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. Novel sulfated glycolipids are expressed on human small cell lung carcinoma cell lines 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 cell 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. Using metabolic labeling, we have demonstrated that T cells express several proteoglycans and release them into the medium. A 120 kDa secreted proteoglycan was identified that binds to TSP1. 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.

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC009174-14
Application #
6756863
Study Section
(LP)
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
MacDonald, Christopher J; Cheng, Robert Y S; Roberts, David D et al. (2009) Modulation of carcinogen metabolism by nitric oxide-aspirin 2 is associated with suppression of DNA damage and DNA adduct formation. J Biol Chem 284:22099-107
Isenberg, Jeff S; Qin, Yan; Maxhimer, Justin B et al. (2009) Thrombospondin-1 and CD47 regulate blood pressure and cardiac responses to vasoactive stress. Matrix Biol 28:110-9
Ridnour, Lisa A; Thomas, Douglas D; Switzer, Christopher et al. (2008) Molecular mechanisms for discrete nitric oxide levels in cancer. Nitric Oxide 19:73-6
Isenberg, Jeff S; Frazier, William A; Krishna, Murali C et al. (2008) Enhancing cardiovascular dynamics by inhibition of thrombospondin-1/CD47 signaling. Curr Drug Targets 9:833-41
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, 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
Ptaszynska, Malgorzata M; Pendrak, Michael L; Bandle, Russell W et al. (2008) Positive feedback between vascular endothelial growth factor-A and autotaxin in ovarian cancer cells. Mol Cancer Res 6:352-63
Isenberg, Jeff S; Maxhimer, Justin B; Powers, Perlita et al. (2008) Treatment of liver ischemia-reperfusion injury by limiting thrombospondin-1/CD47 signaling. Surgery 144:752-61
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
Roberts, D D (2008) Thrombospondins: from structure to therapeutics. Cell Mol Life Sci 65:669-71

Showing the most recent 10 out of 18 publications