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Molecular and Developmental Biology of Neuroblastoma

Akira Nakagawara

Contents

5.1 Neural Crest Development and Neuroblastoma 41

5.1.1 Genes of Neural Development and Molecular Targets of Neuroblastoma 41

5.1.1.1 Bone Morphogenetic Proteins 43

5.1.1.2 MASHl/hASHl 43

5.1.1.3 Phox2a and Phox2b 44

5.2 Molecular Bases of Differentiation and Programmed Cell Death 45

5.2.1 Molecular Aspect of Spontaneous Regression 45

5.2.2 Neurotrophic Factors and Their Receptors 46

5.2.2.1 Neurotrophins and Their Receptors in Neuroblastoma 46

5.2.2.2 Neurotrophin Signaling in Neuroblastoma 46

5.2.2.3 GDNF Family Receptors 48

5.2.2.4 Other Factors and Receptors 48

5.2.3 Functional Role of p53 Family Genes. ... 48

5.2.4 Apoptotic Signals in Neuroblastoma. ... 50

5.3 Conclusions 50

References 51

5.1 Neural Crest Development and Neuroblastoma

Cancer has its own face reflecting the characteristics of the tissue from which it is derived. This can be demonstrated by histopathologic examination, by immunohistochemistry, and/or by in situ hybridization. Recent advances in molecular biology and genetics have also revealed that these morphological distinctions among cancers are associated with differences in gene expression profiles within tumor cell and stromal cell components. Furthermore, the patterns of gene expression unique for each cancer are dictated by genetic abnormalities which have occurred in progenitors of the specific developmental lineage. Neuroblastoma originates from the sympa-thoadrenal lineage, and its biology is closely related to that of normal sympathetic neurons. In this chapter, the molecular and cellular bases for the genesis and biology of neuroblastoma are summarized.

5.1.1 Genes of Neural Development and Molecular Targets of Neuroblastoma

During neural development, neural crest cells migrate and differentiate into several cell lineages, e.g., melanocytes, sensory neurons, enteric ganglion cells, and sympathetic neurons (Fig. 5.1). The first signaling molecules which trigger crest cells to differentiate or migrate are bone morphogenetic proteins (BMPs) and their receptors (Huber et al. 2002). The commitment to differentiate into sympathetic neurons is associated with the transient expression of (a) basic helix-loop-helix transcription factors, e. g., MASH1 (a proneural gene homologous to drosophila achaete-

Neural crest celis

Neural crest celis

Neuroblastoma

Figure 5.1

Neuroblastoma originates from the sympathoadrenal lineage of neural crest. The bone morphogenetic protein (BMP) signals may be important at the early stage of differentiation of neural crest cells.MASH1 (hASH1) may function as one of the key transcription factors which define the direction of differentiation to sympathetic neurons.The other important nuclear factors,e.g., Phox2a, Phox2b, HuD,MYCN, Id2,and p73, may also be involved in the cell-fate determination. Some of those genes are often upregulated or amplified in aggressive neuroblastomas (Nakagawara 2004).At the stage of terminal differentiation of sympathetic neurons followed by programmed cell death,the signals through neuronal tyrosine kinase receptors, e.g., Ret,TrkB,TrkC, and TrkA, are necessary sequentially and/or in a form of crosstalk. The many genes involved in regulation of neuronal terminal differentiation or programmed cell death are often expressed at high levels in favorable neuroblastomas scute), HES1, MYCN, HIF1a and HuD, (b) homeobox genes, e.g., Phox2a and Phox2b, and (c) p73 (a family member of the tumor suppressor gene p53; Naka-gawara 2004). Several lines of investigation support the importance of these genes. MASH1 null mice lack sympathetic ganglion cells (Guillemot et al. 1993). Notch signaling, through its intracellular domain translocation into the nucleus, stimulates the tran-scriptional activation of the HES1 and HES5 genes whose products in turn inhibit transcription of the MASH1 gene (Radtke and Raj 2003). MYCN is indispensable for the normal neural development. It induces Id2 which is a negative regulator of HES1 and pRb, a retinoblastoma suppressor (Lasorella et al. 2000). p73 knockout mice also show abnormalities in cell survival in both the nervous and immune systems (Yang et al. 2000). Gene targeting of HIF2a dis turbs the catecholamine metabolism in sympathetic neurons (Tian et al. 1998). All these genes regulate each other in an orchestrated manner to drive the correct differentiation of neural crest cells into sympathetic neurons.

Further downstream, terminal differentiation to mature sympathetic cells is strongly regulated by the signaling of neurotrophin family members and their receptors (Nakagawara 2001,2004). In addition, other genetic aberrations associated with neuroblas-toma have been mapped to specific genomic regions or genes well known to be important in regulating the normal development of neurons (Nakagawara 2001, 2004). It seems obvious that a relationship should exist between the genetic or biological targets of neu-roblastoma and the key molecules involved in the normal development of neural crest cells.

Figure 5.2

Hedgehog-Gli signaling in neural development and tumorige-nesis. Sonic hedgehog (Hh) signaling activates Gli transcription factors which then induce the target genes important for regulating neural differentiation as well as neuronal tumorigenesis. They include MYCN, cyclin D1, IGF2, and PDGFRa, all of which are known to be players characterizing neuroblastoma biology. T bars show inhibitory interactions. Arrows show positive interactions

5.1.1.1 Bone Morphogenetic Proteins

Bone morphogenetic proteins (BMPs), members of the transforming growth factor-p (TGF-P) superfam-ily, may be the first signal that defines the early phase of differentiation and migration of neural crest cells during development (Oppenheim 1991). The ligand-dependent activation of BMP receptors transduces its signal into the nucleus through the sequential activation of Smad signaling molecules by phosphoryla-tion. Although the role of BMPs in neuroblastoma has long been elusive, Nakamura et al. (2003) have recently reported that SH-SY5Y and RTBM1 neuroblas-toma cell lines are responsive to BMP2 leading to growth arrest and differentiation. Of interest, BMP treatment also induces the downregulation of p53 family members including p53 and p73, as well as their target gene, p21WAF1. In contrast, a similar cyclin-dependent kinase inhibitor, p27KIP1, is markedly induced at the protein level by downregulation of Skp2, a component of its E3 ubiquitin ligase complex. BMP is also a direct transcriptional target of retinoic acid which induces neuroblastoma differentiation (see Chap. 15; Rodriguez-Leon et al. 1999). The DAN fam ily members are inhibitors of BMP, and are also expressed in neuroblastomas (Enomoto et al. 1994). The DAN gene itself, which is mapped to chromosome 1p36,is a transcriptional target of BMP (Nakamura et al. 2003; Shinbo et al. 2002), suggesting that the BMP signaling network may be important in the differentiation and survival of neuroblastoma (Nakamura et al. 2003). The role of other important signals which function during neuronal development, including Sonic Hedgehog (Shh) and Wnt, is less well known in neuroblastoma. Interestingly, the Shh downstream signaling molecule, Gli, can transactivate MYCN and cyclin D1 (Altaba et al. 2004) (Fig. 5.2).

5.1.1.2 MASHl/hASHl

Achaete-Scute homolog-1 (MASH1 in rodents and hASH1 in humans) is a basic helix-loop-helix transcription factor which plays an important role in the early development of neural and neuroendocrine progenitor cells (Ball 2004). Helix-loop-helix proteins include achaete-scute homologs, E proteins, MYCN, Math, NeuroD, neurogenin, Id,and HES. Targeted disruption of MASH1 in mice has led to the absence of

,p RBP-JK/CBF-1 Target genes

HES1, MATH1, NF-kB, Cyclin D1, p21WAF1, Neurogenin

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