Upregulation of galectins‐1 and ‐3 in human colon cancer and their role in regulating cell migration

Abstract

To probe the potential contribution of ␤-galactoside-contributing epitopes and receptor proteins (gal-1 and gal-3) to colon malignancy, we first examined the expression of galectins and binding sites in clinical specimens by lectin and immunohistochemistry. Sixty-seven colonic surgical resections were studied, including 10 normal, 10 mild dysplasias, 10 severe dysplasias and 37 cancers. gal-1 and gal-3 were expressed in variable amounts in the epithelial cells and the connective tissue of normal colon. Their expression significantly increased with the degree of dysplasia, suggesting that gal-1 and gal-3 and their binding sites are related to malignant progression, while gal-8 has been associated with suppressor activity. To study the functional aspects, the influence of these galectins on the migration of 4 human colorectal cancer cell lines (HCT-15, LoVo, DLD-1, CoLo201) was studied. In agreement with histopathologic monitoring, these tumor cells were found to produce gal-3, while only Cell-surface epitopes have a conspicuous bearing on cellular features associated with malignancy. The concept that glycans of surface glycoconjugates can function in information storage and transfer by forming a sugar code 1 is supported by the rather ubiquitous presence of endogenous lectins. Since they are located at branch ends, ␤-galactoside-containing epitopes are spatially accessible for such an interaction. This point and the elaborate enzymatic machinery producing these epitopes imply functional relevance of these glycan sections. A complete family of endogenous lectins act as receptors for ␤-galactosides and derivatives; they are referred to as galectins and are involved in the various aspects of tumor biology, including invasion and metastasis. [2][3][4][5][6][7][8] The members of this family share a jelly roll-like folding and a common topology of the CRD with high-sequence homology scores in intermammal comparison, secretion via a nonclassical pathway and interaction with the extracellular glycans of laminins, fibronectins, integrins and other cell-surface components. 4 -9 With respect to colon tumor biology, gal-1 and gal-3 have been investigated histopathologically with different methods and reagents, yielding conflicting results on correlations with tumor progression. 4,10 -12 Two reports on transfected cells and tissue sections underscore the potential relevance of gal-3 for colon cancer metastasis. 10,13 However, the prototype (homodimeric) gal-1 is encountered less frequently in colon cancer. 11,14,15 This indication of functional divergence prompted us to extend the histopathologic monitoring and to use cell models to test in vitro if and to what extent these 2 galectins influence cell migration. Interestingly, the tandem-repeat-type gal-8 has previously been shown to display the features of a tumor suppressor based on cell-migration measurements and immunologic monitoring of expression. 16 Thus, our aims were to shed further light on the role of gal-1 and gal-3 in the biology of human colon cancers, to presen...

Clinical significance of circulating galectins as colorectal cancer markers

“…recent evidence suggests that the interaction between tumor cells and surrounding stroma plays a critical role in tumor growth, invasion, metastasis, angiogenesis, and chemoresistance (29)(30)(31)(32)(33)(34). It has been shown that galectin-1 regulates cell migration and that galectin-1 binding sites are displayed on cell surfaces in most colon cancer cell lines, while only one of them actually expresses galectin-1 (16). taken together, galectin-1 expression by stroma may play a role in colon cancer cell migration via a paracrine mechanism.…”

Nuclear galectin-3 expression is an independent predictive factor of recurrence for adenocarcinoma and squamous cell carcinoma of the lung

“…18 The specificity of the galectin-3 antibody was checked by immunoblotting and ELISA assays with controls to exclude any crossreactivity to other galectins (especially galectin-1, which is abundant in human lungs), as previously detailed. [18][19][20]33 An internal positive control consisted in the expression of galectin-3 (also labeled Mac-2) by alveolar macrophages. The negative control sections were immunostained under the same conditions, but with the omission of the primary antibody.…”

“…15,16 Galectins are involved in cell growth, apoptosis and cell migration features. [17][18][19][20] Of these 14 galectins, galectin-3, a chimera-type galectin, is of special interest since its structure harbors a sugar-combining site, a collagensensitive stalk and a short N-terminated section, acting as a target for phosphorylation. 21 What is particularly intriguing about this sole chimera-type galectin is its presence in nuclear, cytoplasmic and extracellular sites, 22 its ability to interact with a variety of carbohydrate and protein ligands and to form pentamers with unique crosslinking abilities, 23 its strong antiapoptotic activity coupled with the nuclear export of the phosphorylated form (for example in chemotherapeutic treatment), 24 and its effect on promoter activity of cyclin D1, 25 which is a prognostic marker in the adenocarcinoma subgroup of lung carcinomas.…”

Ly6 family member C4.4A binds laminins 1 and 5, associates with galectin‐3 and supports cell migration

“…59 Furthermore, galectin-3 itself can bind LNs, 60 and multimeric galectin-3 complexes are known to influence cell adhesion and migration. Thus, galectin-3 has been shown to reduce migration of colon carcinoma cells 61 and to support migration of breast cancer cells. 62 Previously, galectin-3 was shown to interact with a3b1 and NG2 proteoglycan, with an impact on cell motility.…”