Expression of Angiogenesis Inhibitors

Tumor angiogenesis is regulated by the balance of angiogenesis stimulators and inhibitors produced by tumor cells, the surrounding stoma, and host cells (Bergers and Benjamin 2003). Neuroblastomas are biologically heterogeneous tumors that consist of two main cell populations: neuroblastic/ganglionic cells and Schwann cells. Regulation of angiogenesis by Schwann cells is suggested by the finding that Schwannian stroma rich/stroma dominant tumors are associated with decreased tumor vascularity (Meitar et al. 1996). Further evidence suggests that Schwann cells can influence angiogenesis by producing inhibitors that can induce endothelial cell apop-tosis and inhibit angiogenesis in vivo (Huang et al. 2000).

hibit PDGF activity on stromal cells (Brekken and Sage 2001).

SPARC expression is inversely correlated with the degree of malignant progression in neuroblastoma tumors (Chlenski et al. 2002). In favorable histology Schwannian stroma-rich/stroma-dominant tumors, SPARC was detected in Schwann cells as well as differentiating neuroblast/ganglion cells. In contrast, minimal to no staining for SPARC was observed in Schwannian stroma-poor tumors. SPARC was critical for the anti-angiogenic phenotype of cultured Schwann cells, as the addition of anti-SPARC neutralizing antibodies largely reversed the anti-angiogenic activity of Schwann cell-conditioned media. Furthermore, at concentrations found in Schwann cell-conditioned media, purified SPARC inhibited angiogen-esis and impaired neuroblastoma tumor growth in vivo.

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