Hypoxia Up-Regulates Galectin-3 in Mammary Tumor Progression and Metastasis

Abstract

The tumor microenvironment encompasses several stressful conditions for cancer cells such as hypoxia, oxidative stress and pH alterations. Galectin-3, a well-studied member of the beta-galactoside-binding animal family of lectins has been implicated in multiple steps of metastasis as cell-cell and cell-ECM adhesion, promotion of angiogenesis, cell proliferation and resistance to apoptosis. However, both its aberrantly up- and down-regulated expression was observed in several types of cancer. Thus, the mechanisms that regulate galectin-3 expression in neoplastic settings are not clear. In order to demonstrate the putative role of hypoxia in regulating galectin-3 expression in canine mammary tumors (CMT), in vitro and in vivo studies were performed. In malignant CMT cells, hypoxia was observed to induce expression of galectin-3, a phenomenon that was almost completely prevented by catalase treatment of CMT-U27 cells. Increased galectin-3 expression was confirmed at the mRNA level. Under hypoxic conditions the expression of galectin-3 shifts from a predominant nuclear location to cytoplasmic and membrane expressions. In in vivo studies, galectin-3 was overexpressed in hypoxic areas of primary tumors and well-established metastases. Tumor hypoxia thus up-regulates the expression of galectin-3, which may in turn increase tumor aggressiveness.

An update on angiogenesis modulators with a potential therapeutic role

“…In Her-2 negative breast cancer cells, galectin-3 in concert with Annexin-A 2 modulates the epidermal growth factor receptor pathway which promotes cancer development [146]. In breast tumour development, hypoxia significantly increases production of galectin-3 which seems to be responsible for an aggressive phenotype while in concert with senescent cell-derived growth factors, galectin-3 induces colorectal cancer cells growth [147,148]. Hoffmann et al (2002) have observed that in the eye, Advanced Glycation End Products (AGEs) not only that increase in newly formed blood vessels but also promote proliferation of Müller cells, retinal pigment epithelial cells, and choroidal endothelial cells [149].…”

Possible diagnostic markers for Mucopolysaccharidoses; Cathepsin-D, Galectin-3 and Chitotriosidase

“…Cat-D has spacious substrate specificity at acidic pH which leads to degradation of proteins and composition of mature activated peptides in endosomes (5) . Galectin-3 (Gal-3) is a carbohydrate-binding protein which mediates cell-cell and cell-extracellular matrix (ECM) interactions (6) . Gal-3 is not only an intracellular protein that can be found both in the cytoplasm and nucleus but it is also an extracellular protein that can be present on the cell surface or the extracellular matrix (7) .…”

The Two Faces of Galectin-3: Roles in Various Pathological Conditions

“…It seems that the translocation of Galectin-3 from the cytoplasm to the nucleus of melanoma cells results in a more aggressive phenotype (57). Interestingly, tumour hypoxia upregulates the expression of Galectin-3 and also leads to changes in its subcellular localization (58). Under hypoxic conditions, the expression of Galectin-3 shifts from a nuclear location to cytoplasmic and membranous locations, suggesting that this shift favours resistance to apoptosis and malignancy of mammary tumour cells (58).…”

“…Interestingly, tumour hypoxia upregulates the expression of Galectin-3 and also leads to changes in its subcellular localization (58). Under hypoxic conditions, the expression of Galectin-3 shifts from a nuclear location to cytoplasmic and membranous locations, suggesting that this shift favours resistance to apoptosis and malignancy of mammary tumour cells (58). Circulating Galectin-3 is also increased in the bloodstream of cancer patients.…”