Galectins: Double-edged Swords in the Cross-roads of Pregnancy Complications and Female Reproductive Tract Inflammation and Neoplasia

Abstract

Galectins are an evolutionarily ancient and widely expressed family of lectins that have unique glycan-binding characteristics. They are pleiotropic regulators of key biological processes, such as cell growth, proliferation, differentiation, apoptosis, signal transduction, and pre-mRNA splicing, as well as homo- and heterotypic cell-cell and cell-extracellular matrix interactions. Galectins are also pivotal in immune responses since they regulate host-pathogen interactions, innate and adaptive immune responses, acute and chronic inflammation, and immune tolerance. Some galectins are also central to the regulation of angiogenesis, cell migration and invasion. Expression and functional data provide convincing evidence that, due to these functions, galectins play key roles in shared and unique pathways of normal embryonic and placental development as well as oncodevelopmental processes in tumorigenesis. Therefore, galectins may sometimes act as double-edged swords since they have beneficial but also harmful effects for the organism. Recent advances facilitate the use of galectins as biomarkers in obstetrical syndromes and in various malignancies, and their therapeutic applications are also under investigation. This review provides a general overview of galectins and a focused review of this lectin subfamily in the context of inflammation, infection and tumors of the female reproductive tract as well as in normal pregnancies and those complicated by the great obstetrical syndromes.

Keywords: Alarmin; Epigenomics; Maternal-fetal interface; Neoplasms; Sex steroids.

Fig. 1.

Galectins in inflammation and infection. The effects and expression changes of galectins in immune cells are depicted around the three-dimensional model of galectin-1 (Protein Data Bank accession number: 1GZW) [35,55]. Galectins’ effects are biological-context and microenvironment dependent and relate to the differentiation or activation status of the cell, the dynamic changes of the glycan partners of galectins on cell surfaces, the redox and oligomerization status of the galectin, or its intracellular or extracellular localization. ECM, extracellular matrix; HIV-1, human immunodeficiency virus 1; iNOS, inducible nitric oxide synthase; IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; NK, natural killer; TNF, tumor necrosis factor. Parts of the figure are adapted from Than et al. Trends Endocrinol Metab 2012; 23: 23-31, with permission of Elsevier [16].

Fig. 2.

Galectins in neoplasia of the female reproductive tract. The functional effects of various galectins in tumorigenesis and their expression changes in certain types of female tract neoplasia are depicted. The effects of galectins are biological-context and microenvironment dependent. Galectins’ expression changes can be different according to the stage and type of various neoplasia as well as the type of the expressing cell. DC, dendritic cell.

Fig. 3.

Physiological aspects of galectins at the maternal-fetal interface. The figure represents multiple roles of galectins in implantation, angiogenesis, maternal-fetal immune tolerance and trophoblast invasion. (A) Embryo implantation. (B) Formation of primary villi by proliferative cytotrophoblasts. (C) Formation of tertiary villi, placental angiogenesis, extravillous trophoblast invasion and spiral artery remodeling. AE, amniotic epithelium; CCT, cell column trophoblast; DC, dendritic cell; DF, decidual fibroblast; EB, embryoblast; EC, endothelial cell; ECM, extracellular matrix; EM, extraembryonic mesoderm; eCTB, endovascular cytotrophoblast; GC, giant cell; ICM, inner cell mass, iCTB, interstitial cytotrophoblast; LUE, luminal uterine epithelium; L, lacunae; MMP, matrix metalloproteinase; NK, natural killer; pF, placental fibroblast; PS, primitive syncytium; pV, placental vessel; SA, spiral artery; S, syncytium; SMC, smooth muscle cell; TE, trophectoderm; UG, uterine gland; uNK, uterine NK cell; UV, uterine vessel; vCTB, villous cytotrophoblast. Cartoons are adapted from Knofler and Pollheimer. Front Genet 2013; 4: 190, under the terms of the Creative Commons Attribution License [217].

Fig. 4.

Galectin expression at the maternal-fetal interface. The figure represents the maternal-fetal interfaces where maternal and fetal cells appose each other from the end of the first trimester of human pregnancy. The villous syncytiotrophoblast (depicted with gold) is bathed in maternal blood, whereas invasive extravillous trophoblasts in the placental bed (depicted in red) and chorionic trophoblasts in the fetal membranes (depicted in red) are in contact with maternal cells in the decidua (depicted in dark blue). The differential expression of galectins is depicted according to the interface where observed in normal pregnancy and in pregnancy complications. Sy., syndrome, Cartoon was adapted from Than et al. Trends Endocrinol Metab 2012; 23: 23-31, with permission of Elsevier [16].