title: Distinct selectin ligands on colon carcinoma mucins can mediate pathological interactions among platelets, leukocytes, and endothelium.
abstract: Selectins are adhesion molecules that mediate calcium-dependent cell-cell interactions among leukocytes, platelets, and endothelial cells. The naturally occurring vascular ligands for the selectins are mostly mucin-type glycoproteins. Increased expression and altered glycosylation of mucins are known to be prominent features of carcinoma progression. We have previously shown that all three selectins bind to colon carcinoma cell lines in a calcium-dependent fashion and that carcinoma growth and metastasis formation are attenuated in P-selectin-deficient mice. Here we show that the three recombinant soluble selectins recognize ligands within primary colon carcinoma tissue samples. Affinity chromatography showed that the ligands for all three selectins are O-sialoglycoprotease-sensitive mucins that are recognized in a calcium- and sialic acid-dependent manner. Furthermore, there are separate binding sites on the mucins for each selectin, allowing cross-binding of a single mucin molecule by more than one selectin. We also show that the selectin ligands on purified carcinoma mucins can mediate at least four different pathological interactions among platelets, leukocytes, and endothelial cells. These findings could explain some of the adhesive events of blood-borne tumor cells reported to occur with leukocytes, platelets, and endothelial cells, which are believed to play a part in modulating some early events in tumor metastases.
authors.affiliation: Glycobiology Research and Training Center, Division Hematology-Oncology, University of California San Diego, La Jolla, California, USA.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Kim
authors.forename: L
authors.initials: L
authors.lastname: Borsig
authors.forename: H L
authors.initials: HL
authors.lastname: Han
authors.forename: N M
authors.initials: NM
authors.lastname: Varki
authors.forename: A
authors.initials: A
authors.lastname: Varki
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology*; D002118:Calcium / Q000494:pharmacology; D002450:Cell Communication; D002846:Chromatography, Affinity; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D019041:L-Selectin / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009077:Mucins / Q000378:metabolism* / Q000494:pharmacology; D009368:Neoplasm Transplantation; D019007:P-Selectin / Q000378:metabolism; D019087:Selectins / Q000502:physiology*; D013917:Thrombin / Q000378:metabolism
chemical_list: D019040:E-Selectin; D008024:Ligands; D009077:Mucins; D019007:P-Selectin; D019087:Selectins; D019041:L-Selectin; D013917:Thrombin; D002118:Calcium