Angiogenesis Inhibitors in Breast Cancer.

摘要

ADAMTSl is a secreted metalloprotease with a disintegrin-like motif and three type-1 thrombospondin domains. ADAMTS1 has been shown to inhibit both endothelial cell proliferation in vitro, as well as angiogenesis in vivo. However, inactivation of the catalytic domain of this protease suppressed its inhibitory activity. Hence, it was important to identify substrates for ADAMTS1 to gain insight into its mechanism of action. We have identified Thrombospondin- 1 (TSP-1) as a novel substrate of ADAMTS-1. This study demonstrated that incubation of TSP-1 with ADAMTS-1 results in a single cleavage adjacent to the procollagen homology domain. Proteolysis by ADANTS-1 releases a C-terminal fragment from a trimerized N-terminal fragment. Analysis of TSP-1 within T47D breast carcinoma tumors reveals that ADAMTS-1 is able to cleave TSP-1 in vivo. Studies using recombinant TSP-1 fragments demonstrated that such fragments are active and possess anti-migratory, anti-proliferative activity (Hizie and Murphy-Ulirich, 2004; Iruela-Arispe et al., 1999; Murphy-Ulirich et al., 1993). We predict that cleavage of TSP-1 by ADAMTS-1 results in the release of bioactive TSP fragments with the potential to suppress angiogenesis. Overall these findings predict an additional mechanism for the inhibitory effects of ADAMTS-1 in tumor angiogenesis.