Childhood tumors of the nervous system as disorders of normal development

Abstract

Medulloblastoma and neuroblastoma exemplify the current embryonal tumor model. Sonic hedgehog signaling is required for cerebellar development and its dysregulation is implicated in formation of medulloblastoma. The transcription factor Mycn orchestrates proliferation and differentiation of the developing peripheral neural crest. Amplification of the MYCN gene is the predominant marker for aggressive neuroblastoma, and correlates with poor prognosis. Current evidence suggests that Mycn is also the primary executor of Sonic hedgehog signaling in the cerebellum and that the Sonic hedgehog pathway regulates levels of both MYCN mRNA and Mycn protein product independently. Destabilization of Myc through inhibition of phosphoinositide 3-kinase signaling exhibits promise not only in medulloblastoma and neuroblastoma, but in a wide range of Myc-driven tumors.

VIP and PACAP analogs regulate therapeutic targets in high-risk neuroblastoma cells

“…The involvement of MYCN in NB tumorigenesis was demonstrated in transgenic mice overexpressing MYCN in neural crest cells [4]. High expression of the transcription factor MYCN disrupts the cell-cycle exit and terminal differentiation that occurs during normal neuroblast development [5,6]. MYCN also plays an important role in cell invasion by directly or indirectly modulating specific target genes involved in cell adhesion, motility and matrix degradation [7].…”

Embryonal neural tumours and cell death

“…Defects in any of the mechanisms controlling these processes could promote transformation, making developing cells prone to tumourigenesis. During the last years, it has become increasingly clear that paediatric neoplasms of the nervous system are linked to disordered mechanisms of normal development, supporting a model of embryonic tumourigenesis [12]. Compared to adult tumours, embryonal tumours have a dramatically shortened latency period and generally harbour fewer genetic aberrations causing oncogene activation or loss of apoptotic regulators.…”

“…Both Hedgehog and Wnt signalling have been shown to induce expression of MYCN, a transcription factor that is widely expressed in the peripheral neural crest and has critical roles in the regulation of cell cycle progression, differentiation, and apoptosis (discussed below). High MYCN expression stimulates proliferation and migration of neuroblasts, while a reduced expression is associated with terminal differentiation [12]. Amplification of MYCN occurs in a large fraction of highrisk neuroblastoma and is associated with aggressive disease in children and poor clinical outcome [6].…”

Tumor Necrosis Factor α Regulates Responses to Nerve Growth Factor, Promoting Neural Cell Survival but Suppressing Differentiation of Neuroblastoma Cells

“…We examined three types of neural cells: BE(2)-C neuroblastoma cells, HCN-1A-nontransformed neural cells and PC-12 pheochromocytoma cells. Neuroblastoma is a malignancy derived from the sympathetic nervous system (Hoehner et al, 1996), and amplification of the MYCN gene is correlated with poor prognosis of this cancer (Grimmer and Weiss, 2006). The MYCN gene is not amplified in SH-SY5Y cells (Smith et al, 2004), and SH-SY5Y cells show weak tumorigenicity in athymic mice (Walton et al, 2004).…”