MODULATION OF TUMOR PROGRESSION BY GLYCOSYLATED TRIPLE‐HELICAL LIGANDS

Abstract

Specific tumor cell interactions with basement membrane (type IV) or fibrillar (types I–III) collagen have been shown previously to represent a regulatory step in metastasis [Nat. Rev. Cancer 3, 422 (2003)]. Interestingly, numerous tumor cell receptors, such as integrins, CD44 proteoglycan, and DDR Tyr kinases, bind sites within distinct triple-helical regions of collagen that are glycosylated. The present study has refined methodology for constructing galactosylated hydroxylysine [Hyl(O-β-D-galactopyranosyl)]-containing triple-helical ligands, and utilized these ligands to evaluate binding and activation of (a) α2β 1 and α3β 1 integrins by α1(IV)382–393 and α1(V)531–543, respectively, (b) CD44/CSPG by α1(IV)1263–1277, and (c) DDR2 by α1(I)79–93. The possible effect of glycosylation on ligand conformation, and hence the correlation of structure with activity, has been studied by CD spectroscopy. Initial results showed that glycosylation significantly decreased CD44-mediated adhesion and spreading of melanoma cells [J. Biol. Chem. 278, 14321 (2003)]. This was the first demonstration of the prophylactic effects of glycosylation on tumor cell interaction with the basement membrane, and suggested a possible cryptic sites mechanism associated with tumor cell invasion.