Chapter 4 - The Connections Between Neural Crest Development and Neuroblastoma
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)
- et al.
Marked and independent prognostic significance of the CpG island methylator phenotype in neuroblastomas
Cancer Lett.
(2007) - et al.
Imbalance of the mitochondrial pro- and anti-apoptotic mediators in neuroblastoma tumours with unfavourable biology
Eur. J. Cancer
(2005) - et al.
A bipotential neuroendocrine precursor whose choice of cell fate is determined by NGF and glucocorticoids
Cell
(1986) - et al.
CHD5 is a tumor suppressor at human 1p36
Cell
(2007) MicroRNAs: Genomics, biogenesis, mechanism, and function
Cell
(2004)- et al.
VEGF-mediated survivin expression in neuroblastoma cells
J. Surg. Res.
(2005) - et al.
Mechanisms of caspase activation
Curr. Opin. Cell Biol.
(2003) - et al.
A unified model for apical caspase activation
Mol. Cell
(2003) - et al.
Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma
Cancer Lett.
(2005) Neural crest cell migration in the developing embryo
Trends Cell Biol.
(1993)
The International Neuroblastoma Risk Groups (INRG): A preliminary repor
Eur. J. Cancer
Cytogenetic evolution of MYCN and MDM2 amplification in the neuroblastoma LS tumour and its cell line
Eur. J. Cancer
Linking of N-Myc to death receptor machinery in neuroblastoma cells
J. Biol. Chem.
Cell death: Critical control points
Cell
Expanding roles of programmed cell death in mammalian neurodevelopment
Semin. Cell Dev. Biol.
Neural crest progenitors and stem cells
C. R. Biol.
The effects of epidermal growth factor on neural crest cells in tissue culture
Exp. Cell Res.
Differentiation of peptidergic neurones in quail-chick chimaeric embryos
Cell Differ.
A 2-Mb sequence-ready contig map and a novel immunoglobulin superfamily gene IGSF4 in the LOH region of chromosome 11q23.2
Genomics
Structure and chromosome localization of the human CASP8 gene
Gene
The expression of the developmentally regulated proto-oncogene Pax-3 is modulated by N-Myc
J. Biol. Chem.
Surviving cell death through epidermal growth factor (EGF) signal transduction pathways: Implications for cancer therapy
Cell. Signal.
CpG island methylator phenotype is a strong determinant of poor prognosis in neuroblastomas
Cancer Res.
Transcriptional regulation and transformation by Myc proteins
Nat. Rev. Mol. Cell Biol.
Specification and differentiation of serotonergic neurons
Stem Cell Rev.
Nucleoside diphosphate kinase A/nm23-H1 promotes metastasis of NB69-derived human neuroblastoma
Mol. Cancer Res.
Natural history and biology of stage A neuroblastoma: A Pediatric Oncology Group Study
J. Pediatr. Hematol. Oncol.
Molecular control of cell fate in the neural crest: The sympathoadrenal lineage
Annu. Rev. Neurosci.
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.
Expression of TSLC1, a candidate tumor suppressor gene mapped to chromosome 11q23, is downregulated in unfavorable neuroblastoma without promoter hypermethylation
Int. J. Cancer
RASSF1A promoter region CpG island hypermethylation in phaeochromocytomas and neuroblastoma tumours
Oncogene
Dissociation of suppression of tumorigenicity and differentiation in vitro effected by transfer of single human chromosomes into human neuroblastoma cells
Cell Growth Differ.
Expression and methylation of CASP8 in neuroblastoma: Identification of a promoter region
Nat. Med.
5' flanking sequences of the rat tyrosine hydroxylase gene target accurate tissue-specific, developmental, and transsynaptic expression in transgenic mice
J. Neurosci.
In situ neuroblastomas: A contribution to the natural history of neural crest tumors
Am. J. Pathol.
PMX2B, a new candidate gene for Hirschsprung's disease
Clin. Genet.
Analysis of early human neural crest development
Dev. Biol.
Programmed cell death is a universal feature of embryonic and postnatal neuroproliferative regions throughout the central nervous system
J. Comp. Neurol.
Extension of life-span by introduction of telomerase into normal human cells
Science
Correlation of MDR1 gene expression with chemotherapy in neuroblastoma
J. Natl. Cancer Inst.
Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma
N Engl J. Med.
A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition
Cancer Res.
Suppression of MYC by high expression of NMYC in human neuroblastoma cells
J. Neurosci. Res.
Neuroblastoma: Biological insights into a clinical enigma
Nat. Rev. Cancer
Trk receptor expression and inhibition in neuroblastomas
Clin. Cancer Res.
Clonal analysis of the avian neural crest: Migration and maturation of mixed neural crest clones injected into host chicken embryos
J. Comp. Neurol.
High incidence of DNA mutations and gene amplifications of the ALK gene in advanced sporadic neuroblastoma tumours
Biochem. J.
Allelic loss of the short arm of chromosome 4 in neuroblastoma suggests a novel tumour suppressor gene locus
Hum. Genet.
Expression of the apoptosis-suppressing protein bcl-2, in neuroblastoma is associated with unfavorable histology and N-myc amplification
Am. J. Pathol.
N-myc regulation of type I insulin-like growth factor receptor in a human neuroblastoma cell line
Cancer Res.
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