Regulation of Tumor Angiogenesis by Syndecan-1

Angiogenesis is the process by which new blood vessels sprout from existing, mature vessels. It is an important process during development and diseases such as diabetic retinopathy, endometriosis and tumorigenesis. Successful tumors are highly dependent on angiogenesis and release potent angiogenic growth factors, including vascular endothelial cell growth factor (VEGF) and fibroblast growth factor (FGF), to promote this process . These two angiogenic factors cause proliferation, migration and chemotaxis of the endothelial cells to the tumor, processes that are closely tied to activity of the α5ß1, αvß3 and/or αvß5 integrins (1,2). However, there are significant differences in the angiogenic programs and responses of the endothelial cells to these two factors. FGF, but not VEGF, reportedly causes expression of the α5ß1 and αvß3 integrins on the newly activated endothelial cells and the response to FGF can be blocked by agents that target these integrins. VEGF, in contrast, does not upregulate these two integrins; rather, it is dependent on the αvß5 integrin. Probably the most critical feature of this collaborative signaling between the growth factors and these integrins is protection from apoptosis (1,2). Endothelial cells proliferating in response to these angiogenic factors are highly susceptible to apoptosis. Thus, compounds that target and disrupt the activation of these two integrins are regarded as promising agents for combating tumorigenesis.

Syndecan-1 (Sdc1) is a cell surface receptor that binds the extracellular matrix via attached heparan sulfate chains. It is implicated in the regulation of heparin-binding growth factors, and more recently, in regulating integrin signaling activity. Our surprising finding is that Sdc1 is a potent regulator of the αvß3 and αvß5 integrins (3-5). Silencing the expression of Sdc1, or, more intriguingly, adding soluble, recombinant ectodomain protein, will disrupt the activation and signaling of both integrins. The regulatory site on the syndecan is in its extracellular protein domain, although we know little else about the mechanism. However, the fact that competing protein can block these two integrins that are critical for the survival of activated endothelial cells suggests a powerful new tool for blocking tumor-induced angiogenesis. This hypothesis is further enhanced by our preliminary finding that although Sdc1 is not expressed by the endothelium of resting blood vessels, its expression is upregulated in endothelial cells undergoing angiogenesis. Indeed, our preliminary in vitro data show that mouse and human endothelial cells that express Sdc1 rely on this receptor for activation of these two integrins, and this is blocked by soluble Sdc1 protein or a peptide derived from the active site in the syndecan that we call “synstatin.”. Understanding this mechanism and devising ways to use exogenous protein or peptides to block it suggests a powerful new tool to simultaneously target both the FGF- and VEGF-mediated angiogenesis pathways.

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