Angiogenesis represents an emerging therapeutic target which by 2006, is expected to command a market of $1.75 billion. Both stimulators and inhibitors of angiogenesis are being developed. Although inhibitors are primarily being developed for the treatment of cancer, these molecules are also receiving growing attention as a strategy for treating retinal diseases and also inflammatory conditions such as rheumatoid arthritis. The increase in interest in angiogenesis has been mirrored by a constantly expanding repertoire of molecular targets. Most recently, researchers at Thomas Jefferson University have identified endorepellin, an inhibitor of angiogenesis derived from the carboxyl terminus of perlecan. Perlecan is a modular proteoglycan that participates in the formation and maintenance of basement membranes in various organs. Although basement membranes can develop in the absence of perlecan, the majority of the perlecan-deficient mice succumb to intra-pericardial hemorrhages during vasculogenic stages of development. Furthermore perlecan null animals exhibit a high incidence of malformations of the cardiac outflow tract further stressing the key role of perlecan in vasculogenesis. In adult tissues, perlecan is a major heparan sulfate proteoglycan secreted by endothelial cells that can modulate FGF2 and FGF7 receptor binding. Furthermore perlecan plays a critical role in regulating the vascular response to injury in vivo and has been implicated in tumor vascularization. In support of the latter perlecan is highly enriched in various cancer cell lines and human tumors, and blocking the endogenous production of perlecan suppresses autocrine and paracrine functions of FGF2 and impairs tumor cell growth and invasion. The Thomas Jefferson group has recently identified endorepellin, the C-terminal domain of perlecan as the binding site for interactions between the C-terminus of type XVIII collagen (endostatin) and perlecan. This interaction could play a key role in the assembly of basement membranes and, perhaps, in the maintenance of their integrity. Although endogenous endorepellin prevented the anti-angiogenic effects of endostatin (possibly through a dominant negative interaction) it displayed potent anti-angiogenic activity when administered alone to a variety of assay systems. In particular it inhibited endothelial cell migration and adhesion at pico-nanomolar concentrations, and blood vessel growth. Strikingly, endorepellin almost completely blocked the angiogenic activity of highly tumorogenic colon cancer cells. These effects were mirrored by high affinity binding of endorepellin to endothelial cells. As well as binding to endothelial cells, endorepellin also bound to tumor cells and like the former it blocked matrix adhesive properties of tumor cells. These data suggest that endorepellin may be able to prevent the tumor progression both through the blockade of angiogenesis and also through the disruption of tumor:matrix interactions and hence the development of endorepellin may be clinically important. This is further supported by suggestions that therapeutic peptides do not induce resistance, and their toxicity is low. Finally, it is important to note that perlecan is highly expressed in cartilage and it may therefore play a role in the pathophysiology of rheumatoid arthritis.

January, 2003

Adapted from Mongiat et al, J Biol Chem 2002 Nov 14