Chapter 4 - The Connections Between Neural Crest Development and Neuroblastoma

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Abstract

Neuroblastoma (NB), the most common extracranial solid tumor in childhood, is an extremely heterogeneous disease both biologically and clinically. Although significant progress has been made in identifying molecular and genetic markers for NB, this disease remains an enigmatic challenge. Since NB is thought to be an embryonal tumor that is derived from precursor cells of the peripheral (sympathetic) nervous system, understanding the development of normal sympathetic nervous system may highlight abnormal events that contribute to NB initiation. Therefore, this review focuses on the development of the peripheral trunk neural crest, the current understanding of how developmental factors may contribute to NB and on recent advances in the identification of important genetic lesions and signaling pathways involved in NB tumorigenesis and metastasis. Finally, we discuss how future advances in identification of molecular alterations in NB may lead to more effective, less toxic therapies, and improve the prognosis for NB patients.

Section snippets

Clinical and Biological Characteristics of Neuroblastoma (NB)

NB is the most common extracranial solid tumor in childhood, accounting for approximately 7–10% of pediatric cancers and 15% of all pediatric cancer deaths in patients less than 15 years old (Brodeur, 2003, Maris et al., 2007, Schor, 1999). NB is an extremely heterogeneous disease both biologically and clinically (Brodeur, 2003, Evans et al., 1971, Maris et al., 2007). NB is thought to be an embryonal tumor that is derived from precursor cells of the peripheral (sympathetic) nervous system (

Neural crest contribution to sympathetic ganglia and adrenal gland

The majority of NB tumors appear to arise from neural crest-derived cells in the abdomen adjacent to the aorta in the region of the kidney or in the medullary region of the adrenal gland (Brodeur, 2003, Maris et al., 2007). Thus, NB is a sympaticoadrenal lineage neural crest-derived tumor. The neural crest arises from the dorsal region of the closing neural tube beneath the ectoderm (Le Dourin and Kalcheim, 1999). This transient population of cells produces multipotential progenitor cells that

Familial genetic lesions

Hereditary NB is both rare and heterogeneous, accounting for less than 5% of all NBs (Maris et al., 2002). In addition to the known hereditary mutations that are described below, hereditary NB predisposition loci have been mapped to chromosomes 16p12–13 and 4p16 indicating other familiar predisposition mutations may exist, but no genes have been shown to be inactivated or mutated in these regions, to date (Maris et al., 2002, Perri et al., 2002).

The Role of Neurotrophins and Growth Factors in the Development of the Sympathetic Nervous System and in NB

As the neural crest cells migrate to the aorta but prior to reaching the adrenal medulla they begin to express TH which in turn controls the expression of other enzymes needed for catecholamine biosynthesis as described above in Section 2.3. Since NB appears to arise from cells that are transformed at various times during this migration, the majority of NB tumors secrete catecholamines. Indeed, the presence of high levels of catecholamines in patient urine samples is used as one of the

The role of cell death in development

Another important process during development of the peripheral nervous system is PCD, also known as apoptosis. This process is used during development to eliminate redundant cells, control cell number, and for remodeling and repair. Cell death also occurs in the developing peripheral nervous system in response to loss of essential growth factors and cytokines (De Zio et al., 2005). Neural crest development therefore is a balance between proliferation, cell death, migration, and differentiation.

EMT in development

Although greater than 50% of all NB patients present with metastatic disease, little is known of the process and the mechanism. Microarray mRNA expression analysis studies comparing highly metastatic human NBs (stage 4) to nonmetastatic human tumors (stage 1 and 2) have provided information on some of the proteins that are involved in NB metastasis (Scaruffi et al., 2005). Of note, transcripts encoding proteins related to the developmental program of the epithelial to mesenchymal transition or

The Role of miRNA in Development and NB

miRNAs are endogenous small noncoding RNAs of ~ 22 nucleotides in length that negatively regulate gene expression by mRNA cleavage or translational repression of the target mRNA (Bartel, 2004). miRNAs play an important role in regulating most cellular processes, and contribute to the process of tumorigenesis and metastasis (Zhang et al., 2010). miRNA expression profiles have been correlated with prognosis, differentiation, and apoptosis in NB tumors (Chen and Stallings, 2007), suggesting that

Telomerase

Telomerase is a specialized ribonucleoprotein polymerase that synthesizes the TTAGGG telomeric repeats found at the end of chromosomes to maintain the length of the telomere. This enzyme is expressed in germ line cells but not in the majority of somatic cells. Thus, telomeres in somatic cells undergo progressive shortening and eventually lose the ability to protect chromosome ends, resulting in cell senescence and/or death. Increased telomerase expression, which results in unlimited cell

Clinical Treatment Overview

Current treatment for NB consists of surgery, chemotherapy, radiation, and biotherapy. The clinical strategy usually depends on a patient's risk stratification (Table 4.1). For examples, exposure to chemotherapy is generally limited for low risk group patients, whereas, high-risk group patients are treated with multiagent chemotherapy to reduce the overall burden of the disease before the surgical removal of the primary tumor (Haase et al., 1999, Park et al., 2008).

Conclusion

The investigation and identification of genomic abnormalities and gene expression changes has improved the understanding of the molecular basis of biological and clinical characteristics of NBs (summary in Table 4.2, Table 4.3). Although great progress has been made in recent 20 years, much work needs to be done to identify tumor-specific targets for therapy. Also, deeper understanding of the development of normal sympathetic nervous system will help us find the important abnormal events that

Acknowledgments

We apologize to all of our colleagues whose work was either not cited or was cited in a review article. We thank the members of the Lahti lab, especially Judith Hyle, for their input. This work was funded by NIH grants R01 CA067938 to JML, Comprehensive Cancer Center Support Grant P01 CA021765 and the American Syrian Lebanese Associated Charities ALSAC.

References (281)

  • R.P. Castleberry et al.

    The International Neuroblastoma Risk Groups (INRG): A preliminary repor

    Eur. J. Cancer

    (1997)
  • R. Corvi et al.

    Cytogenetic evolution of MYCN and MDM2 amplification in the neuroblastoma LS tumour and its cell line

    Eur. J. Cancer

    (1995)
  • H. Cui et al.

    Linking of N-Myc to death receptor machinery in neuroblastoma cells

    J. Biol. Chem.

    (2005)
  • N.N. Danial et al.

    Cell death: Critical control points

    Cell

    (2004)
  • D. De Zio et al.

    Expanding roles of programmed cell death in mammalian neurodevelopment

    Semin. Cell Dev. Biol.

    (2005)
  • E. Dupin et al.

    Neural crest progenitors and stem cells

    C. R. Biol.

    (2007)
  • C.A. Erickson et al.

    The effects of epidermal growth factor on neural crest cells in tissue culture

    Exp. Cell Res.

    (1987)
  • J.C. Fontaine-Perus et al.

    Differentiation of peptidergic neurones in quail-chick chimaeric embryos

    Cell Differ.

    (1982)
  • H. Gomyo et al.

    A 2-Mb sequence-ready contig map and a novel immunoglobulin superfamily gene IGSF4 in the LOH region of chromosome 11q23.2

    Genomics

    (1999)
  • J. Grenet et al.

    Structure and chromosome localization of the human CASP8 gene

    Gene

    (1999)
  • R.G. Harris et al.

    The expression of the developmentally regulated proto-oncogene Pax-3 is modulated by N-Myc

    J. Biol. Chem.

    (2002)
  • E.S. Henson et al.

    Surviving cell death through epidermal growth factor (EGF) signal transduction pathways: Implications for cancer therapy

    Cell. Signal.

    (2006)
  • M. Abe et al.

    CpG island methylator phenotype is a strong determinant of poor prognosis in neuroblastomas

    Cancer Res.

    (2005)
  • S. Adhikary et al.

    Transcriptional regulation and transformation by Myc proteins

    Nat. Rev. Mol. Cell Biol.

    (2005)
  • N. Alenina et al.

    Specification and differentiation of serotonergic neurons

    Stem Cell Rev.

    (2006)
  • M.A. Almgren et al.

    Nucleoside diphosphate kinase A/nm23-H1 promotes metastasis of NB69-derived human neuroblastoma

    Mol. Cancer Res.

    (2004)
  • C.S. Alvarado et al.

    Natural history and biology of stage A neuroblastoma: A Pediatric Oncology Group Study

    J. Pediatr. Hematol. Oncol.

    (2000)
  • D.J. Anderson

    Molecular control of cell fate in the neural crest: The sympathoadrenal lineage

    Annu. Rev. Neurosci.

    (1993)
  • D.J. Anderson et al.

    Antibody markers identify a common progenitor to sympathetic neurons and chromaffin cells in vivo and reveal the timing of commitment to neuronal differentiation in the sympathoadrenal lineage

    J. Neurosci.

    (1991)
  • K. Ando et al.

    Expression of TSLC1, a candidate tumor suppressor gene mapped to chromosome 11q23, is downregulated in unfavorable neuroblastoma without promoter hypermethylation

    Int. J. Cancer

    (2008)
  • D. Astuti et al.

    RASSF1A promoter region CpG island hypermethylation in phaeochromocytomas and neuroblastoma tumours

    Oncogene

    (2001)
  • S.A. Bader et al.

    Dissociation of suppression of tumorigenicity and differentiation in vitro effected by transfer of single human chromosomes into human neuroblastoma cells

    Cell Growth Differ.

    (1991)
  • B. Banelli et al.

    Expression and methylation of CASP8 in neuroblastoma: Identification of a promoter region

    Nat. Med.

    (2002)
  • S.A. Banerjee et al.

    5' flanking sequences of the rat tyrosine hydroxylase gene target accurate tissue-specific, developmental, and transsynaptic expression in transgenic mice

    J. Neurosci.

    (1992)
  • J.B. Beckwith et al.

    In situ neuroblastomas: A contribution to the natural history of neural crest tumors

    Am. J. Pathol.

    (1963)
  • H.K. Benailly et al.

    PMX2B, a new candidate gene for Hirschsprung's disease

    Clin. Genet.

    (2003)
  • E. Betters et al.

    Analysis of early human neural crest development

    Dev. Biol.

    (2010)
  • A.J. Blaschke et al.

    Programmed cell death is a universal feature of embryonic and postnatal neuroproliferative regions throughout the central nervous system

    J. Comp. Neurol.

    (1998)
  • A.G. Bodnar et al.

    Extension of life-span by introduction of telomerase into normal human cells

    Science

    (1998)
  • J. Bourhis et al.

    Correlation of MDR1 gene expression with chemotherapy in neuroblastoma

    J. Natl. Cancer Inst.

    (1989)
  • N. Bown et al.

    Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma

    N Engl J. Med.

    (1999)
  • C.P. Bracken et al.

    A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition

    Cancer Res.

    (2008)
  • S. Breit et al.

    Suppression of MYC by high expression of NMYC in human neuroblastoma cells

    J. Neurosci. Res.

    (1989)
  • G.M. Brodeur

    Neuroblastoma: Biological insights into a clinical enigma

    Nat. Rev. Cancer

    (2003)
  • G.M. Brodeur et al.

    Trk receptor expression and inhibition in neuroblastomas

    Clin. Cancer Res.

    (2009)
  • M. Bronner-Fraser et al.

    Clonal analysis of the avian neural crest: Migration and maturation of mixed neural crest clones injected into host chicken embryos

    J. Comp. Neurol.

    (1980)
  • H. Caren et al.

    High incidence of DNA mutations and gene amplifications of the ALK gene in advanced sporadic neuroblastoma tumours

    Biochem. J.

    (2008)
  • H. Caron et al.

    Allelic loss of the short arm of chromosome 4 in neuroblastoma suggests a novel tumour suppressor gene locus

    Hum. Genet.

    (1996)
  • V.P. Castle et al.

    Expression of the apoptosis-suppressing protein bcl-2, in neuroblastoma is associated with unfavorable histology and N-myc amplification

    Am. J. Pathol.

    (1993)
  • D. Chambery et al.

    N-myc regulation of type I insulin-like growth factor receptor in a human neuroblastoma cell line

    Cancer Res.

    (1999)

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