""""""""We are examining the role of the adhesive protein thrombospondin-1 in regulating tumor growth, angiogenesis, and metastasis. These studies examine the direct effects of thrombospondin expression on tumor cells, the role of thrombospondin in neovascularization of tumors, and its role in other tumor cell interactions with endothelium and the host immune response during metastasis. As is the case for many adhesive proteins, thrombospondin has binding sites for several matrix components and binds to several types of cell surface receptors. We have shown that thrombospondin modulates adhesion, proliferation, and migration of several tumor cell lines and inhibits migration and proliferation of endothelial cells. The latter activities account for the anti-angiogenic activity of thrombospondin-1. Thrombospondin-1 also can directly inhibit proliferation of some tumor cell types, including melanoma. Using synthetic peptides and recombinant fragments, we have identified functional sites in thrombospondin-1 that express these activities. Peptide sequences containing the motif Trp-Ser-Xaa-Trp promote cell adhesion, regulate endothelial cell motility and proliferative responses to basic fibroblast growth factor, inhibit melanoma cell proliferation, and induce programmed cell death in endothelial cells but not in breast tumor cells. The ability of these peptides to induce apoptosis of endothelial cells is inhibited by some extracellular matrix survival signals, and so results in a selective cytotoxicity toward endothelial cells on a provisional matrix such as occurs during neovascularization of tumors. The Arg-Phe-Lys sequence in the second type I repeat activates latent TGF-beta, but this activity is not required for inhibition of endothelial cell growth or induction of apoptosis by the thrombospondin peptides. Stable analogs of these peptides were prepared using D-reverse peptides and inhibit tumor growth in animal models of breast cancer. These stable peptide analogs have potential clinical applications in cancer and other diseases associated with abnormal angiogenesis and for regulating wound repair, inflammatory responses, and fibrosis.""""""""
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