J Pathol Transl Med.  2015 May;49(3):181-208. 10.4132/jptm.2015.02.25.

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

• Than NG
• Romero R
• Balogh A
• Karpati E
• Mastrolia
• Staretz-Chacham O
• Hahn S
• Erez O
• Papp Z
• Kim CJ

• KMID: 2381378
• DOI: http://doi.org/10.4132/jptm.2015.02.25

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.

Keyword

Alarmin; Epigenomics; Maternal-fetal interface; Neoplasms; Sex steroids

MeSH Terms

Apoptosis
Biomarkers
Biological Processes
Carcinogenesis
Cell Movement
Epigenomics
Female
Galectins*
Host-Pathogen Interactions
Humans
Immune Tolerance
Inflammation*
Lectins
Placentation
Pregnancy
Pregnancy Complications*
RNA Precursors
Signal Transduction
Galectins
Lectins
RNA Precursors

Figure

• 

  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].

Reference

1. Apweiler R, Hermjakob H, Sharon N. On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT data-base. Biochim Biophys Acta. 1999; 1473:4–8.

2. Gabius HJ, André S, Kaltner H, Siebert HC. The sugar code: functional lectinomics. Biochim Biophys Acta. 2002; 1572:165–77.

3. Varki A, Cummings RD, Esko JD, et al. Essentials in glycobiology. Cold Spring Harbor: Cold Spring Harbor Laboratory Press;2008.

4. Barondes SH. Bifunctional properties of lectins: lectins redefined. Trends Biochem Sci. 1988; 13:480–2.

5. Hirabayashi J, Kasai K. The family of metazoan metal-independent beta-galactoside-binding lectins: structure, function and molecular evolution. Glycobiology. 1993; 3:297–304.

6. Barondes SH, Cooper DN, Gitt MA, Leffler H. Galectins. Structure and function of a large family of animal lectins. J Biol Chem. 1994; 269:20807–10.

7. Kasai K, Hirabayashi J. Galectins: a family of animal lectins that decipher glycocodes. J Biochem. 1996; 119:1–8.

8. Cummings RD, Liu FT. Galectins. In : Varki A, Cummings R, Esko JD, editors. Essentials of glycobiology. 2nd ed. Cold Spring Harbor: Cold Spring Harbor Laboratory Press;2009. p. 475–88.

9. Cooper DN. Galectinomics: finding themes in complexity. Biochim Biophys Acta. 2002; 1572:209–31.

10. Blois SM, Ilarregui JM, Tometten M, et al. A pivotal role for galectin-1 in fetomaternal tolerance. Nat Med. 2007; 13:1450–7.

11. Rabinovich GA, Toscano MA. Turning ‘sweet’ on immunity: galectin-glycan interactions in immune tolerance and inflammation. Nat Rev Immunol. 2009; 9:338–52.

12. Sato S, St-Pierre C, Bhaumik P, Nieminen J. Galectins in innate immunity: dual functions of host soluble beta-galactoside-binding lectins as damage-associated molecular patterns (DAMPs) and as receptors for pathogen-associated molecular patterns (PAMPs). Immunol Rev. 2009; 230:172–87.

13. Liu FT, Rabinovich GA. Galectins: regulators of acute and chronic inflammation. Ann N Y Acad Sci. 2010; 1183:158–82.

14. Blois SM, Conrad ML, Freitag N, Barrientos G. Galectins in angiogenesis: consequences for gestation. J Reprod Immunol. 2015; 108:33–41.

15. Griffioen AW, Thijssen VL. Galectins in tumor angiogenesis. Ann Transl Med. 2014; 2:90.

16. Than NG, Romero R, Kim CJ, McGowen MR, Papp Z, Wildman DE. Galectins: guardians of eutherian pregnancy at the maternal-fetal interface. Trends Endocrinol Metab. 2012; 23:23–31.

17. Blidner AG, Rabinovich GA. ‘Sweetening’ pregnancy: galectins at the fetomaternal interface. Am J Reprod Immunol. 2013; 69:369–82.

18. Choe YS, Shim C, Choi D, Lee CS, Lee KK, Kim K. Expression of galectin-1 mRNA in the mouse uterus is under the control of ovarian steroids during blastocyst implantation. Mol Reprod Dev. 1997; 48:261–6.

19. Vicovac L, Jankovic’ M, Cuperlovic’ M. Galectin-1 and -3 in cells of the first trimester placental bed. Hum Reprod. 1998; 13:730–5.

20. Koopman LA, Kopcow HD, Rybalov B, et al. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med. 2003; 198:1201–12.

21. Popovici RM, Krause MS, Germeyer A, Strowitzki T, von Wolff M. Galectin-9: a new endometrial epithelial marker for the mid- and late-secretory and decidual phases in humans. J Clin Endocrinol Metab. 2005; 90:6170–6.

22. von Wolff M, Wang X, Gabius HJ, Strowitzki T. Galectin fingerprinting in human endometrium and decidua during the menstrual cycle and in early gestation. Mol Hum Reprod. 2005; 11:189–94.

23. Liu AX, Jin F, Zhang WW, et al. Proteomic analysis on the alteration of protein expression in the placental villous tissue of early pregnancy loss. Biol Reprod. 2006; 75:414–20.

24. Lewis SK, Farmer JL, Burghardt RC, et al. Galectin 15 (LGALS15): a gene uniquely expressed in the uteri of sheep and goats that functions in trophoblast attachment. Biol Reprod. 2007; 77:1027–36.

25. Kopcow HD, Rosetti F, Leung Y, Allan DS, Kutok JL, Strominger JL. T Cell apoptosis at the maternal-fetal interface in early human pregnancy, involvement of galectin-1. Proc Natl Acad Sci U S A. 2008; 105:18472–7.

26. Than NG, Romero R, Erez O, et al. Emergence of hormonal and redox regulation of galectin-1 in placental mammals: implication in maternal-fetal immune tolerance. Proc Natl Acad Sci U S A. 2008; 105:15819–24.

27. Than NG, Romero R, Goodman M, et al. A primate subfamily of galectins expressed at the maternal-fetal interface that promote immune cell death. Proc Natl Acad Sci U S A. 2009; 106:9731–6.

28. Kliman HJ, Sammar M, Grimpel YI, et al. Placental protein 13 and decidual zones of necrosis: an immunologic diversion that may be linked to preeclampsia. Reprod Sci. 2012; 19:16–30.

29. Than NG, Sumegi B, Than GN, Berente Z, Bohn H. Isolation and sequence analysis of a cDNA encoding human placental tissue protein 13 (PP13), a new lysophospholipase, homologue of human eosinophil Charcot-Leyden Crystal protein. Placenta. 1999; 20:703–10.

30. Bozic’ M, Petronijevic’ M, Milenkovic’ S, Atanackovic’ J, Lazic’ J, Vicovac’ L. Galectin-1 and galectin-3 in the trophoblast of the gestational trophoblastic disease. Placenta. 2004; 25:797–802.

31. Than NG, Pick E, Bellyei S, et al. Functional analyses of placental protein 13/galectin-13. Eur J Biochem. 2004; 271:1065–78.

32. Jeschke U, Mayr D, Schiessl B, et al. Expression of galectin-1, -3 (gal-1, gal-3) and the Thomsen-Friedenreich (TF) antigen in normal, IUGR, preeclamptic and HELLP placentas. Placenta. 2007; 28:1165–73.

33. Than NG, Abdul Rahman O, Magenheim R, et al. Placental protein 13 (galectin-13) has decreased placental expression but increased shedding and maternal serum concentrations in patients presenting with preterm pre-eclampsia and HELLP syndrome. Virchows Arch. 2008; 453:387–400.

34. Than NG, Kim SS, Abbas A, et al. Chorioamnionitis and increased galectin-1 expression in PPROM: an anti-inflammatory response in the fetal membranes? Am J Reprod Immunol. 2008; 60:298–311.

35. Than NG, Erez O, Wildman DE, et al. Severe preeclampsia is characterized by increased placental expression of galectin-1. J Matern Fetal Neonatal Med. 2008; 21:429–42.

36. Sekizawa A, Purwosunu Y, Yoshimura S, et al. PP13 mRNA expression in trophoblasts from preeclamptic placentas. Reprod Sci. 2009; 16:408–13.

37. Nhan-Chang CL, Romero R, Tarca AL, et al. Characterization of the transcriptome of chorioamniotic membranes at the site of rupture in spontaneous labor at term. Am J Obstet Gynecol. 2010; 202:462. e1-41.

38. Shankar R, Johnson MP, Williamson NA, et al. Molecular markers of preterm labor in the choriodecidua. Reprod Sci. 2010; 17:297–310.

39. Kolundžic’ N, Bojic’-Trbojevic’ Z, Radojc’ic’ L, Petronijevic’ M, Vic’ovac L. Galectin-8 is expressed by villous and extravillous trophoblast of the human placenta. Placenta. 2011; 32:909–11.

40. Houzelstein D, Goncalves IR, Fadden AJ, et al. Phylogenetic analysis of the vertebrate galectin family. Mol Biol Evol. 2004; 21:1177–87.

41. Burger O, Pick E, Zwickel J, et al. Placental protein 13 (PP-13): effects on cultured trophoblasts, and its detection in human body fluids in normal and pathological pregnancies. Placenta. 2004; 25:608–22.

42. Nicolaides KH, Bindra R, Turan OM, et al. A novel approach to first-trimester screening for early pre-eclampsia combining serum PP-13 and Doppler ultrasound. Ultrasound Obstet Gynecol. 2006; 27:13–7.

43. Chafetz I, Kuhnreich I, Sammar M, et al. First-trimester placental protein 13 screening for preeclampsia and intrauterine growth restriction. Am J Obstet Gynecol. 2007; 197:35. e1-7.

44. Spencer K, Cowans NJ, Chefetz I, Tal J, Meiri H. First-trimester maternal serum PP-13, PAPP-A and second-trimester uterine artery Doppler pulsatility index as markers of pre-eclampsia. Ultrasound Obstet Gynecol. 2007; 29:128–34.

45. Gonen R, Shahar R, Grimpel YI, et al. Placental protein 13 as an early marker for pre-eclampsia: a prospective longitudinal study. BJOG. 2008; 115:1465–72.

46. Huppertz B, Sammar M, Chefetz I, Neumaier-Wagner P, Bartz C, Meiri H. Longitudinal determination of serum placental protein 13 during development of preeclampsia. Fetal Diagn Ther. 2008; 24:230–6.

47. Romero R, Kusanovic JP, Than NG, et al. First-trimester maternal serum PP13 in the risk assessment for preeclampsia. Am J Obstet Gynecol. 2008; 199:122. e1-11.

48. Akolekar R, Syngelaki A, Beta J, Kocylowski R, Nicolaides KH. Maternal serum placental protein 13 at 11-13 weeks of gestation in preeclampsia. Prenat Diagn. 2009; 29:1103–8.

49. Khalil A, Cowans NJ, Spencer K, Goichman S, Meiri H, Harrington K. First-trimester markers for the prediction of pre-eclampsia in women with a-priori high risk. Ultrasound Obstet Gynecol. 2010; 35:671–9.

50. Wortelboer EJ, Koster MP, Cuckle HS, Stoutenbeek PH, Schielen PC, Visser GH. First-trimester placental protein 13 and placental growth factor: markers for identification of women destined to develop early-onset pre-eclampsia. BJOG. 2010; 117:1384–9.

51. Molvarec A, Blois SM, Stenczer B, et al. Peripheral blood galectin-1-expressing T and natural killer cells in normal pregnancy and preeclampsia. Clin Immunol. 2011; 139:48–56.

52. Brewer FC. Binding and cross-linking properties of galectins. Biochim Biophys Acta. 2002; 1572:255–62.

53. Swaminathan GJ, Leonidas DD, Savage MP, Ackerman SJ, Acharya KR. Selective recognition of mannose by the human eosinophil Charcot-Leyden crystal protein (galectin-10): a crystallographic study at 1.8 Å resolution. Biochemistry. 1999; 38:13837–43.

54. Visegrády B, Than NG, Kilár F, Sümegi B, Than GN, Bohn H. Homology modelling and molecular dynamics studies of human placental tissue protein 13 (galectin-13). Protein Eng. 2001; 14:875–80.

55. López-Lucendo MF, Solis’ D, André S, et al. Growth-regulatory human galectin-1: crystallographic characterisation of the structural changes induced by single-site mutations and their impact on the thermodynamics of ligand binding. J Mol Biol. 2004; 343:957–70.

56. Horlacher T, Oberli MA, Werz DB, et al. Determination of carbohydrate-binding preferences of human galectins with carbohydrate microarrays. Chembiochem. 2010; 11:1563–73.

57. Stowell SR, Arthur CM, Dias-Baruffi M, et al. Innate immune lectins kill bacteria expressing blood group antigen. Nat Med. 2010; 16:295–301.

58. Than NG, Romero R, Meiri H, et al. PP13, maternal ABO blood groups and the risk assessment of pregnancy complications. PLoS One. 2011; 6:e21564.

59. Liu FT, Patterson RJ, Wang JL. Intracellular functions of galectins. Biochim Biophys Acta. 2002; 1572:263–73.

60. Camby I, Le Mercier M, Lefranc F, Kiss R. Galectin-1: a small protein with major functions. Glycobiology. 2006; 16:137R–57R.

61. Nickel W. Unconventional secretory routes: direct protein export across the plasma membrane of mammalian cells. Traffic. 2005; 6:607–14.

62. Danielsen EM, Hansen GH. Lipid raft organization and function in brush borders of epithelial cells. Mol Membr Biol. 2006; 23:71–9.

63. Hernandez JD, Baum LG. Ah, sweet mystery of death! Galectins and control of cell fate. Glycobiology. 2002; 12:127R–36R.

64. Balogh A, Pozsgay J, Matkó J, et al. Placental protein 13 (PP13/galectin-13) undergoes lipid raft-associated subcellular redistribution in the syncytiotrophoblast in preterm preeclampsia and HELLP syndrome. Am J Obstet Gynecol. 2011; 205:156. e1-14.

65. Dennis JW, Nabi IR, Demetriou M. Metabolism, cell surface organization, and disease. Cell. 2009; 139:1229–41.

66. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007; 81:1–5.

67. Su AI, Wiltshire T, Batalov S, et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci U S A. 2004; 101:6062–7.

68. Saal I, Nagy N, Lensch M, et al. Human galectin-2: expression profiling by RT-PCR/immunohistochemistry and its introduction as a histochemical tool for ligand localization. Histol Histopathol. 2005; 20:1191–208.

69. Dong M, Ding G, Zhou J, Wang H, Zhao Y, Huang H. The effect of trophoblasts on T lymphocytes: possible regulatory effector molecules: a proteomic analysis. Cell Physiol Biochem. 2008; 21:463–72.

70. Kubach J, Lutter P, Bopp T, et al. Human CD4+CD25+ regulatory T cells: proteome analysis identifies galectin-10 as a novel marker essential for their anergy and suppressive function. Blood. 2007; 110:1550–8.

71. Yang QS, Ying K, Yuan HL, et al. Cloning and expression of a novel human galectin cDNA, predominantly expressed in placenta. Biochim Biophys Acta. 2002; 1574:407–11.

72. Than NG, Romero R, Xu Y, et al. Evolutionary origins of the placental expression of chromosome 19 cluster galectins and their complex dysregulation in preeclampsia. Placenta. 2014; 35:855–65.

73. Vasta GR. Roles of galectins in infection. Nat Rev Microbiol. 2009; 7:424–38.

74. John CM, Jarvis GA, Swanson KV, et al. Galectin-3 binds lactosaminylated lipooligosaccharides from Neisseria gonorrhoeae and is selectively expressed by mucosal epithelial cells that are infected. Cell Microbiol. 2002; 4:649–62.

75. Rabinovich GA, Gruppi A. Galectins as immunoregulators during infectious processes: from microbial invasion to the resolution of the disease. Parasite Immunol. 2005; 27:103–14.

76. Kasamatsu A, Uzawa K, Shimada K, et al. Elevation of galectin-9 as an inflammatory response in the periodontal ligament cells exposed to Porphylomonas gingivalis lipopolysaccharide in vitro and in vivo. Int J Biochem Cell Biol. 2005; 37:397–408.

77. Ouellet M, Mercier S, Pelletier I, et al. Galectin-1 acts as a soluble host factor that promotes HIV-1 infectivity through stabilization of virus attachment to host cells. J Immunol. 2005; 174:4120–6.

78. Fowler M, Thomas RJ, Atherton J, Roberts IS, High NJ. Galectin-3 binds to Helicobacter pylori O-antigen: it is upregulated and rapidly secreted by gastric epithelial cells in response to H. pylori adhesion. Cell Microbiol. 2006; 8:44–54.

79. Gauthier S, Pelletier I, Ouellet M, et al. Induction of galectin-1 expression by HTLV-I Tax and its impact on HTLV-I infectivity. Retrovirology. 2008; 5:105.

80. Okumura CY, Baum LG, Johnson PJ. Galectin-1 on cervical epithelial cells is a receptor for the sexually transmitted human parasite Trichomonas vaginalis. Cell Microbiol. 2008; 10:2078–90.

81. Fichorova RN. Impact of T. vaginalis infection on innate immune responses and reproductive outcome. J Reprod Immunol. 2009; 83:185–9.

82. Hepojoki J, Strandin T, Hetzel U, et al. Acute hantavirus infection induces galectin-3-binding protein. J Gen Virol. 2014; 95(Pt 11):2356–64.

83. Varki A. Nothing in glycobiology makes sense, except in the light of evolution. Cell. 2006; 126:841–5.

84. Mercier S, St-Pierre C, Pelletier I, Ouellet M, Tremblay MJ, Sato S. Galectin-1 promotes HIV-1 infectivity in macrophages through stabilization of viral adsorption. Virology. 2008; 371:121–9.

85. Kim HR, Lin HM, Biliran H, Raz A. Cell cycle arrest and inhibition of anoikis by galectin-3 in human breast epithelial cells. Cancer Res. 1999; 59:4148–54.

86. Ryan CM, Mehlert A, Richardson JM, Ferguson MA, Johnson PJ. Chemical structure of Trichomonas vaginalis surface lipoglycan: a role for short galactose (beta1-4/3) N-acetylglucosamine repeats in host cell interaction. J Biol Chem. 2011; 286:40494–508.

87. Smith LM, Wang M, Zangwill K, Yeh S. Trichomonas vaginalis infection in a premature newborn. J Perinatol. 2002; 22:502–3.

88. Sato S, Ouellet N, Pelletier I, Simard M, Rancourt A, Bergeron MG. Role of galectin-3 as an adhesion molecule for neutrophil extravasation during streptococcal pneumonia. J Immunol. 2002; 168:1813–22.

89. Lebovic DI, Mueller MD, Taylor RN. Immunobiology of endometriosis. Fertil Steril. 2001; 75:1–10.

90. Omwandho CO, Konrad L, Halis G, Oehmke F, Tinneberg HR. Role of TGF-betas in normal human endometrium and endometriosis. Hum Reprod. 2010; 25:101–9.

91. Noël JC, Chapron C, Borghese B, Fayt I, Anaf V. Galectin-3 is overexpressed in various forms of endometriosis. Appl Immunohistochem Mol Morphol. 2011; 19:253–7.

92. Bastón JI, Barañao RI, Ricci AG, et al. Targeting galectin-1-induced angiogenesis mitigates the severity of endometriosis. J Pathol. 2014; 234:329–37.

93. Caserta D, Di Benedetto L, Bordi G, D’Ambrosio A, Moscarini M. Levels of galectin-3 and stimulation expressed gene 2 in the peritoneal fluid of women with endometriosis: a pilot study. Gynecol Endocrinol. 2014; 30:877–80.

94. Vergetaki A, Jeschke U, Vrekoussis T, et al. Galectin-1 overexpression in endometriosis and its regulation by neuropeptides (CRH, UCN) indicating its important role in reproduction and inflammation. PLoS One. 2014; 9:e114229.

95. Chen HL, Liao F, Lin TN, Liu FT. Galectins and neuroinflammation. Adv Neurobiol. 2014; 9:517–42.

96. Borghese B, Vaiman D, Mondon F, et al. Neurotrophins and pain in endometriosis. Gynecol Obstet Fertil. 2010; 38:442–6.

97. Ebrahim AH, Alalawi Z, Mirandola L, et al. Galectins in cancer: carcinogenesis, diagnosis and therapy. Ann Transl Med. 2014; 2:88.

98. Jeschke U, Hutter S, Heublein S, et al. Expression and function of galectins in the endometrium and at the human feto-maternal interface. Placenta. 2013; 34:863–72.

99. Jung EJ, Moon HG, Cho BI, et al. Galectin-1 expression in cancerassociated stromal cells correlates tumor invasiveness and tumor progression in breast cancer. Int J Cancer. 2007; 120:2331–8.

100. Moiseeva EV, Rapoport EM, Bovin NV, et al. Galectins as markers of aggressiveness of mouse mammary carcinoma: towards a lectin target therapy of human breast cancer. Breast Cancer Res Treat. 2005; 91:227–41.

101. Ferrer CM, Reginato MJ. Sticking to sugars at the metastatic site: sialyltransferase ST6GalNAc2 acts as a breast cancer metastasis suppressor. Cancer Discov. 2014; 4:275–7.

102. van den Brule FA, Buicu C, Berchuck A, et al. Expression of the 67-kD laminin receptor, galectin-1, and galectin-3 in advanced human uterine adenocarcinoma. Hum Pathol. 1996; 27:1185–91.

103. Ege CB, Akbulut M, Zekiog˘lu O, Ozdemir N. Investigation of galectin-3 and heparanase in endometrioid and serous carcinomas of the endometrium and correlation with known predictors of survival. Arch Gynecol Obstet. 2011; 284:1231–9.

104. Dalotto-Moreno T, Croci DO, Cerliani JP, et al. Targeting galectin-1 overcomes breast cancer-associated immunosuppression and prevents metastatic disease. Cancer Res. 2013; 73:1107–17.

105. van den Brule F, Califice S, Garnier F, Fernandez PL, Berchuck A, Castronovo V. Galectin-1 accumulation in the ovary carcinoma peritumoral stroma is induced by ovary carcinoma cells and affects both cancer cell proliferation and adhesion to laminin-1 and fibronectin. Lab Invest. 2003; 83:377–86.

106. Kohrenhagen N, Volker HU, Kapp M, Dietl J, Kammerer U. Increased expression of galectin-1 during the progression of cervical neoplasia. Int J Gynecol Cancer. 2006; 16:2018–22.

107. Kim HJ, Do IG, Jeon HK, et al. Galectin 1 expression is associated with tumor invasion and metastasis in stage IB to IIA cervical cancer. Hum Pathol. 2013; 44:62–8.

108. Huang EY, Chanchien CC, Lin H, Wang CC, Wang CJ, Huang CC. Galectin-1 is an independent prognostic factor for local recurrence and survival after definitive radiation therapy for patients with squamous cell carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys. 2013; 87:975–82.

109. Huang EY, Chen YF, Chen YM, et al. A novel radioresistant mechanism of galectin-1 mediated by H-Ras-dependent pathways in cervical cancer cells. Cell Death Dis. 2012; 3:e251.

110. Lee JW, Song SY, Choi JJ, et al. Decreased galectin-3 expression during the progression of cervical neoplasia. J Cancer Res Clin Oncol. 2006; 132:241–7.

111. Logullo AF, Lopes AB, Nonogaki S, et al. C-erbB-2 expression is a better predictor for survival than galectin-3 or p53 in early-stage breast cancer. Oncol Rep. 2007; 18:121–6.

112. Stewart CJ, Crook ML. Galectin-3 expression in uterine endometrioid adenocarcinoma: comparison of staining in conventional tumor glands and in areas of MELF pattern myometrial invasion. Int J Gynecol Pathol. 2010; 29:555–61.

113. Brustmann H, Riss D, Naudé S. Galectin-3 expression in normal, hyperplastic, and neoplastic endometrial tissues. Pathol Res Pract. 2003; 199:151–8.

114. Oishi T, Itamochi H, Kigawa J, et al. Galectin-3 may contribute to cisplatin resistance in clear cell carcinoma of the ovary. Int J Gynecol Cancer. 2007; 17:1040–6.

115. Kim MK, Sung CO, Do IG, et al. Overexpression of galectin-3 and its clinical significance in ovarian carcinoma. Int J Clin Oncol. 2011; 16:352–8.

116. Min KW, Park MH, Hong SR, et al. Clear cell carcinomas of the ovary: a multi-institutional study of 129 cases in Korea with prognostic significance of Emi1 and galectin-3. Int J Gynecol Pathol. 2013; 32:3–14.

117. Lee JH, Zhang X, Shin BK, Lee ES, Kim I. Mac-2 binding protein and galectin-3 expression in mucinous tumours of the ovary: an annealing control primer system and immunohistochemical study. Pathology. 2009; 41:229–33.

118. Dagher SF, Wang JL, Patterson RJ. Identification of galectin-3 as a factor in pre-mRNA splicing. Proc Natl Acad Sci U S A. 1995; 92:1213–7.

119. Honjo Y, Nangia-Makker P, Inohara H, Raz A. Down-regulation of galectin-3 suppresses tumorigenicity of human breast carcinoma cells. Clin Cancer Res. 2001; 7:661–8.

120. Dumic J, Dabelic S, Flögel M. Galectin-3: an open-ended story. Biochim Biophys Acta. 2006; 1760:616–35.

121. Baptiste TA, James A, Saria M, Ochieng J. Mechano-transduction mediated secretion and uptake of galectin-3 in breast carcinoma cells: implications in the extracellular functions of the lectin. Exp Cell Res. 2007; 313:652–64.

122. Yang RY, Hsu DK, Liu FT. Expression of galectin-3 modulates T-cell growth and apoptosis. Proc Natl Acad Sci U S A. 1996; 93:6737–42.

123. Akahani S, Nangia-Makker P, Inohara H, Kim HR, Raz A. Galectin-3: a novel antiapoptotic molecule with a functional BH1 (NWGR) domain of Bcl-2 family. Cancer Res. 1997; 57:5272–6.

124. Matarrese P, Tinari N, Semeraro ML, Natoli C, Iacobelli S, Malorni W. Galectin-3 overexpression protects from cell damage and death by influencing mitochondrial homeostasis. FEBS Lett. 2000; 473:311–5.

125. Moon BK, Lee YJ, Battle P, Jessup JM, Raz A, Kim HR. Galectin-3 protects human breast carcinoma cells against nitric oxide-induced apoptosis: implication of galectin-3 function during metastasis. Am J Pathol. 2001; 159:1055–60.

126. Lin HM, Pestell RG, Raz A, Kim HR. Galectin-3 enhances cyclin D (1) promoter activity through SP1 and a cAMP-responsive element in human breast epithelial cells. Oncogene. 2002; 21:8001–10.

127. Yu F, Finley RL Jr, Raz A, Kim HR. Galectin-3 translocates to the perinuclear membranes and inhibits cytochrome c release from the mitochondria: a role for synexin in galectin-3 translocation. J Biol Chem. 2002; 277:15819–27.

128. Choi JH, Chun KH, Raz A, Lotan R. Inhibition of N-(4-hydroxyphenyl)retinamide-induced apoptosis in breast cancer cells by galectin-3. Cancer Biol Ther. 2004; 3:447–52.

129. Nangia-Makker P, Raz T, Tait L, Hogan V, Fridman R, Raz A. Galectin-3 cleavage: a novel surrogate marker for matrix metalloproteinase activity in growing breast cancers. Cancer Res. 2007; 67:11760–8.

130. Balan V, Nangia-Makker P, Raz A. Galectins as cancer biomarkers. Cancers (Basel). 2010; 2:592–610.

131. Mazurek N, Byrd JC, Sun Y, Ueno S, Bresalier RS. A galectin-3 sequence polymorphism confers TRAIL sensitivity to human breast cancer cells. Cancer. 2011; 117:4375–80.

132. Mazurek N, Sun YJ, Liu KF, et al. Phosphorylated galectin-3 mediates tumor necrosis factor-related apoptosis-inducing ligand signaling by regulating phosphatase and tensin homologue deleted on chromosome 10 in human breast carcinoma cells. J Biol Chem. 2007; 282:21337–48.

133. Guha P, Bandyopadhyaya G, Polumuri SK, et al. Nicotine promotes apoptosis resistance of breast cancer cells and enrichment of side population cells with cancer stem cell-like properties via a signaling cascade involving galectin-3, alpha9 nicotinic acetylcholine receptor and STAT3. Breast Cancer Res Treat. 2014; 145:5–22.

134. Tsai CJ, Sulman EP, Eifel PJ, et al. Galectin-7 levels predict radiation response in squamous cell carcinoma of the cervix. Gynecol Oncol. 2013; 131:645–9.

135. Ueda S, Kuwabara I, Liu FT. Suppression of tumor growth by galectin-7 gene transfer. Cancer Res. 2004; 64:5672–6.

136. Saussez S, Kiss R. Galectin-7. Cell Mol Life Sci. 2006; 63:686–97.

137. Matsui Y, Ueda S, Watanabe J, Kuwabara I, Ogawa O, Nishiyama H. Sensitizing effect of galectin-7 in urothelial cancer to cisplatin through the accumulation of intracellular reactive oxygen species. Cancer Res. 2007; 67:1212–20.

138. St-Pierre Y, Campion CG, Grosset AA. A distinctive role for galectin-7 in cancer? Front Biosci (Landmark Ed). 2012; 17:438–50.

139. Grosset AA, Labrie M, Gagné D, et al. Cytosolic galectin-7 impairs p53 functions and induces chemoresistance in breast cancer cells. BMC Cancer. 2014; 14:801.

140. Campion CG, Labrie M, Lavoie G, St-Pierre Y. Expression of galectin-7 is induced in breast cancer cells by mutant p53. PLoS One. 2013; 8:e72468.

141. Lahm H, Andre S, Hoeflich A, et al. Tumor galectinology: insights into the complex network of a family of endogenous lectins. Glycoconj J. 2004; 20:227–38.

142. Danguy A, Rorive S, Decaestecker C, et al. Immunohistochemical profile of galectin-8 expression in benign and malignant tumors of epithelial, mesenchymatous and adipous origins, and of the nervous system. Histol Histopathol. 2001; 16:861–8.

143. Liang MY, Lu YM, Zhang Y, Zhang SL. Serum galectin-9 in cervical cancer. Zhonghua Yi Xue Za Zhi. 2008; 88:2783–5.

144. Liang CH, Wu CY. Glycan array: a powerful tool for glycomics studies. Expert Rev Proteomics. 2009; 6:631–45.

145. Irie A, Yamauchi A, Kontani K, et al. Galectin-9 as a prognostic factor with antimetastatic potential in breast cancer. Clin Cancer Res. 2005; 11:2962–8.

146. Heusschen R, Griffioen AW, Thijssen VL. Galectin-9 in tumor biology: a jack of multiple trades. Biochim Biophys Acta. 2013; 1836:177–85.

147. Mylonas I, Mayr D, Walzel H, et al. Mucin 1, Thomsen-Friedenreich expression and galectin-1 binding in endometrioid adenocarcinoma: an immunohistochemical analysis. Anticancer Res. 2007; 27:1975–80.

148. Khaldoyanidi SK, Glinsky VV, Sikora L, et al. MDA-MB-435 human breast carcinoma cell homo- and heterotypic adhesion under flow conditions is mediated in part by Thomsen-Friedenreich antigen-galectin-3 interactions. J Biol Chem. 2003; 278:4127–34.

149. Yu LG, Andrews N, Zhao Q, et al. Galectin-3 interaction with Thomsen-Friedenreich disaccharide on cancer-associated MUC1 causes increased cancer cell endothelial adhesion. J Biol Chem. 2007; 282:773–81.

150. Inohara H, Akahani S, Raz A. Galectin-3 stimulates cell proliferation. Exp Cell Res. 1998; 245:294–302.

151. Song L, Tang JW, Owusu L, Sun MZ, Wu J, Zhang J. Galectin-3 in cancer. Clin Chim Acta. 2014; 431:185–91.

152. Zhu H, Wu TC, Chen WQ, et al. Roles of galectin-7 and S100A9 in cervical squamous carcinoma: Clinicopathological and in vitro evidence. Int J Cancer. 2013; 132:1051–9.

153. Park JE, Chang WY, Cho M. Induction of matrix metalloproteinase-9 by galectin-7 through p38 MAPK signaling in HeLa human cervical epithelial adenocarcinoma cells. Oncol Rep. 2009; 22:1373–9.

154. Labrie M, Vladoiu MC, Grosset AA, Gaboury L, St-Pierre Y. Expression and functions of galectin-7 in ovarian cancer. Oncotarget. 2014; 5:7705–21.

155. Demers M, Rose AA, Grosset AA, et al. Overexpression of galectin-7, a myoepithelial cell marker, enhances spontaneous metastasis of breast cancer cells. Am J Pathol. 2010; 176:3023–31.

156. Liu J, Cheng Y, He M, Yao S. Vascular endothelial growth factor C enhances cervical cancer cell invasiveness via upregulation of galectin-3 protein. Gynecol Endocrinol. 2014; 30:461–5.

157. Nangia-Makker P, Wang Y, Raz T, et al. Cleavage of galectin-3 by matrix metalloproteases induces angiogenesis in breast cancer. Int J Cancer. 2010; 127:2530–41.

158. Liu FT, Rabinovich GA. Galectins as modulators of tumour progression. Nat Rev Cancer. 2005; 5:29–41.

159. Chen C, Duckworth CA, Fu B, Pritchard DM, Rhodes JM, Yu LG. Circulating galectins -2, -4 and -8 in cancer patients make important contributions to the increased circulation of several cytokines and chemokines that promote angiogenesis and metastasis. Br J Cancer. 2014; 110:741–52.

160. Fridman WH, Pagès F, Sautès-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012; 12:298–306.

161. Toscano MA, Bianco GA, Ilarregui JM, et al. Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death. Nat Immunol. 2007; 8:825–34.

162. Li H, Wang Y, Zhou F. Effect of ex vivo-expanded γδ-T cells combined with galectin-1 antibody on the growth of human cervical cancer xenografts in SCID mice. Clin Invest Med. 2010; 33:E280–9.

163. Rabinovich GA. Galectin-1 as a potential cancer target. Br J Cancer. 2005; 92:1188–92.

164. Fukumori T, Takenaka Y, Yoshii T, et al. CD29 and CD7 mediate galectin-3-induced type II T-cell apoptosis. Cancer Res. 2003; 63:8302–11.

165. Iurisci I, Tinari N, Natoli C, Angelucci D, Cianchetti E, Iacobelli S. Concentrations of galectin-3 in the sera of normal controls and cancer patients. Clin Cancer Res. 2000; 6:1389–93.

166. Barrow H, Guo X, Wandall HH, et al. Serum galectin-2, -4, and -8 are greatly increased in colon and breast cancer patients and promote cancer cell adhesion to blood vascular endothelium. Clin Cancer Res. 2011; 17:7035–46.

167. Carlsson MC, Balog CI, Kilsgård O, et al. Different fractions of human serum glycoproteins bind galectin-1 or galectin-8, and their ratio may provide a refined biomarker for pathophysiological conditions in cancer and inflammatory disease. Biochim Biophys Acta. 2012; 1820:1366–72.

168. Balasubramanian K, Vasudevamurthy R, Venkateshaiah SU, Thomas A, Vishweshwara A, Dharmesh SM. Galectin-3 in urine of cancer patients: stage and tissue specificity. J Cancer Res Clin Oncol. 2009; 135:355–63.

169. Jerzak M, Bischof P. Apoptosis in the first trimester human placenta: the role in maintaining immune privilege at the maternalfoetal interface and in the trophoblast remodelling. Eur J Obstet Gynecol Reprod Biol. 2002; 100:138–42.

170. Petty HR, Kindzelskii AL, Espinoza J, Romero R. Trophoblast contact deactivates human neutrophils. J Immunol. 2006; 176:3205–14.

171. Moffett A, Loke C. Immunology of placentation in eutherian mammals. Nat Rev Immunol. 2006; 6:584–94.

172. Erlebacher A. Immune surveillance of the maternal/fetal interface: controversies and implications. Trends Endocrinol Metab. 2010; 21:428–34.

173. Mor G, Cardenas I. The immune system in pregnancy: a unique complexity. Am J Reprod Immunol. 2010; 63:425–33.

174. Arck PC, Hecher K. Fetomaternal immune cross-talk and its consequences for maternal and offspring’s health. Nat Med. 2013; 19:548–56.

175. Bianchi DW. Current knowledge about fetal blood cells in the maternal circulation. J Perinat Med. 1998; 26:175–85.

176. Nelson JL. Pregnancy, persistent microchimerism, and autoimmune disease. J Am Med Womens Assoc. 1998; 53:31–2. 47.

177. Lapaire O, Hӧsli I, Zanetti-Daellenbach R, et al. Impact of fetal-maternal microchimerism on women’s health: a review. J Matern Fetal Neonatal Med. 2007; 20:1–5.

178. Redman CW, Sargent IL. Microparticles and immunomodulation in pregnancy and pre-eclampsia. J Reprod Immunol. 2007; 76:61–7.

179. Redman CW, Sargent IL. Circulating microparticles in normal pregnancy and pre-eclampsia. Placenta. 2008; 29 Suppl A:S73–7.

180. Naccasha N, Gervasi MT, Chaiworapongsa T, et al. Phenotypic and metabolic characteristics of monocytes and granulocytes in normal pregnancy and maternal infection. Am J Obstet Gynecol. 2001; 185:1118–23.

181. Hahn S, Giaglis S, Hoesli I, Hasler P. Neutrophil NETs in reproduction: from infertility to preeclampsia and the possibility of fetal loss. Front Immunol. 2012; 3:362.

182. Redman CW, Sacks GP, Sargent IL. Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol. 1999; 180(2 Pt 1):499–506.

183. Gervasi MT, Chaiworapongsa T, Pacora P, et al. Phenotypic and metabolic characteristics of monocytes and granulocytes in preeclampsia. Am J Obstet Gynecol. 2001; 185:792–7.

184. Gervasi MT, Chaiworapongsa T, Naccasha N, et al. Phenotypic and metabolic characteristics of maternal monocytes and granulocytes in preterm labor with intact membranes. Am J Obstet Gynecol. 2001; 185:1124–9.

185. Gervasi MT, Chaiworapongsa T, Naccasha N, et al. Maternal intravascular inflammation in preterm premature rupture of membranes. J Matern Fetal Neonatal Med. 2002; 11:171–5.

186. Ogge G, Romero R, Chaiworapongsa T, et al. Leukocytes of pregnant women with small-for-gestational age neonates have a different phenotypic and metabolic activity from those of women with preeclampsia. J Matern Fetal Neonatal Med. 2010; 23:476–87.

187. Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol. 2004; 5:266–71.

188. Wildman DE, Chen C, Erez O, Grossman LI, Goodman M, Romero R. Evolution of the mammalian placenta revealed by phylogenetic analysis. Proc Natl Acad Sci U S A. 2006; 103:3203–8.

189. Aplin JD. Developmental cell biology of human villous trophoblast: current research problems. Int J Dev Biol. 2010; 54:323–9.

190. Redman CW, Sargent IL. Immunology of pre-eclampsia. Am J Reprod Immunol. 2010; 63:534–43.

191. Romero R. Prenatal medicine: the child is the father of the man. 1996. J Matern Fetal Nonatal Med. 2009; 22:636–9.

192. Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science. 2005; 308:1592–4.

193. Romero R, Espinoza J, Kusanovic JP, et al. The preterm parturition syndrome. BJOG. 2006; 113 Suppl 3:17–42.

194. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008; 371:75–84.

195. DiGiulio DB, Romero R, Amogan HP, et al. Microbial prevalence, diversity and abundance in amniotic fluid during preterm labor: a molecular and culture-based investigation. PLoS One. 2008; 3:e3056.

196. Kim MJ, Romero R, Gervasi MT, et al. Widespread microbial invasion of the chorioamniotic membranes is a consequence and not a cause of intra-amniotic infection. Lab Invest. 2009; 89:924–36.

197. Kim CJ, Romero R, Kusanovic JP, et al. The frequency, clinical significance, and pathological features of chronic chorioamnionitis: a lesion associated with spontaneous preterm birth. Mod Pathol. 2010; 23:1000–11.

198. Ogge G, Romero R, Lee DC, et al. Chronic chorioamnionitis displays distinct alterations of the amniotic fluid proteome. J Pathol. 2011; 223:553–65.

199. Lee J, Romero R, Xu Y, et al. A signature of maternal anti-fetal rejection in spontaneous preterm birth: chronic chorioamnionitis, anti-human leukocyte antigen antibodies, and C4d. PLoS One. 2011; 6:e16806.

200. Lee J, Romero R, Xu Y, et al. Maternal HLA panel-reactive antibodies in early gestation positively correlate with chronic chorioamnionitis: evidence in support of the chronic nature of maternal anti-fetal rejection. Am J Reprod Immunol. 2011; 66:510–26.

201. Xu Y, Tarquini F, Romero R, et al. Peripheral CD300a+CD8+ T lymphocytes with a distinct cytotoxic molecular signature increase in pregnant women with chronic chorioamnionitis. Am J Reprod Immunol. 2012; 67:184–97.

202. Lee J, Romero R, Chaiworapongsa T, et al. Characterization of the fetal blood transcriptome and proteome in maternal anti-fetal rejection: evidence of a distinct and novel type of human fetal systemic inflammatory response. Am J Reprod Immunol. 2013; 70:265–84.

203. Lee J, Romero R, Xu Y, et al. Detection of anti-HLA antibodies in maternal blood in the second trimester to identify patients at risk of antibody-mediated maternal anti-fetal rejection and spontaneous preterm delivery. Am J Reprod Immunol. 2013; 70:162–75.

204. Romero R, Miranda J, Chaiworapongsa T, et al. Prevalence and clinical significance of sterile intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Reprod Immunol. 2014; 72:458–74.

205. Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science. 2014; 345:760–5.

206. Colnot C, Fowlis D, Ripoche MA, Bouchaert I, Poirier F. Embryonic implantation in galectin 1/galectin 3 double mutant mice. Dev Dyn. 1998; 211:306–13.

207. Walzel H, Neels P, Bremer H, et al. Immunohistochemical and glycohistochemical localization of the beta-galactoside-binding S-type lectin in human placenta. Acta Histochem. 1995; 97:33–42.

208. van den Brule FA, Fernandez PL, Buicu C, et al. Differential expression of galectin-1 and galectin-3 during first trimester human embryogenesis. Dev Dyn. 1997; 209:399–405.

209. Kolundžic’ N, Bojic’-Trbojevic’ Ž, Kovac˘evic’ T, Stefanoska I, Kadoya T, Vic’ovac L. Galectin-1 is part of human trophoblast invasion machinery: a functional study in vitro. PLoS One. 2011; 6:e28514.

210. Arikawa T, Simamura E, Shimada H, et al. Expression pattern of Galectin 4 in rat placentation. Placenta. 2012; 33:885–7.

211. Than GN, Bohn H, Szabo DG. Advances in pregnancy-related protein research: functional and clinical applications. Boca Raton: CRC Press;1993.

212. Bischof P, Irminger-Finger I. The human cytotrophoblastic cell, a mononuclear chameleon. Int J Biochem Cell Biol. 2005; 37:1–16.

213. Ahmed MS, Aleksunes LM, Boeuf P, et al. IFPA Meeting 2012 Workshop Report II: epigenetics and imprinting in the placenta, growth factors and villous trophoblast differentiation, role of the placenta in regulating fetal exposure to xenobiotics during pregnancy, infection and the placenta. Placenta. 2013; 34 Suppl:S6–10.

214. Chiariotti L, Salvatore P, Frunzio R, Bruni CB. Galectin genes: regulation of expression. Glycoconj J. 2004; 19:441–9.

215. Segerer S, Kammerer U, Kapp M, Dietl J, Rieger L. Upregulation of chemokine and cytokine production during pregnancy. Gynecol Obstet Invest. 2009; 67:145–50.

216. Hammer A. Immunological regulation of trophoblast invasion. J Reprod Immunol. 2011; 90:21–8.

217. Knöfler M, Pollheimer J. Human placental trophoblast invasion and differentiation: a particular focus on Wnt signaling. Front Genet. 2013; 4:190.

218. Lima PD, Zhang J, Dunk C, Lye SJ, Croy BA. Leukocyte driven-decidual angiogenesis in early pregnancy. Cell Mol Immunol. 2014; 11:522–37.

219. Godbole G, Suman P, Gupta SK, Modi D. Decidualized endometrial stromal cell derived factors promote trophoblast invasion. Fertil Steril. 2011; 95:1278–83.

220. Phillips B, Knisley K, Weitlauf KD, Dorsett J, Lee V, Weitlauf H. Differential expression of two beta-galactoside-binding lectins in the reproductive tracts of pregnant mice. Biol Reprod. 1996; 55:548–58.

221. Lee VH, Lee AB, Phillips EB, Roberts JK, Weitlauf HM. Spatiotemporal pattern for expression of galectin-3 in the murine uteroplacental complex: evidence for differential regulation. Biol Reprod. 1998; 58:1277–82.

222. Yang H, Lei C, Zhang W. Expression of galectin-3 in mouse endometrium and its effect during embryo implantation. Reprod Biomed Online. 2012; 24:116–22.

223. Shimizu Y, Kabir-Salmani M, Azadbakht M, Sugihara K, Sakai K, Iwashita M. Expression and localization of galectin-9 in the human uterodome. Endocr J. 2008; 55:879–87.

224. Yang H, Lei CX, Zhang W. Human chorionic gonadotropin (hCG) regulation of galectin-3 expression in endometrial epithelial cells and endometrial stromal cells. Acta Histochem. 2013; 115:3–7.

225. Blois SM, Barrientos G. Galectin signature in normal pregnancy and preeclampsia. Reprod Immunol. 2014; 101-102:127–34.

226. Tirado-González I, Freitag N, Barrientos G, et al. Galectin-1 influences trophoblast immune evasion and emerges as a predictive factor for the outcome of pregnancy. Mol Hum Reprod. 2013; 19:43–53.

227. Heusschen R, Freitag N, Tirado-González I, et al. Profiling Lgals9 splice variant expression at the fetal-maternal interface: implications in normal and pathological human pregnancy. Biol Reprod. 2013; 88:22.

228. Knӧfler M, Pollheimer J. IFPA Award in Placentology lecture: molecular regulation of human trophoblast invasion. Placenta. 2012; 33 Suppl:S55–62.

229. Elola MT, Chiesa ME, Alberti AF, Mordoh J, Fink NE. Galectin-1 receptors in different cell types. J Biomed Sci. 2005; 12:13–29.

230. Crider-Pirkle S, Billingsley P, Faust C, Hardy DM, Lee V, Weitlauf H. Cubilin, a binding partner for galectin-3 in the murine utero-placental complex. J Biol Chem. 2002; 277:15904–12.

231. Garin MI, Chu CC, Golshayan D, Cernuda-Morollon E, Wait R, Lechler RI. Galectin-1: a key effector of regulation mediated by CD4+CD25+ T cells. Blood. 2007; 109:2058–65.

232. Karimi K, Arck PC. Natural killer cells: keepers of pregnancy in the turnstile of the environment. Brain Behav Immun. 2010; 24:339–47.

233. Zhu C, Anderson AC, Schubart A, et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005; 6:1245–52.

234. Wang F, Wan L, Zhang C, Zheng X, Li J, Chen ZK. Tim-3-Galectin-9 pathway involves the suppression induced by CD4+CD25+ regulatory T cells. Immunobiology. 2009; 214:342–9.

235. Li YH, Zhou WH, Tao Y, et al. The galectin-9/Tim-3 pathway is involved in the regulation of NK cell function at the maternal-fetal interface in early pregnancy. Cell Mol Immunol. 2015 Jan 12 [Epub]. http://dx.doi.org/10.1038/cmi.2014.126.

236. Meggyes M, Miko E, Polgar B, et al. Peripheral blood TIM-3 positive NK and CD8+ T cells throughout pregnancy: TIM-3/galectin-9 interaction and its possible role during pregnancy. PLoS One. 2014; 9:e92371.

237. Nangia-Makker P, Baccarini S, Raz A. Carbohydrate-recognition and angiogenesis. Cancer Metastasis Rev. 2000; 19:51–7.

238. Freitag N, Tirado-González I, Barrientos G, et al. Interfering with Gal-1-mediated angiogenesis contributes to the pathogenesis of preeclampsia. Proc Natl Acad Sci U S A. 2013; 110:11451–6.

239. Hsieh SH, Ying NW, Wu MH, et al. Galectin-1, a novel ligand of neuropilin-1, activates VEGFR-2 signaling and modulates the migration of vascular endothelial cells. Oncogene. 2008; 27:3746–53.

240. Douglas NC, Tang H, Gomez R, et al. Vascular endothelial growth factor receptor 2 (VEGFR-2) functions to promote uterine decidual angiogenesis during early pregnancy in the mouse. Endocrinology. 2009; 150:3845–54.

241. Halder JB, Zhao X, Soker S, et al. Differential expression of VEGF isoforms and VEGF(164)-specific receptor neuropilin-1 in the mouse uterus suggests a role for VEGF(164) in vascular permeability and angiogenesis during implantation. Genesis. 2000; 26:213–24.

242. Baston-Buest DM, Porn AC, Schanz A, Kruessel JS, Janni W, Hess AP. Expression of the vascular endothelial growth factor receptor neuropilin-1 at the human embryo-maternal interface. Eur J Obstet Gynecol Reprod Biol. 2011; 154:151–6.

243. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoformspecific receptor for vascular endothelial growth factor. Cell. 1998; 92:735–45.

244. Gizurarson S, Huppertz B, Osol G, Skarphedinsson JO, Mandala M, Meiri H. Effects of placental protein 13 on the cardiovascular system in gravid and non-gravid rodents. Fetal Diagn Ther. 2013; 33:257–64.

245. Sammar M, Nisamblatt S, Gonen R, et al. The role of the carbohydrate recognition domain of placental protein 13 (PP13) in pregnancy evaluated with recombinant PP13 and the DelT221 PP13 variant. PLoS One. 2014; 9:e102832.

246. Romero R, Espinoza J, Gonçalves LF, Kusanovic JP, Friel LA, Nien JK. Inflammation in preterm and term labour and delivery. Semin Fetal Neonatal Med. 2006; 11:317–26.

247. Hassan SS, Romero R, Tarca AL, et al. The transcriptome of cervical ripening in human pregnancy before the onset of labor at term: identification of novel molecular functions involved in this process. J Matern Fetal Neonatal Med. 2009; 22:1183–93.

248. Hassan SS, Romero R, Tarca AL, et al. The molecular basis for sonographic cervical shortening at term: identification of differentially expressed genes and the epithelial-mesenchymal transition as a function of cervical length. Am J Obstet Gynecol. 2010; 203:472. e1-14.

249. Mittal P, Romero R, Tarca AL, et al. Characterization of the myometrial transcriptome and biological pathways of spontaneous human labor at term. J Perinat Med. 2010; 38:617–43.

250. Romero R, Mazor M, Munoz H, Gomez R, Galasso M, Sherer DM. The preterm labor syndrome. Ann N Y Acad Sci. 1994; 734:414–29.

251. Kim SS, Romero R, Kim JS, et al. Coexpression of myofibroblast and macrophage markers: novel evidence for an in vivo plasticity of chorioamniotic mesodermal cells of the human placenta. Lab Invest. 2008; 88:365–74.

252. Fulcher JA, Hashimi ST, Levroney EL, et al. Galectin-1-matured human monocyte-derived dendritic cells have enhanced migration through extracellular matrix. J Immunol. 2006; 177:216–26.

253. Sutton L, Mason DY, Redman CW. HLA-DR positive cells in the human placenta. Immunology. 1983; 49:103–12.

254. Eis AL, Brockman DE, Myatt L. Immunolocalization of the inducible nitric oxide synthase isoform in human fetal membranes. Am J Reprod Immunol. 1997; 38:289–94.

255. Benirschke K, Kaufmann P, Baergen RN. Pathology of the human placenta. 5th ed. New York: Springer-Verlag;2006.

256. Espinoza J, Chaiworapongsa T, Romero R, et al. Antimicrobial peptides in amniotic fluid: defensins, calprotectin and bacterial/permeability-increasing protein in patients with microbial invasion of the amniotic cavity, intra-amniotic inflammation, preterm labor and premature rupture of membranes. J Matern Fetal Neonatal Med. 2003; 13:2–21.

257. Gil CD, Cooper D, Rosignoli G, Perretti M, Oliani SM. Inflammation-induced modulation of cellular galectin-1 and -3 expression in a model of rat peritonitis. Inflamm Res. 2006; 55:99–107.

258. Barrionuevo P, Beigier-Bompadre M, Ilarregui JM, et al. A novel function for galectin-1 at the crossroad of innate and adaptive immunity: galectin-1 regulates monocyte/macrophage physiology through a nonapoptotic ERK-dependent pathway. J Immunol. 2007; 178:436–45.

259. Correa SG, Sotomayor CE, Aoki MP, Maldonado CA, Rabinovich GA. Opposite effects of galectin-1 on alternative metabolic pathways of L-arginine in resident, inflammatory, and activated macrophages. Glycobiology. 2003; 13:119–28.

260. Demmert M, Faust K, Bohlmann MK, et al. Galectin-3 in cord blood of term and preterm infants. Clin Exp Immunol. 2012; 167:246–51.

261. Savman K, Heyes MP, Svedin P, Karlsson A. Microglia/macrophage-derived inflammatory mediators galectin-3 and quinolinic acid are elevated in cerebrospinal fluid from newborn infants after birth asphyxia. Transl Stroke Res. 2013; 4:228–35.

262. Sundqvist M, Osla V, Jacobsson B, Rudin A, Sävman K, Karlsson A. Cord blood neutrophils display a galectin-3 responsive phenotype accentuated by vaginal delivery. BMC Pediatr. 2013; 13:128.

263. Kollar S, Sandor N, Molvarec A, et al. Prevalence of intracellular galectin-1-expressing lymphocytes in umbilical cord blood in comparison with adult peripheral blood. Biol Blood Marrow Transplant. 2012; 18:1608–13.

264. Doverhag C, Keller M, Karlsson A, et al. Pharmacological and genetic inhibition of NADPH oxidase does not reduce brain damage in different models of perinatal brain injury in newborn mice. Neurobiol Dis. 2008; 31:133–44.

265. Bamberg C, Kalache KD. Prenatal diagnosis of fetal growth restriction. Semin Fetal Neonatal Med. 2004; 9:387–94.

266. Matthiesen L, Berg G, Ernerudh J, Ekerfelt C, Jonsson Y, Sharma S. Immunology of preeclampsia. Chem Immunol Allergy. 2005; 89:49–61.

267. ACOG Committee on Practice Bulletins--Obstetrics. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Obstet Gynecol. 2002; 99:159–67.

268. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. 2005; 365:785–99.

269. Barker DJ. Fetal nutrition and cardiovascular disease in later life. Br Med Bull. 1997; 53:96–108.

270. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ. 2001; 323:1213–7.

271. Powe CE, Levine RJ, Karumanchi SA. Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease. Circulation. 2011; 123:2856–69.

272. Than NG, Vaisbuch E, Kim CJ, et al. Early-onset preeclampsia and HELLP syndrome: an overview. In : Preedy VR, editor. Handbook of growth and growth monitoring in health and disease. New York: Springer;2012. p. 1867–91.

273. Ness RB, Roberts JM. Heterogeneous causes constituting the single syndrome of preeclampsia: a hypothesis and its implications. Am J Obstet Gynecol. 1996; 175:1365–70.

274. von Dadelszen P, Magee LA, Roberts JM. Subclassification of preeclampsia. Hypertens Pregnancy. 2003; 22:143–8.

275. Burton GJ, Jauniaux E. Placental oxidative stress: from miscarriage to preeclampsia. J Soc Gynecol Investig. 2004; 11:342–52.

276. Burton GJ, Woods AW, Jauniaux E, Kingdom JC. Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta. 2009; 30:473–82.

277. Roberts JM, Hubel CA. The two stage model of preeclampsia: variations on the theme. Placenta. 2009; 30 Suppl A:S32–7.

278. Brosens IA, Robertson WB, Dixon HG. The role of the spiral arteries in the pathogenesis of preeclampsia. Obstet Gynecol Annu. 1972; 1:177–91.

279. Brosens I, Pijnenborg R, Vercruysse L, Romero R. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol. 2011; 204:193–201.

280. Lee X, Keith JC Jr, Stumm N, et al. Downregulation of placental syncytin expression and abnormal protein localization in pre-eclampsia. Placenta. 2001; 22:808–12.

281. Chen CP, Chen CY, Yang YC, Su TH, Chen H. Decreased placental GCM1 (glial cells missing) gene expression in pre-eclampsia. Placenta. 2004; 25:413–21.

282. Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol. 1989; 161:1200–4.

283. Sacks GP, Studena K, Sargent K, Redman CW. Normal pregnancy and preeclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis. Am J Obstet Gynecol. 1998; 179:80–6.

284. Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fmslike tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003; 111:649–58.

285. Chaiworapongsa T, Romero R, Espinoza J, et al. Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia. Young Investigator Award. Am J Obstet Gynecol. 2004; 190:1541–7.

286. Gupta AK, Hasler P, Holzgreve W, Gebhardt S, Hahn S. Induction of neutrophil extracellular DNA lattices by placental microparticles and IL-8 and their presence in preeclampsia. Hum Immunol. 2005; 66:1146–54.

287. Levine RJ, Lam C, Qian C, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med. 2006; 355:992–1005.

288. Venkatesha S, Toporsian M, Lam C, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med. 2006; 12:642–9.

289. Rusterholz C, Holzgreve W, Hahn S. Oxidative stress alters the integrity of cell-free mRNA fragments associated with placenta-derived syncytiotrophoblast microparticles. Fetal Diagn Ther. 2007; 22:313–7.

290. Burton GJ, Yung HW, Cindrova-Davies T, Charnock-Jones DS. Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia. Placenta. 2009; 30 Suppl A:S43–8.

291. Rusterholz C, Messerli M, Hoesli I, Hahn S. Placental microparticles, DNA, and RNA in preeclampsia. Hypertens Pregnancy. 2011; 30:364–75.

292. Redman CW, Sargent IL, Staff AC. IFPA Senior Award Lecture: making sense of pre-eclampsia - two placental causes of preeclampsia? Placenta. 2014; 35 Suppl:S20–5.

293. Webster RP, Roberts VH, Myatt L. Protein nitration in placenta: functional significance. Placenta. 2008; 29:985–94.

294. Burton GJ, Yung HW. Endoplasmic reticulum stress in the pathogenesis of early-onset pre-eclampsia. Pregnancy Hypertens. 2011; 1:72–8.

295. Thijssen VL, Postel R, Brandwijk RJ, et al. Galectin-1 is essential in tumor angiogenesis and is a target for antiangiogenesis therapy. Proc Natl Acad Sci U S A. 2006; 103:15975–80.

296. Sasaki Y, Darmochwal-Kolarz D, Suzuki D, et al. Proportion of peripheral blood and decidual CD4(+) CD25(bright) regulatory T cells in pre-eclampsia. Clin Exp Immunol. 2007; 149:139–45.

297. Toldi G, Saito S, Shima T, et al. The frequency of peripheral blood CD4+ CD25high FoxP3+ and CD4+ CD25- FoxP3+ regulatory T cells in normal pregnancy and pre-eclampsia. Am J Reprod Immunol. 2012; 68:175–80.

298. Saito S, Sakai M, Sasaki Y, Nakashima A, Shiozaki A. Inadequate tolerance induction may induce pre-eclampsia. J Reprod Immunol. 2007; 76:30–9.

299. Miko E, Meggyes M, Bogar B, et al. Involvement of Galectin-9/TIM-3 pathway in the systemic inflammatory response in early-onset preeclampsia. PLoS One. 2013; 8:e71811.

300. Gebhardt S, Bruiners N, Hillermann R. A novel exonic variant (221delT) in the LGALS13 gene encoding placental protein 13 (PP13) is associated with preterm labour in a low risk population. J Reprod Immunol. 2009; 82:166–73.

301. Shimizu H, Sekizawa A, Purwosunu Y, et al. PP13 mRNA expression in the cellular component of maternal blood as a marker for preeclampsia. Prenat Diagn. 2009; 29:1231–6.

302. Farina A, Zucchini C, Sekizawa A, et al. Performance of messenger RNAs circulating in maternal blood in the prediction of preeclampsia at 10-14 weeks. Am J Obstet Gynecol. 2010; 203:575. e1-7.

303. Huppertz B, Meiri H, Gizurarson S, Osol G, Sammar M. Placental protein 13 (PP13): a new biological target shifting individualized risk assessment to personalized drug design combating pre-eclampsia. Hum Reprod Update. 2013; 19:391–405.

304. Khalil A, Cowans NJ, Spencer K, Goichman S, Meiri H, Harrington K. First trimester maternal serum placental protein 13 for the prediction of pre-eclampsia in women with a priori high risk. Prenat Diagn. 2009; 29:781–9.

305. Audibert F, Boucoiran I, An N, et al. Screening for preeclampsia using first-trimester serum markers and uterine artery Doppler in nulliparous women. Am J Obstet Gynecol. 2010; 203:383. e1-8.

306. Akolekar R, Syngelaki A, Sarquis R, Zvanca M, Nicolaides KH. Prediction of early, intermediate and late pre-eclampsia from maternal factors, biophysical and biochemical markers at 11-13 weeks. Prenat Diagn. 2011; 31:66–74.

307. Odibo AO, Zhong Y, Goetzinger KR, et al. First-trimester placental protein 13, PAPP-A, uterine artery Doppler and maternal characteristics in the prediction of pre-eclampsia. Placenta. 2011; 32:598–602.

308. Di Lorenzo G, Ceccarello M, Cecotti V, et al. First trimester maternal serum PIGF, free beta-hCG, PAPP-A, PP-13, uterine artery Doppler and maternal history for the prediction of preeclampsia. Placenta. 2012; 33:495–501.

309. El Sherbiny WS, Soliman A, Nasr AS. Placental protein 13 as an early predictor in Egyptian patients with preeclampsia, correlation to risk, and association with outcome. J Investig Med. 2012; 60:818–22.

310. Moslemi Zadeh N, Naghshvar F, Peyvandi S, Gheshlaghi P, Ehetshami S. PP13 and PAPP-A in the First and Second Trimesters: Predictive Factors for Preeclampsia? ISRN Obstet Gynecol. 2012; 2012:263871.

311. Myatt L, Clifton RG, Roberts JM, et al. First-trimester prediction of preeclampsia in nulliparous women at low risk. Obstet Gynecol. 2012; 119:1234–42.

312. Schneuer FJ, Nassar N, Khambalia AZ, et al. First trimester screening of maternal placental protein 13 for predicting preeclampsia and small for gestational age: in-house study and systematic review. Placenta. 2012; 33:735–40.

313. Svirsky R, Meiri H, Herzog A, Kivity V, Cuckle H, Maymon R. First trimester maternal serum placental protein 13 levels in singleton vs. twin pregnancies with and without severe pre-eclampsia. J Perinat Med. 2013; 41:561–6.

314. Cuckle HS. Screening for pre-eclampsia: lessons from aneuploidy screening. Placenta. 2011; 32 Suppl:S42–8.

315. Spencer K, Cowans NJ, Chefetz I, Tal J, Kuhnreich I, Meiri H. Second-trimester uterine artery Doppler pulsatility index and maternal serum PP13 as markers of pre-eclampsia. Prenat Diagn. 2007; 27:258–63.

316. Kuc S, Wortelboer EJ, van Rijn BB, Franx A, Visser GH, Schielen PC. Evaluation of 7 serum biomarkers and uterine artery Doppler ultrasound for first-trimester prediction of preeclampsia: a systematic review. Obstet Gynecol Surv. 2011; 66:225–39.

317. Nicolaides KH. Turning the pyramid of prenatal care. Fetal Diagn Ther. 2011; 29:183–96.

318. Than NG, Balogh A, Romero R, et al. Placental protein 13 (PP13): a placental immunoregulatory galectin protecting pregnancy. Front Immunol. 2014; 5:348.

319. Grimpel YI, Kivity V, Cohen A, et al. Effects of calcium, magnesium, low-dose aspirin and low-molecular-weight heparin on the release of PP13 from placental explants. Placenta. 2011; 32 Suppl:S55–64.

320. Sammar M, Nisemblat S, Fleischfarb Z, et al. Placenta-bound and body fluid PP13 and its mRNA in normal pregnancy compared to preeclampsia, HELLP and preterm delivery. Placenta. 2011; 32 Suppl:S30–6.