NB and Adrenal Medullary Development

During development of human adrenal medullary chromaffin tissue, cells express TH, chromogranin A (CgA), and neuropeptide Y (NPY) within the first 10 weeks of gestation (Cooper et al. 1990). By 26 weeks of gestation, cells co-express delta (a ligand for the notch receptor) but lose NPY expression until after birth when they express p2-microglobulin, the light chain receptor of the major histocompatibility complex, and re-express NPY. A second population of fetal ganglionic neuroblasts develops in the medullary region that expresses HNK-1 but not TH, CgA, or delta (Cooper et al. 1990). The NB cell lines also express these patterns of gene expression indicating that some NB tumors may arise from tumori-genic events occurring at different stages of adrenal medullary cell development (Cooper et al. 1990). Furthermore, NB tumor tissue express patterns of chro-maffin-related genes that correlate with the patterns of gene expression observed during maturation of adrenal medullary chromaffin tissues (Cohen et al. 1990; Cooper et al. 1992).

In vitro studies showed that NB cell lines treated with compounds that raised intracellular cAMP levels stimulated a more neuroendocrine pattern of gene expression, while signal transduction pathways regulated by retinoid receptors stimulated more neuronal gene expression patterns (Gaetano et al. 1991). Oxygen deprivation, as would occur in a necrotic area may cause a hypoxic response and induction of the transcription factor HIF1a. In vitro, the induction of HIF1a leads to decreased expression of more mature neuronal and neuroendocrine markers such as NPY, CgA, and TH, and increased expression of growth factors such as VEGF, IGF-2, and a bHLH transcription factor inhibitor of differentiation, Id-2. These genes are more highly expressed in immature neural crest cells (Jogi et al. 2002), and VEGF (Eggert et al. 2000) is expressed in more immature and aggressive NBs, suggesting that the underlying biologic features of tumor cells are influenced not only by genetic events involved in tumorigenesis but also by their environment.

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