Transdifferentiation is the process whereby cells change from one unique phenotype into another unique phenotype without going through a develop-mentally less mature stage (Liu and Rao 2003). This process has been reported for cells from all three germ layers and, in particular, for cells of the hematopoietic and neural systems. However, distinguishing de-differentiation/re-differentiation (a two-stage process involving reversion to a more immature stage before expression of the novel phenotype) from transdifferentiation is not easy, especially in heterogeneous populations of cells or those where the intermediate cell type is not readily identifiable (Liu and Rao 2003). In studies with SH-SY5Y (N-type) and SH-EP (S-type), clones of the SK-N-SH cell line, cells with morphological and biochemical features of the other phenotype arose spontaneously and were subcloned (Ross et al. 1995). Of importance, transdifferentiated subclones each have a marker chromosome unique to the clone of origin; therefore,these lines did not arise by clonal selection of pre-existing variants, as has been suggested (Cohen et al. 2003), but represent the conversion to a new cell phenotype. Similar pheno-typic conversions have been seen for the LA-N-1 and SK-N-BE(2) cell lines: N-type LA1-55n arose spontaneously and was cloned from the S-type LA1-5s as were S-type LA1-19Bs cells from the N-type LA1-19n clonal cell line. Likewise, the twice-cloned BE(2)-M17 cell line gave rise to the BE(2)-M17F S-type clone. In all cases, the interconversion/transd-ifferentiation process occurred spontaneously and morphological, biochemical, and cytogenetic criteria were used to confirm the phenotype and cell of origin. Transdifferentiation is very rare and it is the ability to select for the different cell types in culture that has permitted its documentation. Whether the phenomenon observed in NB represents true transdifferentiation or a more complex process involving dedifferentiation followed by differentiation along a second neural crest pathway has not been resolved. Nevertheless, the interconversion of N- and S-type cells in culture would suggest that it may occur in vivo. The evolution of quiescent S-type cells into highly proliferative N or I cells mimics the clinical picture of a rapidly recurrent neuroblastoma following a period of clinical remission.

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