A b s t r a c t a-L-Fucose is a 6-carbon deoxyhexose that is commonly incorporated into human glycoproteins and glycolipids. It is found at the terminal or preterminal positions of many cell-surface oligosaccharide ligandsRecent data suggest that the sugar a-L-fucose is essential for the expression of the fully transformed phenotype in many human cell populations. Evidence for such a role comes from studies of common adenocarcinomas and Hodgkin's disease, as well as certain melanomas, neuroblastomas, and leukemias. a-L-Fucose (hereafter denoted as fucose) is not unique or even specific to malignant tissues; in fact, fucose is incorporated into a variety of molecules, not only in humans, but also across the animal kingdom (including bacteria) and in plants. It would seem unlikely that a molecule so widely distributed should have any particular significance in cancer or other pathologic processes. Research concerned with fucose metabolism has been performed using a broad range of biologic sciences, including not only experimental oncology, but also anatomy, embryology, immunopharmacology, glycobiology, cell-adhesion biochemistry, microbiology, parasitology, and plant physiology. The breadth of studies of fucose, combined with the existence of confusing and evolving terminology among these fields, has not been conducive to the dissemination of significant results across disciplinary boundaries.Several years ago a consistent series of intriguing results was reported from the laboratory of Carolyn Mountford, PhD, one of the pioneers in application of nuclear magnetic resonance methods to human oncology. Mountford and colleagues 1 had obtained evidence, in the form of nuclear magnetic resonance spectra from malignant cells and tissues, suggesting that fucose was detectable in these cells but was limited or undetectable in nonmalignant cells from which they were believed to be derived IFigure II.

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Glycosylation drives critical processes important for mammalian cell-cell and cell-matrix interactions. Alpha-L-fucose (alpha-L-f) is a key monosaccharide component of oligosaccharides that has been found to be overexpressed during tumor progression. Modification of cell surface fucosylation, we hypothesized, alters tumor cell phenotype and function at the end of the neoplastic progression cascade including tumor invasion. Alpha-L-fucosidase (alpha-L-fase) is a glycosidase that specifically removes (alpha-L-f) from oligosaccharide sites. We first verified the effectiveness of the alpha-L-fase to specifically decrease the level of alpha-L-f on the cell surface of several human breast cancer cell lines and also examined the recovery time for these cells to repopulate their surfaces. To investigate the potential effect of defucosylation on tumor functions, we studied the proliferation, and invasion in vitro of human breast cancer MDA-MB-231 cells as the representative cell model. We further examined several fucose-associated molecules previously shown to be involved in tumor progression, including CD44 and CD15 (Lewis X antigen). We found that alpha-L: -fase pretreatment significantly decreased the invasive capability of breast cancer cells. Deoxyfuconojirimycin (DFJ), a specific alpha-L: -fase inhibitor, reversed this effect. After fucosidase treatment, the level of both CD15 and CD44 were found to be reduced as measured by flow cytometry. alpha-L-fase treatment, further, did not affect tumor cell proliferation in vitro under identical experimental conditions. Gelatin zymography of conditioned media from tumor cells treated with alpha-L-fase demonstrated no change in MMP-2 activity while MMP-9 was significantly reduced. In summary, fucose containing glycans were found widely distributed on the cell surface of breast cancer cells and could be effectively removed by alpha-L-fase treatment. This decreased fucosylation, in turn, was seen to impair the interaction between tumor cells and extracellular matrices, and thus affected key cell functions modulating tumor invasion. Further elucidation of the molecular pathways involved in the inhibition of tumor cell invasion may suggest a rationale for the use of glycobiologic therapeutics to deter tumor progression.