Anti-cancer Activity and Mechanism of ADAMTS-1 Fragments

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DESCRIPTION (provided by applicant): ADAMTS-1 (A Disintegrin And Metalloproteinase with ThromboSpondin motifs-1) contains the metalloproteinase and thrombospondin type I (TSP-1) like motifs, and plays important roles in organogenesis, tissue remodeling, and tumorigenesis. However, the exact role of ADAMTS-1 and the underlying mechanism of its involvement in tumor growth and metastasis have not been established. We have shown that ADAMTS-1 undergoes auto-proteolytic cleavage and that full- length ADAMTS-1 and the ADAMTS-1 fragments that contain the TSP-1 domains display pro- and anti-tumor activity, respectively. Full-length ADAMTS-1 promotes shedding of heparin-binding EGF (HB-EGF) and amphiregulin (AR) transmembrane precursors, which in turn promote tumor cell proliferation/survival and tumor angiogenesis, suggesting that ADAMTS-1 is an attractive target for cancer therapy. On the contrary, the ADAMTS-1 fragments that contain the TSP-1 domains displayed potent anti-tumor activity and inhibit activity of soluble HB-EGF and AR. We hypothesize that (1) full-length ADAMTS-1 promotes tumor growth and metastasis by enhancing tumor cell proliferation/survival and tumor angiogenesis through shedding/activating HB-EGF and AR transmembrane precursors; (2) ADAMTS-1 binds to its substrates through the spacer domain directly or indirectly via heparin sulfate proteoglycans (HSPGs); (3) the spacer domain of ADAMTS-1 can be used as a dominant negative inhibitor of ADAMTS-1; and (4) anti-tumor activity of the ADAMTS-1 fragments resides in the TSP-1 domains which exert the anti-tumor activity by inhibiting bioactivity of several soluble heparin binding growth factors including HB- EGF and AR. To test these hypotheses, we will determine (1) the regions in the spacer domain of ADAMTS-1 that display dominant negative inhibitory effect and the exact segments in the TSP-1 domains that contain anti-tumor activity; (2) the mechanisms underlying the dominant negative inhibitory effect of the spacer domain and anti-tumor activity of the ADAMTS-1 fragments that contain the TSP-1 domains; and 3) whether the ADAMTS-1 fragments/Fc-fusion proteins/peptides derived from the spacer and the TSP-1 domains can be used as the effective anti-tumor agents. We have established the biochemical, molecular, and cell biology techniques and the in vivo tumor growth and metastasis models that are necessary to carry out the proposed experiments. The results obtained will provide the evidence to support that ADAMTS-1 is an important target for cancer therapy, and that the ADAMTS-1 fragments/peptides have potential to be used as the potent anti- cancer agents.