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 g/ml) similar to those found in the sera of patients with metastatic cancer increased adhesion of MUC1-expressing human breast ( Galectin-3 is one of 15 known members of the galectin family of naturally occurring galactoside-binding lectins that are expressed intracellularly and extracellularly by many cell types (1). Galectin-3 concentrations are increased up to 5-fold in the sera of patients with breast, gastrointestinal, or lung cancer (2). Moreover, higher galectin-3 concentrations are seen in the sera of patients with metastatic disease than in the sera of patients with localized tumors (2). The source of increased circulating galectin-3 in cancer patients is not clear, but it is probably generated by tumor cells as well as by peritumoral inflammatory and stromal cells (2). It is not known whether this increased circulating galectin-3 has any functional implications for cancer progression.Cytoplasmic galectin-3 is known to be anti-apoptotic (3), whereas nuclear galectin-3 promotes pre-mRNA splicing (4, 5). Cell surface galectin-3 is involved in various cell-cell and cellmatrix interactions (1, 6, 7) and enhances cancer cell adhesion to and invasion through basement membrane by interacting with extracellular matrix proteins such as fibronectin, collagen, or laminin (1,8,9). Galectin-3 expressed on the endothelial cell surface has been shown to promote the adhesion of breast cancer cells to endothelium by interaction with cancer-associated Thomsen-Friedenreich (galactose 1,3N-acetylgalactosamine ␣Ϫ (TF)) 2 antigen expressed by unknown cell surface molecules (10 -14). TF antigen is the core I structure of mucin-type O-linked glycans, but in its simplest nonsialylated, nonextended form it acts as an oncofetal antigen, and its presence/expression is increased in malignant and premalignant epithelia (15).MUC1 (also known as episialin and DF3) is a large (M r Ͼ 250,000) transmembrane mucin protein expressed on the apical surface of most normal secretory epithelia including those in the mammary gland, and the gastrointestinal, respiratory, urinary, and reproductive tracts. The MUC1 extracellular domain consists of variable numbers of 20-amino acid tandem repeat peptides (VNTR) that are rich in serines, threonines, and prolines. These tandem repeat domains are heavily glycosylated
BackgroundFormation of tumour cell aggregation/emboli prolongs the survival of circulating tumour cells in the circulation, enhances their physical trapping in the micro-vasculature and thus increases metastatic spread of the cancer cells to remote sites.ResultsIt shows here that the presence of the galactoside-binding galectin-3, whose concentration is markedly increased in the blood circulation of cancer patients, increases cancer cell homotypic aggregation under anchorage-independent conditions by interaction with the oncofetal Thomsen-Friedenreich carbohydrate (Galβ1,3GalNAcα-, TF) antigen on the cancer-associated transmembrane mucin protein MUC1. The galectin-3-MUC1 interaction induces MUC1 cell surface polarization and exposure of the cell surface adhesion molecules including E-cadherin. The enhanced cancer cell homotypic aggregation by galectin-MUC1 interaction increases the survival of the tumour cells under anchorage-independent conditions by allowing them to avoid initiation of anoikis (suspension-induced apoptosis).ConclusionThese results suggest that the interaction between free circulating galectin-3 and cancer-associated MUC1 promotes embolus formation and survival of disseminating tumour cells in the circulation. This provides new information into our understanding of the molecular mechanisms of cancer cell haematogenous dissemination and suggests that targeting the interaction of circulating galectin-3 with MUC1 in the circulation may represent an effective therapeutic approach for preventing metastasis.
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 (GalB1,3GalNAc-) 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. [Cancer Res 2009;69(17):6799-806]
Purpose: Adhesion of disseminating tumor cells to the blood vascular endothelium is a pivotal step in metastasis. Previous investigations have shown that galectin-3 concentrations are increased in the bloodstream of patients with cancer and that galectin-3 promotes adhesion of disseminating tumor cells to vascular endothelium in vitro and experimental metastasis in vivo. This study determined the levels of galectin-1, -2, -3, -4, -8, and -9 in the sera of healthy people and patients with colon and breast cancer and assessed the influence of these galectins on cancer-endothelium adhesion.Experimental Design: Serum galectins and auto-anti-MUC1 antibodies were assessed using ELISA and mucin protein (MUC1) glycan microarrays, and cancer-endothelium adhesion was determined using monolayers of human microvascular lung endothelial cells.Results: The levels of serum galectin-2, -3, -4, and -8 were significantly increased up to 31-fold in patients with cancer and, in particular, those with metastases. As previously shown for galectin-3, the presence of these galectins enhances cancer-endothelium adhesion by interaction with the Thomsen-Friedenreich (TF; Galb1,3GalNAca-) disaccharide on cancer-associated MUC1. This causes MUC1 cell surface polarization, thus exposing underlying adhesion molecules that promote cancer-endothelium adhesion. Elevated circulating galectin-2 levels were associated with increased mortality in patients with colorectal cancer, but this association was suppressed when anti-MUC1 antibodies with specificity for the TF epitope of MUC1 were also present in the circulation.Conclusions: Increased circulation of several members of the galectin family is common in patients with cancer and these may, like circulating galectin-3, also be involved in metastasis promotion. Clin Cancer Res; 17(22); 7035-46. Ó2011 AACR.
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