title: Alterations in human breast cancer adhesion-motility in response to changes in cell surface glycoproteins displaying alpha-L-fucose moieties.
abstract: Glycosylation of proteins plays multiple roles in cell-cell and cell-matrix interactions. Fucose is a monosaccharide associated with glycosylation events and is known to be over-expressed in many malignant tumors. By using alpha-L-fucosidase (alpha-L-fase), a glycosidase that specifically removes alpha-L-fucose (alpha-L-f), we have examined the potential effects of defucosylation on tumor functions, focusing on tumor progression in the context of the interaction of tumor cells with the extracellular microenvironment. In this submission, we report that alpha-L-fase treatment decreases, in static assays, tumor cell adhesion to a wide variety of ECM components including fibronectin, laminin, collagen I, hyaluronic acid and the complex human biomatrix, HuBiogel(R). By immunofluorescence, co-localization of beta1 integrin and alpha-L-f was found to decrease accordingly. Sialyl Lewis X, an alpha-L-f-containing tetrasaccharide, which modulates the rolling of leukocytes and tumor cells on endothelium, was found to be diminished on human breast cancer cells after alpha-L-fase treatment. Using a dynamic flow chamber system, we were able to determine that defucosylation impaired the rolling of mammary cancer cells on human umbilical vein endothelial cells while significantly increasing their flow speed. Further, the rolling capability of these defucosylated tumor cells was also impaired on purified E and P-selectin matrices. Based on these data, we hypothesize that decreased fucosylation impairs the interaction between tumor cells and their external milieu, which in turn, affects key cell functions modulating tumor progression. Building on our previous studies which demonstrated alpha-L-fase decreased tumor cell invasion while significantly reducing MMP-9 activity, when added to the fact that decreased adhesion on HUVEC occurs in the presence of alpha-L-fase also leads us to propose that defucosylation may modulate metastasis, and thus provides a promising additional glycobiotic target for novel therapies.
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors: Kun
authors: K
authors: Yuan
authors: Dennis
authors: D
authors: Kucik
authors: Raj K
authors: RK
authors: Singh
authors: Catherine M
authors: CM
authors: Listinsky
authors: Jay J
authors: JJ
authors: Listinsky
authors: Gene P
authors: GP
authors: Siegal
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D019040:E-Selectin / Q000032:analysis; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D005643:Fucose / Q000502:physiology*; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D009844:Oligosaccharides / Q000097:blood; D019007:P-Selectin / Q000032:analysis; D000080506:Sialyl Lewis X Antigen; D005644:alpha-L-Fucosidase / Q000494:pharmacology
chemical_list: D019040:E-Selectin; D006023:Glycoproteins; D009844:Oligosaccharides; D019007:P-Selectin; D000080506:Sialyl Lewis X Antigen; D018799:Intercellular Adhesion Molecule-1; D005643:Fucose; D005644:alpha-L-Fucosidase