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J. Biol. Chem., Vol. 282, Issue 1, 773-781, January 5, 2007

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Galectin-3 Interaction with Thomsen-Friedenreich Disaccharide on Cancer-associated MUC1 Causes Increased Cancer Cell Endothelial Adhesion^*

Lu-Gang Yu¹, Nigel Andrews, Qicheng Zhao, Daniel McKean, Jennifer F. Williams, Lucy J. Connor, Oleg V. Gerasimenko, John Hilkens^¶, Jun Hirabayashi^||, Kenichi Kasai^||, and Jonathan M. Rhodes

From the Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, School of Clinical Science and the Physiological Laboratory, School of Biomedical Science, University of Liverpool, Liverpool L69 3BX, United Kingdom, the ^¶Division of Tumour Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands, and the ^||Department of Biological Chemistry, Teikyo University, Kanagawa 199-0195, Japan

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 µg/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 (Gal1,3 GalNAc- (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-1, 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.

Received for publication, July 19, 2006 , and in revised form, November 1, 2006.

^* This work was supported by Mizutani Foundation for Glycoscience Grant 040002 (to L.-G. Y. and J. M. R.), Royal Society Grant 21/2768 (to L.-G. Y.), and Cancer Research UK Grant C7596 (to L.-G. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: The Henry Wellcome Laboratory, School of Clinical Science, University of Liverpool, Liverpool L69 3BX, United Kingdom. Tel.: 44-151-7946820; Fax: 44-151-7946825; E-mail: lgyu{at}liv.ac.uk.

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