest as a fourth germ layer and vertebrates as quadroblastic not triploblastic. Evol. Dev. 2:3–5 [Google Scholar]
  10. Prasad MS, Sauka-Spengler T, Labonne C. 10.  2012. Induction of the neural crest state: control of stem cell attributes by gene regulatory, post-transcriptional and epigenetic interactions. Dev. Biol. 366:10–21 [Google Scholar]
  11. Mayanil CS.11.  2013. Transcriptional and epigenetic regulation of neural crest induction during neurulation. Dev. Neurosci. 35:5361–72 [Google Scholar]
  12. Strobl-Mazzulla PH, Bronner ME. 12.  2012. Epithelial to mesenchymal transition: new and old insights from the classical neural crest model. Semin. Cancer Biol. 22:5-6411–16 [Google Scholar]
  13. Pegoraro C, Monsoro-Burq AH. 13.  2013. Signaling and transcriptional regulation in neural crest specification and migration: lessons from xenopus embryos. Wiley Interdiscip. Rev. Dev. Biol. 2:247–59 [Google Scholar]
  14. Shtukmaster S, Schier MC, Huber K. 14.  et al. 2013. Sympathetic neurons and chromaffin cells share a common progenitor in the neural crest in vivo. Neural Dev. 18:812 [Google Scholar]
  15. Denecker G, Vandamme N, Akay O. 15.  et al. 2014. Identification of a ZEB2-MITF-ZEB1 transcriptional network that controls melanogenesis and melanoma progression. Cell Death Differ. 21:81250–61 [Google Scholar]
  16. Powell DR, Hernandez-Lagunas L, LaMonica K, Artinger KB. 16.  2013. Prdm1a directly activates foxd3 and tfap2a during zebrafish neural crest specification. Development 140:3445–55 [Google Scholar]
  17. Hernandez-Lagunas L, Powell DR, Law J. 17.  et al. 2011. prdm1a and olig4 act downstream of Notch signaling to regulate cell fate at the neural plate border. Dev. Biol. 356:496–505 [Google Scholar]
  18. Rogers CD, Saxena A, Bronner ME. 18.  2013. Sip1 mediates an E-cadherin-to-N-cadherin switch during cranial neural crest EMT. J. Cell Biol. 203:835–47 [Google Scholar]
  19. Beck B, Blanpain C. 19.  2013. Unravelling cancer stem cell potential. Nat. Rev. Cancer 13:727–38 [Google Scholar]
  20. Howk CL, Voller Z, Beck BB, Dai D. 20.  2013. Genetic diversity in normal cell populations is the earliest stage of oncogenesis leading to intra-tumor heterogeneity. Front. Oncol. 5:361 [Google Scholar]
  21. Hsu DM, Agarwal S, Benham A. 21.  et al. 2013. G-CSF receptor positive neuroblastoma subpopulations are enriched in chemotherapy-resistant or relapsed tumors and are highly tumorigenic. Cancer Res. 73:4134–46 [Google Scholar]
  22. Nuchtern JG, London WB, Barnewolt CE. 22.  et al. 2012. A prospective study of expectant observation as primary therapy for neuroblastoma in young infants: a Children's Oncology Group study. Ann. Surg. 256:573–80 [Google Scholar]
  23. Strother DR, London WB, Schmidt ML. 23.  et al. 2012. Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children's Oncology Group study P9641. J. Clin. Oncol. 30:1842–48 [Google Scholar]
  24. Rinon A, Molchadsky A, Nathan E. 24.  et al. 2011. p53 coordinates cranial neural crest cell growth and epithelial-mesenchymal transition/delamination processes. Development 138:1827–38 [Google Scholar]
  25. Chen Z, Lin Y, Barbieri E. 25.  et al. 2009. Mdm2 deficiency suppresses MYCN-driven neuroblastoma tumorigenesis in vivo. Neoplasia 11:753–62 [Google Scholar]
  26. Kim E, Shohet J. 26.  2009. Targeted molecular therapy for neuroblastoma: the ARF/MDM2/p53 axis. J. Natl. Cancer Inst. 101:1527–29 [Google Scholar]
  27. Pugh TJ, Morozova O, Attiyeh EF. 27.  et al. 2013. The genetic landscape of high-risk neuroblastoma. Nat. Genet. 45:279–84 [Google Scholar]
  28. Fujita T, Igarashi J, Okawa ER. 28.  et al. 2008. CHD5, a tumor suppressor gene deleted from 1p36.31 in neuroblastomas. J. Natl. Cancer Inst. 100:940–49 [Google Scholar]
  29. Theissen J, Oberthuer A, Hombach A. 29.  et al. 2014. Chromosome 17/17q gain and unaltered profiles in high resolution array-CGH are prognostically informative in neuroblastoma. Genes Chromosomes Cancer 53:8639–49 [Google Scholar]
  30. De Preter K, Vermeulen J, Brors B. 30.  et al. 2010. Accurate outcome prediction in neuroblastoma across independent data sets using a multigene signature. Clin. Cancer Res. 16:1532–41 [Google Scholar]
  31. Westermann F, Muth D, Benner A. 31.  et al. 2008. Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas. Genome Biol. 13;9:10R1509 [Google Scholar]
  32. Bilke S, Chen QR, Westerman F. 32.  et al. 2005. Inferring a tumor progression model for neuroblastoma from genomic data. J. Clin. Oncol. 23:7322–31 [Google Scholar]
  33. Hansford LM, Thomas WD, Keating JM. 33.  et al. 2004. Mechanisms of embryonal tumor initiation: distinct roles for MycN expression and MYCN amplification. Proc. Natl. Acad. Sci. USA 101:12664–69 [Google Scholar]
  34. Weiss WA, Aldape K, Mohapatra G. 34.  et al. 1997. Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO J. 16:2985–95 [Google Scholar]
  35. Schramm A, Koster J, Marschall T. 35.  et al. 2013. Next-generation RNA sequencing reveals differential expression of MYCN target genes and suggests the mTOR pathway as a promising therapy target in MYCN-amplified neuroblastoma. Int. J. Cancer 132:E106–15 [Google Scholar]
  36. Stallings RL.36.  2009. MicroRNA involvement in the pathogenesis of neuroblastoma: potential for microRNA mediated therapeutics. Curr. Pharm. Des. 15:456–62 [Google Scholar]
  37. Valentijn LJ, Koster J, Haneveld F. 37.  et al. 2012. A functional MYCN signature predicts outcome of neuroblastoma irrespective of MYCN amplification. Proc. Natl. Acad. Sci. USA 109:4719190–95 [Google Scholar]
  38. Shohet JM, Ghosh R, Coarfa C. 38.  et al. 2011. A genome-wide search for promoters that respond to increased MYCN reveals both new oncogenic and tumor suppressor microRNAs associated with aggressive neuroblastoma. Cancer Res. 71:3841–51 [Google Scholar]
  39. Huang M, Weiss WA. 39.  2013. Neuroblastoma and MYCN. Cold Spring Harb. Perspect. Med. 3:a014415 [Google Scholar]
  40. Wakamatsu Y, Watanabe Y, Nakamura H, Kondoh H. 40.  1997. Regulation of the neural crest cell fate by N-myc: promotion of ventral migration and neuronal differentiation. Development 124:1953–62 [Google Scholar]
  41. Van Maerken T, Ferdinande L, Taildeman J. 41.  et al. 2009. Antitumor activity of the selective MDM2 antagonist nutlin-3 against chemoresistant neuroblastoma with wild-type p53. J. Natl. Cancer Inst. 101:1562–74 [Google Scholar]
  42. Barbieri E, Mehta P, Chen Z. 42.  et al. 2006. MDM2 inhibition sensitizes neuroblastoma to chemotherapy-induced apoptotic cell death. Mol. Cancer Ther. 5:2358–65 [Google Scholar]
  43. Evageliou NF, Hogarty MD. 43.  2009. Disrupting polyamine homeostasis as a therapeutic strategy for neuroblastoma. Clin. Cancer Res. 15:5956–61 [Google Scholar]
  44. Bagatell R, Norris R, Ingle AM. 44.  et al. 2014. Phase 1 trial of temsirolimus in combination with irinotecan and temozolomide in children, adolescents and young adults with relapsed or refractory solid tumors: a Children's Oncology Group Study. Pediatr. Blood Cancer 61:833–39 [Google Scholar]
  45. Di Giannatale A, Dias-Gastellier N, Devos A. 45.  et al. 2014. Phase II study of temozolomide in combination with topotecan (TOTEM) in relapsed or refractory neuroblastoma: a European Innovative Therapies for Children with Cancer–SIOP–European Neuroblastoma study. Eur. J. Cancer 50:170–77 [Google Scholar]
  46. Maris JM.46.  2010. Recent advances in neuroblastoma. N. Engl. J. Med. 362:2202–11 [Google Scholar]
  47. Ardini E, Magnaghi P, Orsini P. 47.  et al. 2010. Anaplastic lymphoma kinase: role in specific tumours, and development of small molecule inhibitors for cancer therapy. Cancer Lett. 299:81–94 [Google Scholar]
  48. Mosse YP, Laudenslager M, Longo L. 48.  et al. 2008. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455:930–35 [Google Scholar]
  49. Minuti G, D'Incecco A, Landi L, Cappuzzo F. 49.  2014. Protein kinase inhibitors to treat non-small-cell lung cancer. Expert Opin. Pharmacother. 15:91203–13 [Google Scholar]
  50. Ulivi P, Zoli W, Capelli L. 50.  et al. 2013. Target therapy in NSCLC patients: relevant clinical agents and tumour molecular characterisation. Mol. Clin. Oncol. 1:575–81 [Google Scholar]
  51. Reiff T, Huber L, Kramer M. 51.  et al. 2011. Midkine and Alk signaling in sympathetic neuron proliferation and neuroblastoma predisposition. Development 138:4699–708 [Google Scholar]
  52. Wang M, Zhou C, Sun Q. 52.  et al. 2013. ALK amplification and protein expression predict inferior prognosis in neuroblastomas. Exp. Mol. Pathol. 95:124–30 [Google Scholar]
  53. Schulte JH, Lindner S, Bohrer A. 53.  et al. 2013. MYCN and ALKF1174L are sufficient to drive neuroblastoma development from neural crest progenitor cells. Oncogene 32:1059–65 [Google Scholar]
  54. Mosse YP, Laudenslager M, Khazi D. 54.  et al. 2004. Germline PHOX2B mutation in hereditary neuroblastoma. Am. J. Hum. Genet. 75:727–30 [Google Scholar]
  55. Trochet D, Bourdeaut F, Janoueix-Lerosey I. 55.  et al. 2004. Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. Am. J. Hum. Genet. 74:761–64 [Google Scholar]
  56. Pei D, Luther W, Wang W. 56.  et al. 2013. Distinct neuroblastoma-associated alterations of PHOX2B impair sympathetic neuronal differentiation in zebrafish models. PLOS Genet. 9:e1003533 [Google Scholar]
  57. Butler Tjaden NE, Trainor PA. 57.  2013. The developmental etiology and pathogenesis of Hirschsprung disease. Transl. Res. 162:1–15 [Google Scholar]
  58. Di Lascio S, Bachetti T, Saba E. 58.  et al. 2013. Transcriptional dysregulation and impairment of PHOX2B auto-regulatory mechanism induced by polyalanine expansion mutations associated with congenital central hypoventilation syndrome. Neurobiol. Dis. 50:187–200 [Google Scholar]
  59. Wang W, Zhong Q, Teng L. 59.  et al. 2013. Mutations that disrupt PHOXB interaction with the neuronal calcium sensor HPCAL1 impede cellular differentiation in neuroblastoma. Oncogene 33:253316–24 [Google Scholar]
  60. Bachetti T, Di Paolo D, Di Lascio S. 60.  et al. 2010. PHOX2B-mediated regulation of ALK expression: in vitro identification of a functional relationship between two genes involved in neuroblastoma. PLOS ONE 1:5(10)
  61. Burney MJ, Johnston C, Wong KY. 61.  et al. 2013. An epigenetic signature of developmental potential in neural stem cells and early neurons. Stem Cells 31:1868–80 [Google Scholar]
  62. Rada-Iglesias A, Bajpai R, Prescott S. 62.  et al. 2012. Epigenomic annotation of enhancers predicts transcriptional regulators of human neural crest. Cell Stem Cell 11:633–48 [Google Scholar]
  63. Eroglu B, Wang G, Tu N. 63.  et al. 2006. Critical role of Brg1 member of the SWI/SNF chromatin remodeling complex during neurogenesis and neural crest induction in zebrafish. Dev. Dyn. 235:2722–35 [Google Scholar]
  64. Martins-Taylor K, Schroeder DI, LaSalle JM. 64.  et al. 2012. Role of DNMT3B in the regulation of early neural and neural crest specifiers. Epigenetics 7:71–82 [Google Scholar]
  65. Ostler KR, Yang Q, Looney TJ. 65.  et al. 2012. Truncated DNMT3B isoform DNMT3B7 suppresses growth, induces differentiation, and alters DNA methylation in human neuroblastoma. Cancer Res. 72:4714–23 [Google Scholar]
  66. Newhart A, Rafalska-Metcalf IU, Yang T. 66.  et al. 2012. Single-cell analysis of Daxx and ATRX-dependent transcriptional repression. J. Cell Sci. 125:5489–501 [Google Scholar]
  67. Cheung NK, Zhang J, Lu C. 67.  et al. 2012. Association of age at diagnosis and genetic mutations in patients with neuroblastoma. JAMA 307:1062–71 [Google Scholar]
  68. Ma L, Young J, Prabhala H. 68.  et al. 2010. miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat. Cell Biol. 12:247–56 [Google Scholar]
  69. Molenaar JJ, Domingo-Fernandez R, Ebus ME. 69.  et al. 2012. LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. Nat. Genet. 44:111199–206 [Google Scholar]
  70. Mestdagh P, Bostrom AK, Impens F. 70.  et al. 2010. The miR-17–92 microRNA cluster regulates multiple components of the TGF-beta pathway in neuroblastoma. Mol. Cell 40:762–73 [Google Scholar]
  71. Hamilton MP, Rajapakshe K, Hartig SM. 71.  et al. 2013. Identification of a pan-cancer oncogenic microRNA superfamily anchored by a central core seed motif. Nat. Commun. 4:2730:1–13 [Google Scholar]
  72. Buechner J, Einvik C. 72.  2012. N-myc and noncoding RNAs in neuroblastoma. Mol. Cancer Res. 10:101243–53 [Google Scholar]
  73. Ara T, Nakata R, Sheard MA. 73.  et al. 2013. Critical role of STAT3 in IL-6-mediated drug resistance in human neuroblastoma. Cancer Res. 73:3852–64 [Google Scholar]
  74. Liu D, Song L, Wei J. 74.  et al. 2012. IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity. J. Clin. Invest. 122:2221–33 [Google Scholar]
  75. Schleiermacher G, Mosseri V, London WB. 75.  et al. 2012. Segmental chromosomal alterations have prognostic impact in neuroblastoma: a report from the INRG project. Br. J. Cancer 107:1418–22 [Google Scholar]
  76. Brodeur GM, Seeger RC, Barrett A. 76.  et al. 1988. International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J. Clin. Oncol. 6:1874–81 [Google Scholar]
  77. Owens C, Irwin M. 77.  2012. Neuroblastoma: the impact of biology and cooperation leading to personalized treatments. Crit. Rev. Clin. Lab. Sci. 49:85–115 [Google Scholar]
  78. Cohn SL, Pearson AD, London WB. 78.  et al. 2009. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J. Clin. Oncol. 27:289–97 [Google Scholar]
  79. Morgenstern DA, Baruchel S, Irwin MS. 79.  2013. Current and future strategies for relapsed neuroblastoma: challenges on the road to precision therapy. J. Pediatr. Hematol. Oncol. 35:337–47 [Google Scholar]
  80. Castel V, Segura V, Berlanga P. 80.  2013. Emerging drugs for neuroblastoma. Expert Opin. Emerg. Drugs 18:155–71 [Google Scholar]
  81. Heczey A, Louis CU. 81.  2013. Advances in chimeric antigen receptor immunotherapy for neuroblastoma. Discov. Med. 16:287–94 [Google Scholar]
  82. Baker DL, Schmidt ML, Cohn SL. 82.  et al. 2010. Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N. Engl. J. Med. 363:1313–23 [Google Scholar]
  83. Hero B, Simon T, Spitz R. 83.  et al. 2008. Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97. J. Clin. Oncol. 26:1504–10 [Google Scholar]
  84. Rubie H, De Bernardi B, Gerrard M. 84.  et al. 2011. Excellent outcome with reduced treatment in infants with nonmetastatic and unresectable neuroblastoma without MYCN amplification: results of the prospective INES 99.1. J. Clin. Oncol. 29:449–55 [Google Scholar]
  85. Bagatell R, Beck-Popovic M, London WB. 85.  et al. 2009. Significance of MYCN amplification in international neuroblastoma staging system stage 1 and 2 neuroblastoma: a report from the International Neuroblastoma Risk Group database. J. Clin. Oncol. 27:365–70 [Google Scholar]
  86. De Bernardi B, Mosseri V, Rubie H. 86.  et al. 2008. Treatment of localised resectable neuroblastoma. Results of the LNESG1 study by the SIOP Europe Neuroblastoma Group. Br. J. Cancer 99:1027–33 [Google Scholar]
  87. Matthay KK, Perez C, Seeger RC. 87.  et al. 1998. Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children's Cancer Group study. J. Clin. Oncol. 16:1256–64 [Google Scholar]
  88. Nickerson HJ, Matthay KK, Seeger RC. 88.  et al. 2000. Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study. J. Clin. Oncol. 18:477–86 [Google Scholar]
  89. Yu AL, Gilman AL, Ozkaynak MF. 89.  et al. 2010. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N. Engl. J. Med. 363:1324–34 [Google Scholar]
  90. Endres S.90.  2014. Long-term infusion of ch14-18/CHO combined with s.c. interleukin-2 applied in a single center treatment program effectively stimulates anti-neuroblastoma activity with reduced pain in high-risk neuroblastoma patients. Presented at Advances in Neuroblastoma Res. Conf. (ANR2014), Cologne
  91. Ladenstein R.91.  2014. Myeloablative therapy (MAT) and immunotherapy (IT) with ch14.18/CHO for high risk neuroblastoma: update and news of randomised results from the HR-NBL1/SIOPEN trial. Presented at Advances in Neuroblastoma Res. Conf. (ANR2014), Cologne [Google Scholar]
  92. Schmidt M, Simon T, Hero B. 92.  et al. 2008. The prognostic impact of functional imaging with 123I-mIBG in patients with stage 4 neuroblastoma >1 year of age on a high-risk treatment protocol: results of the German Neuroblastoma Trial NB97. Eur. J. Cancer 44:1552–58 [Google Scholar]
  93. Matthay KK, Edeline V, Lumbroso J. 93.  et al. 2003. Correlation of early metastatic response by 123I-metaiodobenzylguanidine scintigraphy with overall response and event-free survival in stage IV neuroblastoma. J. Clin. Oncol. 21:2486–91 [Google Scholar]
  94. Beiske K, Burchill SA, Cheung IY. 94.  et al. 2009. Consensus criteria for sensitive detection of minimal neuroblastoma cells in bone marrow, blood and stem cell preparations by immunocytology and QRT-PCR: recommendations by the International Neuroblastoma Risk Group Task Force. Br. J. Cancer 100:1627–37 [Google Scholar]
  95. Modak S.95.  2014. Generation and administration of autologous T cells transduced with a 3rd generation GD2 chimeric antigen receptor for patients with relapsed or refractory neuroblastoma. Presented at Advances in Neuroblastoma Res. Conf. (ANR2014), Cologne
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