Altered glycosylation of glycolipids, glycoproteins, or proteoglycans are frequently observed in tumor tissues and cultured cancer cell lines. These changes have diagnostic use but also can contribute to the ability of tumor cells to grow, induce neovascularization, metastasize, and avoid host immune surveillance. We are primarily studying sulfated and sialylated glycoconjugates and their interaction with extracellular matrix and cell surface adhesion molecules, including thrombospondin-1, laminin, and apolipoprotein E. Human small cell lung carcinoma cell lines are used to examine expression and function of novel sulfated glycolipids. These glycolipids interact with thrombospondin-1 and contribute to adhesion of SCLC cells on a thrombospondin-1 matrix. Endothelial cell heparan sulfate proteoglycans are used to examine the specificity of thrombospondin-1 for binding to proteoglycans required for signaling by angiogenic growth factors. Heparin oligosaccharides are being used to define the molecular basis for interactions of heparin and heparan sulfate proteoglycans with two binding motifs on the thrombospondin-1 molecule. Inhibitors of these interactions are being tested for effects on angiogenesis and tumor growth. Using heparin and defined heparin oligosaccharides, we demonstrated that inhibition of T cel activation by thrombospondin-1 (TSP1) is mediated in part by heparan sulfate proteoglycans on the T cell surface. Engaging this proteoglycan inhibited CD69 expression on anti-CD3 stimulated T cells. The proteoglycan functions in conjunction with CD47 to antagonize TCR signaling downstream of ZAP70 and LAT but upstream of NF-AT. Glycoconjugates may function both as ligands for cell surface receptors and as inhibitors of other receptor-ligand interactions. To better understand how glycoconjugates could sterically inhibit these interactions we used defined polyethylene glycol oligomers to examine the effects of steric hindrance on receptor interactions of the extracellular matrix protein fibronectin. Controlled modification of fibronectin established conditions to selectively inhibit interactions of fibronectin with a5b1 integrin.
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