Galectin-3 interaction with Thomsen-Friedenreich disaccharide on cancer-associated MUC1 causes increased cancer cell endothelial adhesion.
Patients with metastatic cancer commonly have increased serum galectin-3 concentrations, but it is not known whether this has any functional implications for cancer progression. We report that MUC1, a large transmembrane mucin protein that is overexpressed and aberrantly glycosylated in epithelial cancer, is a natural ligand for galectin-3. Recombinant galectin-3 at concentrations (0.2-1.0 microg/ml) similar to those found in the sera of patients with metastatic cancer increased adhesion of MUC1-expressing human breast (ZR-75-1) and colon (HT29-5F7) cancer cells to human umbilical vein endothelial cells (HUVEC) by 111% (111 +/- 21%, mean +/- S.D.) and 93% (93 +/- 17%), respectively. Recombinant galectin-3 also increased adhesion to HUVEC of MUC1 transfected HCA1.7+ human breast epithelial cells that express MUC1 bearing the oncofetal Thomsen-Friedenreich antigen (Galbeta1,3 GalNAc-alpha (TF)) but did not affect adhesion of MUC1-negative HCA1.7-cells. MUC1-transfected, Ras-transformed, canine kidney epithelial-like (MDE9.2+) cells, bearing MUC1 that predominantly carries sialyl-TF, only demonstrated an adhesive response to galectin-3 after sialidase pretreatment. Furthermore, galectin-3-mediated adhesion of HCA1.7+ to HUVEC was reduced by O-glycanase pretreatment of the cells to remove TF. Recombinant galectin-3 caused focal disappearance of cell surface MUC1 in HCA1.7+ cells, suggesting clustering of MUC1. Co-incubation with antibodies against E-Selectin or CD44H, but not integrin-beta1, ICAM-1 or VCAM-1, largely abolished the epithelial cell adhesion to HUVEC induced by galectin-3. Thus, galectin-3, by interacting with cancer-associated MUC1 via TF, promotes cancer cell adhesion to endothelium by revealing epithelial adhesion molecules that are otherwise concealed by MUC1. This suggests a critical role for circulating galectin-3 in cancer metastasis and highlights the functional importance of altered cell surface glycosylation in cancer progression.
Yu
Lu-Gang
LG
Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, School of Clinical Science, University of Liverpool, UK. lgyu@liv.ac.uk
Andrews
Nigel
N
Zhao
Qicheng
Q
McKean
Daniel
D
Williams
Jennifer F
JF
Connor
Lucy J
LJ
Gerasimenko
Oleg V
OV
Hilkens
John
J
Hirabayashi
Jun
J
Kasai
Kenichi
K
Rhodes
Jonathan M
JM
D015295:Antigens, Tumor-Associated, Carbohydrate / Q000737:chemistry*; D002448:Cell Adhesion; D004187:Disaccharides / Q000737:chemistry*; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D037502:Galectin 3 / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D019012:Integrin beta1 / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008958:Models, Molecular; D018396:Mucin-1 / Q000737:chemistry*; D009369:Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry
D015295:Antigens, Tumor-Associated, Carbohydrate; D004187:Disaccharides; D037502:Galectin 3; D018960:Hyaluronan Receptors; D019012:Integrin beta1; D018396:Mucin-1; D011994:Recombinant Proteins; D018799:Intercellular Adhesion Molecule-1; C016467:Thomsen-Friedenreich antigen