title: Chondroitin sulfate glycosaminoglycans as major P-selectin ligands on metastatic breast cancer cell lines.
abstract: The metastatic breast cancer cell line, 4T1, abundantly expresses the oligosaccharide sialylated Lewis x (sLe(x)). SLe(x) oligosaccharide on tumor cells can be recognized by E- and P-selectin, contributing to tumor metastatic process. We observed that both selectins reacted with this cell line. However, contrary to the E-selectin reactivity, which was sLe(x) dependent, P-selectin reactivity with this cell line was sLe(x)-independent. The sLe(x)-Neg variant of the 4T1 cell line with markedly diminished expression of sLe(x) and lack of sLe(a), provided a unique opportunity to characterize P-selectin ligands and their contribution to metastasis in the absence of overlapping selectin ligands and E-selectin binding. We observed that P-selectin binding was Ca(2+)-independent and sulfation-dependent. We found that P-selectin reacted primarily with cell surface chondroitin sulfate (CS) proteoglycans, which were abundantly and stably expressed on the surface of the 4T1 cell line. P-selectin binding to the 4T1 cells was inhibited by heparin and CS glycosaminoglycans (GAGs). Moreover, Heparin administration significantly inhibited experimental lung metastasis. In addition, the data suggest that surface CS GAG chains were involved in P-selectin mediated adhesion of the 4T1 cells to murine platelets and human umbilical vein endothelial cells. The data suggest that CS GAGs are also the major P-selectin-reactive ligands on the surface of human MDA-MET cells. The results warrant conducting clinical studies on the involvement of cell surface CS chains in breast cancer metastasis and evaluation of various CS types and their biosynthetic pathways as target for development of treatment strategies for antimetastatic therapy of this disease.
authors.affiliation: Arkansas Cancer Research Center and Department of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA. karbassi@uams.edu
authors.forename: Behjatolah
authors.initials: B
authors.lastname: Monzavi-Karbassi
authors.forename: J Steven
authors.initials: JS
authors.lastname: Stanley
authors.forename: Leah
authors.initials: L
authors.lastname: Hennings
authors.forename: Fariba
authors.initials: F
authors.lastname: Jousheghany
authors.forename: Cecile
authors.initials: C
authors.lastname: Artaud
authors.forename: Saeid
authors.initials: S
authors.lastname: Shaaf
authors.forename: Thomas
authors.initials: T
authors.lastname: Kieber-Emmons
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane; D002809:Chondroitin Sulfates / Q000032:analysis / Q000378:metabolism*; D005647:Fucosyltransferases / Q000235:genetics; D006025:Glycosaminoglycans / Q000032:analysis / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009844:Oligosaccharides / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism*; D011509:Proteoglycans / Q000032:analysis / Q000378:metabolism; D000080506:Sialyl Lewis X Antigen; D014162:Transfection
chemical_list: D006025:Glycosaminoglycans; D008024:Ligands; D009844:Oligosaccharides; D019007:P-Selectin; D011509:Proteoglycans; D000080506:Sialyl Lewis X Antigen; C038142:chondroitin sulfate glycosaminoglycan; D006493:Heparin; D002809:Chondroitin Sulfates; D005647:Fucosyltransferases; C019818:3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase; D002118:Calcium