CELLULAR INTERACTIONS WITH THROMBOSPONDIN

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Our objective is to understand the role of the adhesive protein thrombospondin in regulating tumor cell adhesion, growth, motility, and 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 promotes adhesion and migration of melanoma and several other tumor cell lines and modulates migration and proliferation of endothelial cells. We found that at least two domains of thrombospondin are required for these activities and that thrombospondin interacts with both protein and sulfated glycoconjugate receptors on cell membranes. Using synthetic peptides and recombinant fragments, we have identified three functional sites including a novel adhesive sequence in the type I repeats of thrombospondin that mimics the activities of the whole molecule for regulating cell adhesion, migration and proliferation. Recently, we have also identified specific sequences in thrombospondin that activate latent TGF-beta or inhibit its activation by intact thrombospondin. These peptides have potential clinical applications in cancer and other diseases associated with abnormal angiogenesis and in regulating wound repair, inflammatory responses, and fibrosis. We are developing experimental approaches to understand the molecular mechanisms of these multiple interactions of cells with thrombospondin and the cellular responses they elicit. We are interested in 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 during metastasis.