Circulating galectin-3 promotes metastasis by modifying MUC1 localization on cancer cell surface.
Adhesion of circulating tumor cells to the blood vessel endothelium is a critical step in cancer metastasis. We show in this study that galectin-3, the concentration of which is greatly increased in the circulation of cancer patients, increases cancer cell adhesion to macrovascular and microvascular endothelial cells under static and flow conditions, increases transendothelial invasion, and decreases the latency of experimental metastasis in athymic mice. These effects of galectin-3 are shown to be a consequence of its interaction with cancer-associated MUC1, which breaks the "protective shield" of the cell-surface MUC1 by causing MUC1 polarization, leading to exposure of smaller cell-surface adhesion molecules/ligands including CD44 and ligand(s) for E-selectin. Thus, the interaction in the bloodstream of cancer patients between circulating galectin-3 and cancer cells expressing MUC1 bearing the galectin-3 ligand TF (Galbeta1,3GalNAc-) promotes metastasis. This provides insight into the molecular regulation of metastasis and has important implications for the development of novel therapeutic strategies for prevention of metastasis.
Zhao
Qicheng
Q
Gastroenterology Research Unit, School of Clinical Sciences, University of Liverpool, Liverpool, United Kingdom.
Guo
Xiuli
X
Nash
Gerard B
GB
Stone
Philip C
PC
Hilkens
John
J
Rhodes
Jonathan M
JM
Yu
Lu-Gang
LG
D000818:Animals; D002448:Cell Adhesion; D002450:Cell Communication; D045744:Cell Line, Tumor; D002462:Cell Membrane; D016764:Cell Polarity; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D037502:Galectin 3 / Q000097:blood*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018396:Mucin-1 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding
D019040:E-Selectin; D037502:Galectin 3; D018960:Hyaluronan Receptors; C060192:MUC1 protein, human; D018396:Mucin-1
J Clin Invest. 1991 Mar;87(3):1037-45
1999484
Clin Cancer Res. 2000 Apr;6(4):1389-93
10778968
Am J Pathol. 2008 Dec;173(6):1839-52
18988806
Glycoconj J. 2004;19(7-9):543-9
14758078
Clin Exp Metastasis. 2005;22(6):475-83
16320110
Int J Cancer. 2001 Dec 15;94(6):783-91
11745478
Cancer Cell. 2005 Feb;7(2):167-78
15710329
Glycoconj J. 1996 Oct;13(5):693-707
8909996
Cancer Metastasis Rev. 2001;20(3-4):245-77
12085965
Cancer. 2000 Apr 1;88(7):1536-43
10738210
Oral Oncol. 2008 Jan;44(1):86-93
17350328
Trends Cell Biol. 2006 Sep;16(9):467-76
16904320
Gastroenterology. 1994 Feb;106(2):353-61
7905449
J Biol Chem. 2007 Jan 5;282(1):773-81
17090543
Histol Histopathol. 1999 Oct;14(4):1153-8
10506931
Neoplasia. 2006 Nov;8(11):939-48
17132226
J Cell Biol. 1995 Apr;129(1):255-65
7698991
J Biol Chem. 1996 Dec 27;271(52):33325-34
8969192
Glycobiology. 2001 Jul;11(7):587-92
11447138
Gastroenterology. 1998 Aug;115(2):287-96
9679034
Glycoconj J. 1997 Aug;14(5):569-76
9298689
J Biol Chem. 2003 Feb 7;278(6):4127-34
12438311
Cancer Res. 2001 Jun 15;61(12):4851-7
11406562
Cancer Metastasis Rev. 2008 Mar;27(1):75-83
18046511
Clin Exp Metastasis. 2008;25(4):305-24
17906932
Nat Med. 2008 May;14(5):518-27
18438415
Curr Opin Cell Biol. 2003 Oct;15(5):531-8
14519387
Oncology. 2001;61(2):147-55
11528254
Cancer. 1998 Mar 15;82(6):1019-27
9506345
Int J Oncol. 2005 Nov;27(5):1289-97
16211224
Biochemistry. 2002 Aug 6;41(31):9946-61
12146959
Biol Cell. 2004 Mar;96(2):145-51
15050369
Tumour Biol. 1998;19 Suppl 1:35-45
9422087
Trends Biochem Sci. 1992 Sep;17(9):359-63
1412714
J Biol Chem. 1990 Apr 5;265(10):5573-8
2318825
Blood. 2003 Oct 15;102(8):2828-34
12829609
Clin Cancer Res. 2001 Mar;7(3):661-8
11297262
J Cell Biochem. 1996 Mar 15;60(4):538-49
8707893
Acta Oncol. 2007;46(3):316-23
17450466
J Biol Chem. 2004 Jul 9;279(28):29386-90
15169768
Cancer Res. 2004 Aug 15;64(16):5702-11
15313910
Breast Cancer. 2006;13(1):58-63
16518063
Clin Exp Metastasis. 1999 May;17(3):183-92
10432003
Nat Rev Cancer. 2005 Jan;5(1):29-41
15630413
Mol Biol Cell. 1996 Apr;7(4):565-77
8730100
Clin Exp Dermatol. 2006 Jan;31(1):105-9
16309497
Glycoconj J. 2007 Nov;24(8):411-20
17457671
Cancer Res. 1999 Sep 1;59(17):4427-34
10485493