Biological Functions of Iduronic Acid in Chondroitin/Dermatan Sulfate in Tumor and Brain Development

Sammanfattning: Cell behavior such as migration and proliferation, especially during cancer development, are balanced by the surrounding environment. Complex polysaccharides called glycosaminoglycans (GAGs) are part of this environment and they are known to modulate tumor development. One of these GAGs, dermatan/chondroitin sulfate (CS/DS), is attached to proteins either bound to the cell surface or secreted in the extracellular space. CS/DS is a long linear polysaccharide consisting of alternating disaccharide units (i.e. N-acetylgalactosamine and glucuronic acid/iduronic acid). CS/DS is a very dynamic structure, as it can be greatly modified by epimerization and sulfation. Epimerization is catalyzed by two enzymes, DS-epimerase 1 (DS-epi1) and 2 (DS-epi2), resulting in the formation of iduronic acid (IdoA). The aim of this thesis was to investigate the role of iduronic acid in cancer and brain development.
The first part of this thesis gives a general review of the biosynthesis of CS/DS, tumorigenesis and finally intertwines these fields. It also comprises the role of CS/DS in neuritogenesis. The present investigation section presents the potential role of DS-epimerase 1 in tumor biology with emphasis on migration of tumor cells. Downregulation of DS-epi1 in a esophageal cancer cell line results in reduced invasion and migration. This effect was found to be partially mediated by presentation of hepatocyte growth factor to the MET receptor by IdoA. Furthermore, DS-epi1-silenced cells had malfunctioning disassembly of adhesion complexes and abnormal cytoskeleton architecture. During brain development, DS-epi2 is known to be highly expressed. We generated a DS-epi2-deficient mice, which displayed no anatomical, histological or morphological abnormalities in brain.
In summary, this thesis have identified new functions for IdoA in tumor development, which maybe of potential use in generation of novel therapeutics.