Liver metastasis and adhesion to the sinusoidal endothelium by human colon cancer cells is related to mucin carbohydrate chain length.
Mucin production by human colon cancer cells correlates with liver metastasis in animal models, but it is not known which steps in metastasis depend on specific alterations in mucin synthesis. Clonal variants of cell line LS174T selected for differences in mucin core carbohydrate expression have been further characterized biochemically, and tested for their ability to participate in metastasis-related events. LS-C mucin contains truncated carbohydrates enriched for sialyl Tn and these cells bind to basement membrane matrix to a greater extent than LS-B cells. This binding is partially inhibitable by antibody to sialyl Tn. LS-B produces more fully glycosylated mucin and preferentially binds to hepatic sinusoidal endothelial cells and E-selectin through sialylated peripheral mucin-associated carbohydrate structures. Adhesion of LS-B to endothelial cells is inhibited by neutralizing antibody to E-selectin, and inhibition of glycosylation or desialylation of LS-B mucin abrogates binding to E-selectin in vitro. LS-B cells spontaneously metastasized from cecum to liver and colonized the liver of athymic mice after splenic-portal injection to a significantly greater extent than LS-C, suggesting that expression of peripheral mucin carbohydrate structures is most important for metastasis of human colon cancer cells.
Bresalier
R S
RS
Department of Medicine, Henry Ford Health Sciences Center, Detroit, MI 48202, USA. rbresal@mich.com
Byrd
J C
JC
Brodt
P
P
Ogata
S
S
Itzkowitz
S H
SH
Yunker
C K
CK
D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000378:metabolism; D001485:Basement Membrane / Q000378:metabolism; D002241:Carbohydrates / Q000737:chemistry*; D002448:Cell Adhesion; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019040:E-Selectin / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology; D008113:Liver Neoplasms / Q000556:secondary*; D051379:Mice; D009077:Mucins / Q000737:chemistry*; D009362:Neoplasm Metastasis; D014407:Tumor Cells, Cultured
D015295:Antigens, Tumor-Associated, Carbohydrate; D002241:Carbohydrates; D019040:E-Selectin; D009077:Mucins; C055491:sialosyl-Tn antigen