Galectins as markers of aggressiveness of mouse mammary carcinoma: towards a lectin target therapy of human breast cancer

Abstract

Galectins, beta-galactoside binding proteins, expressed selectively in human breast carcinoma are attractive targets to employ lectin-aimed therapeutics. We examined beta-galactoside binding potency of neoplastic cells using fluorescein-labelled synthetic glycoconjugates as probes for flow cytometry. As a result, surface beta-galactoside binding proteins/galectins were discovered on mouse mammary carcinoma cells in vitro and in vivo unlike non-malignant cells from the several tissues; and asialo-GM1 ganglioside carbohydrate part--containing probe was the most specific one. However, in liver and lung metastatic cells galectins seem to be expressed within cytoplasm and/or nuclei. Galectin expression correlated directly with aggressive tumour potential in the A/Sn transplantable model similar to findings in several human breast carcinoma cell lines. However, galectin expression was reduced during tumour progression in more aggressive forms of spontaneous BLRB mammary carcinomas like it was shown for human breast carcinoma specimens. Analysis of the histopathological data led, however, to the conclusion that galectin expression hardly might be a suitable marker of aggressiveness of heterogeneous mammary carcinomas as the observed level of galectin expression is influenced by the amount of the stroma in a tumour sample and/or probably, galectin expression inversely correlates with tumour aggressiveness during the initial and advanced steps of mammary tumour progression. We conclude that surface beta-galactoside binding proteins/galectins that are selectively expressed during mouse mammary carcinoma progression, similarly to human breast carcinomas, seem to be proper targets for asialo-GM1-vectored cytotoxics and our mouse model system might be a relevant instrument to further test novel modes of anti-breast cancer therapy.

Varied expression and localization of multiple galectins in different cancer cell lines

“…Galectin-1 is expressed in a variety of cell types including breast epithelial, thymic epithelial, endothelial and dendritic cells, macrophages, fibroblasts and bone marrow cells (2,(16)(17)(18)(19)(20). There is an increased galectin-1 expression in many cancer types including colon, breast, ovary and prostate carcinomas and aggressive gliomas, and an increased accumulation of galectin-1 in the stroma surrounding tumors in ovarian and prostate carcinoma (2,(21)(22)(23)(24)(25). Other galectins, specifically galectin-3 and -8, are involved in a variety of cellular and carcinogenic processes similar to galectin-1.…”

Conjugates of polyhedral boron compounds with carbohydrates. 4. hydrolytic stability of carborane–lactose conjugates depends on the structure of a spacer between the carborane cage and sugar moiety

“…5 Malignant transformation often results in the change in lectin composition of the cell surface and is usually accompanied by over-expression of these lectins. 6,7 Conjugates of polyhedral boron compounds with carbohydrates representing ligands of the lectins can serve as promising agents for BNCT. 5 -8 The selection of an oligosaccharide 'vector' suitable for glycotargeting is based on the knowledge of the carbohydratebinding specificity of the tissue in question, which depends on its lectin composition.…”

Synthesis of β-d-galactopyranosylamine derivatives with the terminal amino group in the spacer as mono-, di-, and trivalent ligands of galectins

“…1 This feature of tumor cells was successfully used for targeted delivery of glycoconjugates to breast carcinoma cells. 2 One of accessible ligands of galectins is the disaccharide lactose with the terminal O linked β D galactose residue. Earlier, we developed methods for the synthesis of mono , di , and trivalent ligands of galectins, lactosylamine derivatives, 3,4 and obtained some monovalent glycocon jugates of polyhedral boron compounds (with ortho carboranylacetic acid as an example), 5 which are poten tial agents for boron neutron capture therapy of cancer.…”

“…It is thought that the spacer linking a carbohydrate with a physiologically active compound should be long enough in order not to hinder an interaction of the carbohydrate with the lectin. 8 For this reason, the spacer in compound 1 was lengthened by coupling with N benzyloxycarbonyl glycine (2) in the presence of N,N´´ dicyclohexylcar bodiimide (DCC) and N hydroxysuccinimide (NHS). Hydrogenolysis of the resulting compound 3 gave the monovalent ligand N diglycyl β D galactopyranosyl amine (4) with a spacer consisting of seven atoms with a terminal amino group (Scheme 1).…”