Our objective is to understand the role of the adhesive protein thrombospondin-1 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. The latter activities account for the anti-angiogenic acitivty of thrombospondin-1. Using synthetic peptides and recombinant fragments, we have identified three functional sites in thrombospondin-1. Specific peptide sequences containing the motif Trp-Ser-Xaa-Trp were identified that promote cell adhesion and regulate endothelial cell motility and proliferation. The Arg-Phe-Lys sequence in the second type I repeat activates latent TGF-beta, whereas adjacent peptides inhibit its activation by intact thrombospondin-1. Stable analogs of these peptides inhibit tumor growth in animal models of breast cancer and 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC009172-08
Application #
2464497
Study Section
Special Emphasis Panel (LP)
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
1996
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Isenberg, Jeff S; Yu, Christine; Roberts, David D (2008) Differential effects of ABT-510 and a CD36-binding peptide derived from the type 1 repeats of thrombospondin-1 on fatty acid uptake, nitric oxide signaling, and caspase activation in vascular cells. Biochem Pharmacol 75:875-82
Calzada, Maria J; Kuznetsova, Svetlana A; Sipes, John M et al. (2008) Calcium indirectly regulates immunochemical reactivity and functional activities of the N-domain of thrombospondin-1. Matrix Biol 27:339-51
Isenberg, Jeff S; Romeo, Martin J; Maxhimer, Justin B et al. (2008) Gene silencing of CD47 and antibody ligation of thrombospondin-1 enhance ischemic tissue survival in a porcine model: implications for human disease. Ann Surg 247:860-8
Isenberg, Jeff S; Romeo, Martin J; Yu, Christine et al. (2008) Thrombospondin-1 stimulates platelet aggregation by blocking the antithrombotic activity of nitric oxide/cGMP signaling. Blood 111:613-23
Roberts, D D (2008) Thrombospondins: from structure to therapeutics. Cell Mol Life Sci 65:669-71
Isenberg, Jeff S; Pappan, Loretta K; Romeo, Martin J et al. (2008) Blockade of thrombospondin-1-CD47 interactions prevents necrosis of full thickness skin grafts. Ann Surg 247:180-90
Kuznetsova, Svetlana A; Mahoney, David J; Martin-Manso, Gema et al. (2008) TSG-6 binds via its CUB_C domain to the cell-binding domain of fibronectin and increases fibronectin matrix assembly. Matrix Biol 27:201-10
Isenberg, Jeff S; Hyodo, Fuminori; Ridnour, Lisa A et al. (2008) Thrombospondin 1 and vasoactive agents indirectly alter tumor blood flow. Neoplasia 10:886-96
Isenberg, J S; Frazier, W A; Roberts, D D (2008) Thrombospondin-1: a physiological regulator of nitric oxide signaling. Cell Mol Life Sci 65:728-42
Isenberg, Jeff S; Roberts, David D; Frazier, William A (2008) CD47: a new target in cardiovascular therapy. Arterioscler Thromb Vasc Biol 28:615-21

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