Neovascularization is a hallmark of cancer progression, in fact, expansion of tumors and metastatic events have been shown to depend on angiogenesis. Consequently the identification of molecules that could specifically block the recruitment and/or growth of capillaries in tumors has propelled investigations in both the academic and private sectors. A few years ago, we cloned two potential angiogenesis inhibitors, these molecules were identified in a search for proteins that harbored the anti-angiogenic motif of thrombospondin-1. In addition to thrombospondin repeats, they also contained metalloproteinase and disintegrin domains and because of this structure, they are named: ADAMTS1 and ADAMTS8. The focus of the preceding proposal was to test the effect or ADAMTS1 in tumor angiogenesis and elucidate its mechanism of action. We found that ADAMTS1 strongly blocks angiogenesis in tumors. While the thrombospondin repeats are required, the metalloprotease domain is essential (but not sufficient) for the suppression of capillary growth. We have subsequently found that ADAMTS1 sheds proteins from the surface of endothelial cells, one of these proteins, syndecan-4 appears to be linked to the anti-tumor and anti-angiogenic properties of ADAMTSI. Removal of syndecan-4 from the surface of carcinoma cells and endothelial cells affects growth factor signaling and anchorage to the extracellular matrix. In addition, shedding of syndecan-4 appears to be needed for diapedesis of inflammatory cells from the blood stream. These results indicate that ADAMTS1 anti-tumor and anti-angiogenic effects rely in its ability to shed syndecan4 and that this function also modulates the recruitment of inflammatory cells to sites of tumor growth. In this renewal, we will pursue the leads from these findings to test the hypothesis that ADAMTS1 is a syndecan-4 sheddase that affects responses to growth factors and that due to its proteolytic activity, ADAMTS1 impacts specific morphogenic events during development and leukocyte recruitment in pathological conditions.
Our specific aims i nclude: (1) To ascertain the significance of syndecan-4 shedding to the anti-angiogenic effects mediated by ADAMTS1; (2) To identify the spectrum of endothelial and epithelial cell surface substrates for ADAMTS1; (3) To further elucidate the physiological role of ADAMTS1 during development, inflammatory conditions and cancer progression. We anticipate that results from these experiments will shed light into the biology of tumor growth and angiogenesis.
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