Sialylation regulates galectin-3/ligand interplay during mammary tumour progression - a case of targeted uncloaking

Abstract

Galectin-3 is involved both in facilitating detachment of cells from primary tumour sites and favouring cancer cell adhesion and survival to anoikis in the blood stream. The mechanisms behind these apparently contradictory roles of the lectin have not yet been resolved. In order to investigate possible interplays between galectin-3 and its ligands underlying their role in the metastatic process, we examined mucin-1 (MUC1) and epidermal growth factor receptor (EGFR), well-known galectin-3 ligands, as well as galectin-3-binding site expression in a series of spontaneous canine malignant mammary tumours (CMMT) and a metastatic CMMT cell line. Despite the fact that CMMT cells expressed MUC1 and EGFR homogeneously over their plasma membrane, intravascular tumour cells, positive for galectin-3, expressed MUC1 and EGFR in a more focal membrane localization. Moreover, MUC1 overexpression in primary CMMT was present in parallel with down-regulation of galectin-3. Furthermore, in the CMT-U27 cell line, galectin-3 knock-down led to increased MUC1 expression, while MUC1 knock-down led to down-regulation of the lectin. Finally, removal of sialic acid from both CMMT and CMT-U27 xenograft samples exposed galectin-3-ligands throughout the tumour tissue, whereas these ligands were only present in galectin-3-positive invading cells in untreated samples. Interestingly indeed, we show that in vessel-invading cells, there is interaction between galectin-3 and the T antigen in vivo. We therefore hypothesized that loss of galectin-3 and sialylation-related masking of its ligands, in conjunction with their overexpression in specific tumour cell subpopulations, are crucial in regulating adhesive/de-adhesive events in the progression and invasive capacity of metastatic cells.

β-Galactoside α2,6-Sialyltranferase 1 Promotes Transforming Growth Factor-β-mediated Epithelial-Mesenchymal Transition

“…In line with our observations, much of the literature showed that ST6GAL1 promotes cell migration and invasion during cancer progression (28,29). The function of ST6GAL1 in promoting cell migration might be partially mediated through affecting galectin-involved signalings because galectin-3 is highly correlated with cancer malignancy by regulating various biological processes (30,31), and ␣2,6-sialylation of ␤1 integrin could impair their interaction with galectin-3, thereby facilitating cell migration (32). On the other hand, accumulating evidence suggested that ST6GAL1 renders the cells resistant to apoptosis.…”

Galectin-1-mediated cell adhesion, invasion and cell death in human anaplastic large cell lymphoma: Regulatory roles of cell surface glycans

“…Sialylation was reported to regulate interaction between galectin-3 and ligand in tumor cells and the mechanisms are crucial in regulating adhesive and de-adhesive events in the invasive capacity of metastatic cells (26). We hypothesized that the masking effect of ligand by sialylation may be important in cell adhesion and invasion to galectins which are known to deposit in the tumor environment.…”

MUC1 and metastatic cancer

“…This includes the activation of Slug and Snail transcription factors and the as opposed to uniform cell membrane expression, further suggesting a role for MUC1 and EGFR in cell motility. 86 Recently, our laboratory published evidence that MUC1 and EGFR regulate the expression of c-Met, the hepatocyte growth factor/scatter factor receptor. c-Met is a receptor tyrosine kinase that is often upregulated in metastatic cancers and is involved in metastatic progression (reviewed in Peschard).…”