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Circulating tumour cell homotypic aggregation, heterotypic adhesion to and subsequent invasion through the blood vessel wall endothelium are key components in tumour cell haematogenous spreading to remote turnour sites.The molecular mechanisms underlying these key metastatic steps are still not fully understood.Our recent studies have demonstrated that cell surface MUC1, a huge and heavily glycosylated transmembrane mucin protein that is expressed over 10-folds and aberrantly glycosylated in epithelial cancer cells, is a natural ligand of galectin-3 in human cancer cells.Galectin-3 is galactoside-binding protein that is expressed intracellularly and extracellularly in many cell types and shows up to 5-folds increased circulation in the blood of cancer patients than in healthy people.It was revealed that the expression of cell surface MUC 1 has a natural protective effect on epithelial cancer cell homotypic and heterotypic cell-cell interaction by shielding the smaller cell surface adhesion molecules due to its huge size and length on the cell surface.The interaction of cancer-associated MUC1 with galectin-3 induces MUC1 cell surface polarization and the exposure of smaller cell adhesion molecules.This consequently breaks up the shield protection of MUC1 on the cell surface and causes increased cell-cell aggregation, adhesion and trans-endothelial invasion.Thus, MUC1-galectin-3 interaction represents one of the fundamental molecular mechanisms in promoting the spread of disseminated epithelial cancer cells to secondary tumour sites.This novel knowledge will have significant implication in the development of effective therapeutic strategies against metastasis and prognosis.