Apoptotic Signals in Neuroblastoma

To date, the spontaneous regression of neuroblas-toma,has occurred only in vivo. Although this makes the analysis difficult, there are some important reports. An anti-apoptotic protein, Bcl-2, is expressed in primary neuroblastomas and neuroblastoma cell lines. The expression levels of Bcl-2 and Bcl-XL are high in aggressive tumor cells but are low in regressing cells (Ikeda et al. 1995; Ikegaki et al. 1995). Cas-pase-1 and caspase-3 are expressed at significantly higher levels in favorable neuroblastomas (Naka-gawara et al. 1997), and caspase-8 is silenced in aggressive neuroblastomas by the methylation of its promoter as one of mechanisms (Teitz et al. 2000). Silencing of caspase-8 is observed in 25-35% of primary neuroblastomas with a high frequency in more aggressive tumors (Teitz et al. 2000; Eggert et al. 2001; van Noesel et al. 2003). Survivin, a member of the inhibitors of apoptosis protein (IAP), is mapped to the long arm of chromosome 17. In neuroblastoma, survivin is highly expressed in high-risk tumors, and its overexpression inhibits cellular apoptosis (Islam et al. 2000). Kitanaka et al. (2002) have recently reported an interesting observation that "autophagy" may be involved in the regression of neuroblastoma cells.

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