Research / Clinical Summary

Jeffrey Esko, PhD Professor, Cellular & Molecular Medicine / Medicine Tumor Growth, Invasion & Metastasis Program Contact by Email Visit the Website

Our work has focused on two areas of cancer biology. First, we have continued our development of glycoside decoys for altering glycosylation on the surface of tumor cells as a strategy for inhibiting metastasis. Secondly, we have continued our studies of proteoglycans in tumor formation and have devised strategies for identifying small molecule inhibitors of glycosaminoglycan biosynthesis.

Disaccharide based decoys. Sialyl Lewis X (sLeX) is a cell surface carbohydrate antigen expressed on many carcinomas that facilitates tumor metastasis by binding to the selectin class of cell adhesion receptors located on platelets and endothelia. Patient survival studies after surgical resection of tumors indicate higher mortality for those patients whose tumors express sLeX. Therefore, the development of a pharmacological approach to inhibit sLeX on tumor cells could improve patient survival. Towards this goal, we have developed a metabolic inhibitor of sLeX. In vitro, peracetylated GlcNAc3Gal-O-naphthalenemethanol acts as a primer of oligosaccharide synthesis, diverting the assembly of mucin type oligosaccharides on endogenous glycoproteins. Priming in mouse LLC Lewis lung carcinoma and B16BL6 melanoma cells results in inhibition of tumor cell sLeX expression and a concomitant reduction in adhesion to purified P-selectin. Treated tumor cells in a syngeneic immunocompetent mouse metastasis model have reduced survival, resulting in a reduction in pulmonary metastasis. Furthermore, administration of the compound to mice reduces spontaneous metastatic seeding of the lungs from primary subcutaneous tumors. Analogs have been made that no longer act as primers, but which retain sLeX inhibitory activity. These metabolic inhibitors represent a novel treatment strategy for reducing tumor metastasis and are under development as therapeutic agents in collaboration with Zacharon Pharmaceuticals, Inc (La Jolla, CA).

Endothelial heparan sulfate: A novel target in tumor angiogenesis. During tumor angiogenesis, heparan sulfate proteoglycans facilitates binding of key growth factors to their receptors on the endothelial surface. To examine the role of endothelial heparan sulfate during angiogenesis, we generated mice bearing an endothelial-targeted deletion in one of the sulfotransferases involved in heparan sulfate biosynthesis (Ndst1). Physiological angiogenesis during cutaneous wound repair was unaffected as was growth and reproductive capacity of the mice. In contrast, pathological angiogenesis in experimental tumors was altered, resulting in significantly smaller tumors and reduced microvascular density and branching. To simulate the angiogenic environment of the tumor, endothelial cells were isolated and propagated in vitro with proangiogenic growth factors. Binding of FGF-2 and VEGF164 to cells and to purified heparan sulfate was dramatically reduced. Mutant endothelial cells also exhibited altered sprouting responses to FGF-2 and VEGF164, reduced Erk phosphorylation, and an increase in apoptosis in branching assays. Corresponding changes in growth factor binding to tumor endothelium and apoptosis were also observed in vivo. These findings demonstrate a cell-autonomous effect of heparan sulfate on endothelial cell growth in the context of tumor angiogenesis and supports endothelial heparan sulfate as a target for future anti-angiogenic therapy.