Ntype Neuroblastic Cells

In vitro, the predominant neuroblastic (N) cells resemble sympathoadrenoblasts - immature neural/ neuroendocrine precursors, with small rounded cell bodies and neuritic processes that vary widely in number and length. Cells adhere poorly to the under lying substrate but adhere well to each other to form cell clumps (pseudoganglia), achieving high saturation densities in culture (Rettig et al. 1987; Biedler et al. 1997; Spengler et al. 1997). Biochemically, they express proteins for synthesis, binding, and degradation of norepinephrine and acetylcholine (the two major neurotransmitters of the peripheral nervous system), as well as opioid and cholinergic receptors. They express the neuroectodermal stem cell intermediate filament nestin, as well as all three neurofilament proteins and chromogranin A (CgA) and secre-togranin II (Sgll), depending on their degree of differentiation (Biedler et al. 1997; Ross et al. 2002; Thomas 2003). In addition, they express dHAND and HASH-1,transcription factors that are markers of the early stages of neural crest development (Jögi et al. 2002).

Another transcription factor associated with NB and early neuronal development is MYCN (Chap. 4). Expression of the oncoprotein is associated with increased mitosis and a dedifferentiated state in neu-roectodermal cells of the CNS. High-level expression requires a neuroblastic phenotype, as non-neuronal variants do not express the protein even in the cell lines with transcriptionally active, amplified MYCN genes (Spengler et al. 1997).

N-type cells are tumorigenic. They form colonies in soft agar and tumors in mice,with variable degrees of malignancy (Spengler et al. 1997); however,too few MYCN-nonamplified N-type cell lines have been tested to discern a relation between MYCN amplification status and malignant potential.

Experimental protocols can induce N-type cells to differentiate along either a neuronal or a neuroendocrine pathway or de-differentiate to an immature neural crest-like phenotype. Neuronal differentiation following addition of retinoids or cyclic AMP-elevating agents is characterized by decreases in cell division and amounts of CgA and MYCN protein and increases in SgII and neurofilament proteins and in the number and length of neurites (Ross et al. 2002). Neuroendocrine differentiation induced by synthetic glucocorticoids results in cell flattening, increases in CgA and MYCN levels, and decreases in neurite formation, Sgll, and neurofilaments (Ross et al. 2002). Hypoxia has also been shown to affect neuroblastic

Figure 6.1

Phase-contrast photomicrographs of phenotypic cell variants derived from the LA-N-1 (N), SK-N-BE(2) (/), and SMS-KCN (S) neuroblastoma cell lines (magnification X500)

Figure 6.1

Phase-contrast photomicrographs of phenotypic cell variants derived from the LA-N-1 (N), SK-N-BE(2) (/), and SMS-KCN (S) neuroblastoma cell lines (magnification X500)

differentiation. Growth of N-type cells under hypoxic conditions causes decreased expression of neuronal/ neuroendocrine-specific genes (e.g., CgA and neuropeptide Y) and increased expression of genes present in early neural crest development (c-kit, Notch-1, and HES-1) - indicators of de-differentiation (Jogi et al. 2002).

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