| Aberrant glycosylation typically accompanies the transformation of normal cells into tumor cells. A longstanding observation has been the correlation between sialylated Lewis blood group antigen expression and carcinoma progression. The selectin adhesion molecules expressed on vasculature cells recognize mucin-type glycoproteins that contain such sialyl Lewis structures. Structural studies on the mucin-type of selectin ligands failed to show that unique oligosaccharide sequences are solely responsible for physiological high affinity binding. Biochemical characterizations of various L-selectin binding mucins, including cancer mucins, suggested that only the combination of the appropriate oligosaccharide sequences and their unique presentations on a protein backbone can generate the L-selectin ligand. Interestingly, all three selectins recognized the cancer mucins from the colon cancer cell line, LS180. Immunohistochemical analysis of primary colon cancer tissues showed that all three selectins stained both cell surface and secreted mucins in a calcium dependent manner. The staining was heterogeneous, and regions positive for any one selectin did not co-localize with those of the others. Affinity chromatography with immobilized selectin molecules and competition studies between the three selectins for the mucin molecules showed that the binding sites for each selectins are almost completely separate. To investigate the biological consequences of selectin-cancer mucin interactions, mice deficient in P-selectin were used for in vivo metastasis experiments. P-selectin null mutants had significantly slower tumor growth rate of human colon cancer cells, less seeding to the lung, and fewer lung metastasis. Tumors on some P-selectin mutant animals temporarily regressed. Finally, cancer mucins were shown to facilitate platelet aggregation in a P-selectin dependent manner, suggesting that P-selectin-cancer mucin interactions may mediate tumor embolization that can promote metastatic seeding. |
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