Stype Non Neural Cells

In addition to neuroblasts, a second, clearly non-neu-ronal cell type is frequently observed in NB cell lines. Termed S, for "substrate adherent", it exhibits contact inhibition of growth, extensive migration on a substrate, and a limited lifespan in culture. Unlike the clearly defined neuronal lineage of N cells, the biochemical signature of S-type cells is more variable. Studies have identified melanocytic properties (ty-rosinase, melanosomal glycoproteins, and melano-somes), Schwann or glial cell markers (chondroitin sulfate proteoglycans and large amounts of laminins and fibronectin), and/or smooth muscle cell features (alpha-smooth muscle actin and calponin) (Rettig et al. 1987; Tsokos et al. 1987; Jessen and Mirsky 1999;

Sugimoto et al. 2000). All of these lineages are consistent with a neural crest origin for the S cell, as developing crest cells of the trunk give rise to non-neu-ronal Schwann, glial, melanocytic, and smooth muscle cell components in vivo. The presence of nestin in these cells is consistent with the S-cell phenotype as a neuroectodermal precursor of the non-neuronal lineages of the neural crest (Thomas 2003).

S cells differ from N cells in two other aspects. Firstly, S cells display markers for HLA class-I antigens and ß2-microglobulin, which are absent on N-type cells (Rettig et al. 1987). Secondly, unlike N cells, S-type cells will not grow in soft agar or form tumors in nude mice (Biedler et al. 1988; Spengler et al. 1997).

The NB tumors with abundant stroma (stroma-rich) generally have a better prognosis than stroma-poor tumors (Ambros and Ambros 1995; Shimada et al. 1999; Brodeur 2003). The discovery that, in vitro, N and S cells arise from a common precursor suggested that, in vivo, stromal cells could be of tumor origin. One study, using paraffin nonisotopic in situ hybridization, concluded that stromal cells are of nontumor origin, presumably recruited by the neu-roblasts in the tumor (Ambros and Ambros 1995). Subsequent studies, using short-term culture of bone marrow tumor cells or laser-capture microdissection with bicolor fluorescence in situ hybridization, showed that both neuroblasts and Schwann cells had identical genetic markers - strong evidence that they arise from a neoplastic precursor (Valent et al. 1999; Mora et al. 2001). This topic is still under debate.

Equally important is the extent of the interaction between Schwann (or S-type) cells and neuroblastic (or N-type) cells in the survival/proliferation/differentiation of each phenotype. In early experiments, N cells co-cultured with S cells were much more differentiated and grew more slowly (B.A. Spengler and J.L. Biedler, personal communication). Such results are consistent with studies of developing neurons and Schwann cells which show that reciprocal contact determines survival and differentiation (Jessen and Mirsky 1999). Also, conditioned medium from normal Schwann cells in culture increases NB cell survival and differentiation (Kwiatkowski et al. 1998) and contains a potent inhibitor of angiogenesis, thus providing a mechanistic basis for the benign behavior of stroma-rich tumors (Huang et al. 2000).

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