Endostatin

Endostatin, a peptide fragment of collagen XVIII, was initially purified from a hemangioendothelioma based on its ability to inhibit endothelial proliferation in vitro and tumor growth in vivo (O'Reilly et al. 1997). Endostatin appears to act by disrupting en-dothelial interactions with anchoring proteins in extracellular matrix (Dixelius et al. 2002; Kim et al. 2000; Rehn et al. 2001). Another report suggests that endostatin may also directly block VEGFR2 signaling (Kim et al. 2002b). Despite these findings, activity of endostatin in murine models of neuroblastoma has not been consistently demonstrated, with groups detecting either modest or no effect on tumor growth

Neuroblastoma Differentiated

Tumor cells Tumor Cells Schwann cells

Neuroblastoma Differentiated

Tumor cells Tumor Cells Schwann cells

Figure 16.1

Model of angiogenesis in neuroblastoma.Tumor cells produce both proangiogenic factors and inhibitors of angiogene-sis.The relative expression of these factors may depend on the differentiation status of the tumor cells. More differentiated tumors may express more angiogenesis inhibitors. Schwann cells produce not only inhibitors of angiogenesis, but also factors,e.g.,neurotrophins (NTs) and pigment epithelium-derived factor (PEDF),that promote differentiation of neuroblastoma tumor cells. VEGF vascular endothelial growth factor, PDGF platelet-derived growth factor, SPARC secreted protein acidic and rich in cysteine, FGFfibroblast growth factor, TGFtransforming growth factor,MMP metalloprotease, TSP thrombospondin, TIMP tissue inhibitor metalloproteinase

(Davidoff et al. 2001a; Jouanneau et al. 2001; Kuroiwa et al. 2001). Davidoff and colleagues report enhancement of a modest anti-tumor effect of endostatin in experimental neuroblastoma by combination of this agent with an immunomodulatory strategy (Davidoff et al. 2001a).

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