Placenta
Volume 31, Issue 9 , Pages 747-755, September 2010

Cadherins in the human placenta – epithelial–mesenchymal transition (EMT) and placental development

  • M.I. Kokkinos

      Affiliations

    • Department of Perinatal Medicine, Pregnancy Research Centre, The Royal Women’s Hospital, Flemington Road, Parkville 3052, Victoria, Australia
    • Department of Obstetrics and Gynaecology, University of Melbourne, Level 7, The Royal Women’s Hospital, Flemington Road, Parkville 3052, Victoria, Australia
    • Corresponding Author InformationCorresponding author. Department of Perinatal Medicine, Pregnancy Research Centre, The Royal Women’s Hospital, Flemington Road, Parkville 3052, Victoria, Australia.
    • ,
  • P. Murthi

      Affiliations

    • Department of Perinatal Medicine, Pregnancy Research Centre, The Royal Women’s Hospital, Flemington Road, Parkville 3052, Victoria, Australia
    • Department of Obstetrics and Gynaecology, University of Melbourne, Level 7, The Royal Women’s Hospital, Flemington Road, Parkville 3052, Victoria, Australia
    • ,
  • R. Wafai

      Affiliations

    • Department of Surgery, University of Melbourne, Clinical Sciences Building, St. Vincent’s Hospital, 29 Regent St, Fitzroy, Melbourne 3065, Australia
    • ,
  • E.W. Thompson

      Affiliations

    • Department of Surgery, University of Melbourne, Clinical Sciences Building, St. Vincent’s Hospital, 29 Regent St, Fitzroy, Melbourne 3065, Australia
    • St. Vincent’s Institute, Melbourne, Australia
    • ,
  • D.F. Newgreen

      Affiliations

    • Murdoch Children’s Research Institute, Royal Children’s Hospital, Flemington Road, Parkville, Victoria 3052, Australia

Accepted 26 June 2010. published online 26 July 2010.

Article Outline

Abstract 

Colonisation of the maternal uterine wall by the trophoblast involves a series of alterations in the behaviour and morphology of trophoblast cells. Villous cytotrophoblast cells change from a well-organised coherently layered phenotype to one that is extravillous, acquiring a proliferative, migratory and invasive capacity, to facilitate fetal–maternal interaction. These changes are similar to those of other developmental processes falling under the umbrella of an epithelial–mesenchymal transition (EMT). Modulation of cell adhesion and cell polarity occurs through changes in cell–cell junctional molecules, such as the cadherins. The cadherins, particularly the classical cadherins (e.g. Epithelial-(E)-cadherin), and their link to adaptors called catenins at cell–cell contacts, are important for maintaining cell attachment and the layered phenotype of the villous cytotrophoblast. In contrast, reduced expression and re-organization of cadherins from these cell junctional regions promote a loosened connection between cells, coupled with reduced apico-basal polarity. Certain non-classical cadherins play an active role in cell migration processes. In addition to the classical cadherins, two other cadherins which have been reported in placental tissues are vascular endothelial (VE) cadherin and cadherin-11. Cadherin molecules are well placed to be key regulators of trophoblast cell behaviour, analogous to their role in other developmental EMTs. This review addresses cadherin expression and function in normal and diseased human placental tissues, especially in fetal growth restriction and pre-eclampsia where trophoblast invasion is reduced.

Keywords: Placenta, Epithelial–mesenchymal transition, Cadherin, Trophoblast migration, Invasion

 

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1. Introduction 

1.1. Cytotrophoblast in establishment of the placenta 

During human placental development trophoblast cells differentiate along either the a) villous cytotrophoblast (VCT) lineage to form the syncytiotrophoblast (ST), that secretes the majority of placental hormones, or b) the invasive extravillous cytotrophoblast (EVT) lineage implicated in the anchoring of chorionic villi in the uterus. Invasive EVTs arise from the proliferative zone of the proximal column of the anchoring villi. EVTs migrate through the endometrium, interact with decidual cells and immunocompetent cells, and differentiate into multinucleated placental bed giant cells. In addition, they can invade the maternal spiral arteries, mediate the destruction of the arterial wall, and replace the endothelium, forming endovascular trophoblasts [1], [2]. The transition between the proliferative and invasive phenotype is characterised by down-regulation of molecules associated with mitosis such as epidermal growth factor receptor (EGFR) and adhesion molecules such as connexin and upregulation of cell cycle inhibitors and proto-oncogene c-erbB2 [3], [4], [5], [6]. These adhesive and migratory processes are important in the success of early pregnancy, as well as the continual development of a healthy placenta. Hence, EVTs acquire proliferative, migratory and invasive capabilities in order to allow for continual growth into the decidua. The invasive capacity of trophoblasts is a well-orchestrated process, following similar changes to those identified in processes in various pathologies including tumour progression as choriocarcinoma.

1.2. Placental insufficiency in fetal growth restriction and pre-eclampsia 

Two very different but clinically relevant pregnancy disorders characteristically present with shallow trophoblast invasion into the maternal environment. These are fetal growth restriction (FGR) and pre-eclampsia (PE). FGR, also commonly known as intra-uterine growth restriction, is defined by fetal birth weight lower than the 10th percentile for gestational age. Perinatal complications as well as long-term health problems are associated with FGR. One third of FGR cases are a result of known causes, including genetic factors, and placental and maternal influences. Two-thirds of all FGR cases are classified as idiopathic, due to unknown cause and are frequently associated with placental insufficiency [7], [8]. Interestingly, placentae of idiopathic FGR patients are smaller in size and also show evidence of reduced trophoblast proliferation as well as a shortening of placental villous structures [9]. In addition, these placentae may be ischemic, indicating that cytotrophoblasts are unable to invade efficiently in the placental bed. This is consistent with the notion that originating EVTs are not activated sufficiently to undergo full scale invasion of the uterus. Furthermore, trophoblasts of FGR placentae are defective in survival and differentiation potential in the presence of cytokines [7]. All These features highlight the relevance of efficient trophoblast migration into the uterus for the healthy development of the placenta. Hence, reduced migration, and survival potential of trophoblasts in FGR may be a key feature leading to the development of this pregnancy disorder. FGR is often detected by ultrasound in the third trimester of pregnancy.

PE is a hypertensive disease, which is clinically identified as a pregnancy-induced high blood pressure of more than 140/90 with proteinuria of greater than 300 mg protein in a 24 h period. PE arises in 5–6% of pregnancies and may be caused by dietary factors, maternal infection, genetic factors, calcium deficiency and immunological activation, as well as insufficient blood flow to the uterus. Although several factors may influence both PE and eclampsia, this pathology is well known to present with reduced trophoblast invasion into the placental bed. Hence, placental factors, specifically, insufficient trophoblast differentiation and invasion, may also contribute to this serious pregnancy disorder [10], [11].

The growth, migration and invasion of placental cells into the uterine milieu are relevant to the initial establishment of a healthy pregnancy, and are compromised in both FGR and PE. In addition, since these same processes are continual in normal placental development, placental growth, migration and invasion in later stage pregnancies are also critical. This raises the question as to what factors regulate these migratory events and how the altered regulation manifests pathologically.

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2. Epithelial–mesenchymal transition 

Tissues are normally comprised of cells, which are either epithelial or mesenchymal. Characteristic features of epithelial cells include: a) adhesion to one another through lateral and apico-lateral cell–cell junctions; b) adhesion to specialised extracellular matrix (ECM) at the basal surface; c) apico-basal polarisation. This leads to the arrangement in a layer which often, when viewed en face present a cobble-stone appearance [12]. Cell–cell cohesion is mediated, in part, through the interaction of homophilic cadherin molecules, especially the classical types, E-cadherin, N-cadherin and P-cadherin, at specialised cell junction regions called adherens junctions (AJ). These cadherin molecules couple via adaptor proteins such as catenins and vinculin, to the F-actin cytoskeleton. AJs are associated with tight junctions marked by distinctive molecules such as ZO-1 and claudin. Together, these junctions prevent uncontrolled molecular flow across the epithelial layer. These AJs serve not only the structural role of holding cells together, but are also regulating important signaling events. Additional cell–cell adhesion capacity is provided in many epithelia by desmosomes, based around different cadherins (desmocollins, desmogleins), different link molecules (plakoglobin, plakophillin, desmoplakin) and coupled to different cytoskeletal elements (intermediate filaments e.g. cytokeratins) [13]. Adhesion to ECM typically involves adhesive/signaling transmembrane receptors of a different class, termed integrins, coupled to a complex of adaptor and signaling proteins such as vinculin, focal adhesion kinase (FAK), paxillin and integrin linked kinase (ILK) at the cytoplasmic face.

In contrast, mesenchymal cells: a) have reduced expression (or at least presence in the membrane) of cell–cell junction molecules such as E-cadherin, ZO-1, desmoplakin, vinculin; b) adhere to interstitial ECM via integrins on any part of the cell surface; and c) lack apico-basal polarity, but are elongated or multi-polar, with transient and changeable “front-back” polarity [14]. Consequently these cells are not arranged in an organised layer, are embedded in (rather than on) ECM and may have migratory and invasive potential [15]. Epithelial cells may be induced to change to a mesenchymal phenotype through the epithelial–mesenchymal transition (EMT). Following migration (often also termed invasion especially in pathologies), cells may revert back to an epithelial phenotype through mesenchymal–epithelial transition (MET). EMT is an organised process which was first recognized in developmental biology as a means to achieve morphogenetic change. EMT events have been well described in gastrulation leading to mesoderm formation and ultimately, through a secondary MET, to various transient epithelia which undergo further rounds of EMT. In addition, EMT events have been well studied in neural crest cells, an archetypal migratory cell type which stems from neural epithelium (reviewed by [16], [17]). EMT is now well recognized in some pathologies such as carcinoma invasion and fibrosis [18]. EMT was initially presented as an extreme “all-or-nothing” change in cell phenotype, but a more recent and balanced view is that the definition of EMT can encompass a spectrum of partial or “hybrid” states [19].

2.1. Cytotrophoblast invasion as an EMT 

It has been proposed that the process by which placental cytotrophoblast cells change from a coherently attached to a migratory phenotype which invades the maternal decidua, resembles other developmental EMTs. We present this hypothesis diagrammatically in Fig. 1. Although some researchers have suggested this (e.g. [20], [21]), few studies have addressed the possibility in great detail. Given the centrality of modulation of cell–cell adhesion to EMT in general, by investigating the factors that regulate cell adhesion as well as invasion in the placenta, we may be able to further understand the early events of placental development in normal and in pathological pregnancies.

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  • Fig. 1 

    Migration of extravillous trophoblasts into the maternal decidua-possible EMT? Villous cytotrophoblasts are bound together tightly and develop into proliferative cell columns prior to commencing migration as extravillous trophoblasts. Upon acquisition of this migratory ability, extravillous trophoblasts tend to lose their tight epithelial assembly and phenotype, becoming loosely attached, subsequently invading the maternal decidua as interstitial cytotrophoblasts. The process by which placental trophoblasts originate as epithelial cells and are subsequently triggered to change from a epithelial to a mesenchyme-like migratory phenotype, resembling epithelial-to-mesenchymal transition (EMT) identified in other developmental processes. Hence, this change in morphology is likely to involve changes in cadherin expression and function, as has been observed in all other EMTs.

In instances where EMT is not controlled, pathologies arise whereby cells have altered abilities to grow, proliferate and migrate or invade. A key example of this is carcinoma progression, whereby cells acquire a mesenchymal migratory potential from a resting epithelial morphology, using this to initiate translocations to distant sites before reverting back, often, to an epithelial phenotype [22], [23]. Expression of epithelial markers is reduced, while mesenchymal marker expression is heightened. For instance E-cadherin and β-catenin are reduced or lost from cell–cell junctions and re-localised to the cytoplasm or nucleus, often with evidence of altered transcriptional expression which typically favour mesenchymal markers and suppresses typical epithelial markers. The mesenchymal intermediate filament vimentin is regularly elevated, coupled with the decline of epithelial intermediate filaments, the cytokeratins [22].

In normal development, EMT events are regulated and controlled, and in cancer they are spatio-temporally dysregulated. However, both normal and pathological EMTs are often and typically associated with increased invasion of local tissue. In contrast, the two important pregnancy disorders, FGR and PE, involve trophoblast cells with apparently reduced invasion into the maternal environment [7], [24]. Although few studies have addressed this in the human placenta, there is speculation that normal EMT-like events are compromised in these placental disorders, compared to those in regulated normal placentae [25].

Expression and localisation of cadherins are highly relevant to the behaviour and morphology of cells at different stages of development, especially during EMT. For instance, localisation and expression at cell–cell junctions is particularly relevant for maintaining a stable epithelial structure, whilst loss of certain types of cadherins from these sites leads to a migratory phenotype. This review will address the role of cadherins in modulating EMT in normal and diseased placental development.

2.2. Cadherins and the cytoskeleton complex: components and structure 

Cadherins associate with the cytoskeleton, which is comprised of a network of proteins such as actin microfilaments, microtubules, and intermediate filaments (Fig. 2). These dynamic networks of structural proteins are particularly relevant in maintaining and also changing cellular architecture, and in promoting movement and attachment of cells to one another and to the ECM. Actin filaments in the cell cortex subjacent to the inner plasma membrane form networks, and also fibres, referred to as cortical bundling. In epithelial cells these bundles are arranged in a circumferential pattern and maintain links with the cadherin AJs. In mesenchymal cells, monomeric actin polymerises in the direction of movement, forming stress fibres that run across the cell. Changes in how these actin filaments are organised and positioned allow for changes in cellular shape and movement. Actin filaments may also draw membrane regions inwards, in processes such as forming vesicles or during cell division. These actin dynamics occur in association with members of the myosin protein family. In development, actin and myosin are identified in polarized, non-migratory cells at the apical surface, whilst in mesenchymal cells, actin forms stress fibres which allows cells to elongate and stretch over the ECM.

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  • Fig. 2 

    Cell junctional complexes linking epithelial cells. The localisation of major cell junctional molecules in epithelial cells. Epithelial cells maintain their attachment and morphology through molecules located at the cytoskeleton, and cell–cell junctions. Gap junctions allow for cell–cell communication and interchange of molecules between cells. Tight junctions enable cells to form a barrier to uncontrolled molecular diffusion from one side of the cell sheet to the other. The structure of these adhesions is buttressed by adherens junctions linked via circumferential ring bundles of actin fibrils. Further adhesive stabilisation is via desmosomal junctions with intermediate filaments. The specific cell–cell link of these adherens and desmosomal junctions is via cadherins, and integration with the actin cytoskeleton involves β-catenin. Loss of these junctional components can lead to epithelial–mesenchymal transition (EMT).

Adhesion and cytoskeletal markers have been reported in the human placenta. As discussed in a review by Aplin et al. [25], connexins (gap junction components) have been reported at the cytotrophoblast–syncytiotrophoblast linkage. Cell tight junctions contain proteins claudin, occludin and zonula scaffolding proteins (ZO-1,2,3; [25]), allowing for cells to maintain a barrier from one side of the cell sheet to the other, facilitating ion transport, as well as linking to the actin cytoskeleton. Specifically, ZO-1 has been reported to link cytotrophoblasts to one another, as well as cytotrophoblasts with syncytiotrophoblast. In early stages of pregnancy, occludin is reported in villous trophoblasts, and claudin 1 is reported at linkages of cytotrophoblasts and syncytiotrophoblast [25].

Cadherins include at least 6 sub-families which can be distinguished on the basis of their structural or functional organization, including their protein domain composition, genomic structure and phylogenetic analysis of the protein sequences [26]. These sub-families comprise a) the classical (or type-I) cadherins and b) the atypical (or type-II) cadherins, which are mainly localised to the AJs and are the definitive group of the cadherin family, c) the desmosomal cadherins, which form desmosomal junctions, d) the proto-cadherins, which are implicated in neural development, e) the flamingo cadherins which consists of seven transmembrane cadherins, and f) the FAT-like cadherins [27], [28].

The classical cadherins, Epithelial (E)-cadherin, Neuronal (N)-cadherin and Placental (P)-cadherin, were the first cadherins to be described [29], [30], [31]. They are the most widely studied and definitive group of the cadherin superfamily and were originally identified in vertebrates [32], [33], [34]. These classical cadherins are usually identified in tissues which require a stable and tight integrity [35].

Classical cadherins are composed of three structural segments. These are a) an extracellular domain of 110 amino acids, that mediates adhesion, b) a single-pass transmembrane domain, and c) a highly conserved cytoplasmic domain that interacts with a group of proteins known as catenins, to link the cadherins to the actin cytoskeleton [36], [37].

Cadherins mediate calcium-dependent homotypic cell–cell adhesion [38], [39] and have been implicated in diverse biological processes such as cell adhesion, cell signaling [39], [40], cell recognition, control of cell division, inhibition of apoptosis [41], migration, differentiation, morphogenesis [28], [37], embryo implantation, and tumour invasion suppression [42]. Thus, they play significant roles in embryological development and maintenance of normal tissue architecture and in cancer [42], [44], [45], [46], [47], [48]. The altered expressions of these cadherins have been associated with the pathology of cancer [43]. Table 1 describes the general distribution and function of major cadherins.

Table 1. Cadherin distribution and major function.
CadherinDistributionMajor functionReferences
Epithelial (E)-cadherinAdherens junctions; Calcium dependence; luminal epithelium and mammary glands; required for murine epithelial trophectoderm development in mouseCell adhesion; polarity; blastomeres in early developmental processes;[53], [96], [97]
Neuronal (N)-cadherinNeuronal tissue; Cardiac tissuesMediates cell–cell adhesion in development; promotes invasion in certain malignancies; cell sorting in cardiac development[73], [75], [98]
Placental (P)-cadherinMurine placenta, mammary ducts, myoepithelia and alveoli. NOT expressed in human placenta;Facilitates binding of murine placenta to the uterus; important in regulating mammary duct development[67], [77]
Vascular endothelial (VE)-cadherinEndothelial cells; interface of extravillous trophoblasts and decidual endothelial cells;Cell–cell attachment[79], [82]
Cadherin-11Epithelial cells in placenta and early decidua; extravillous cytotrophoblasts and cell columnsEarly differentiation events; terminal differentiation of cytotrophoblasts into syncytiotrophoblast[92], [93]

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3. Cadherin expression in normal development, placenta and disease 

Classical cadherins, as well as VE cadherin and Cadherin-11, will be described in the following sections with regard to their role in the placenta. Summary of cadherins that are known in the placenta are presented in Table 2.

Table 2. Expression of common cadherins in human placentae.
CadherinLocalization in human placentaReference
Epithelial (E) cadherinNormal Placentae: Cytotrophoblasts; Anchoring cell columns; Reduced from first to third trimester; Membrane of villous trophoblasts; Pre-eclamptic placentae: Higher expression compared to normal placentae; strong expression in cytotrophoblasts[21], [59], [60], [62], [64], [67]
Vascular endothelial (VE) cadherinVessels and extravillous trophoblasts; Connection between maternal and fetal arteries; Interface of extravillous trophoblasts and decidual endothelial cells[58], [80], [82]
Cadherin-11Differentiation of cytotrophoblasts into syncytiotrophoblast; Cell columns; Epithelial placental cells and decidua; Glandular epithelium of endometrium and stroma[92], [93]

3.1. Epithelial (E)-cadherin 

Epithelial (E)- cadherin is an important adhesion molecule and its expression may be necessary, particularly with reference to EMT, in regulating human placental development. In cells of many epithelia, E-cadherin is found associated with the actin cytoskeleton, and is implicated in forming specialised cell–cell junctions, promoting cell–cell adhesion, and hence defining cell polarity. E-cadherin expression in normal cells is thought to stabilize the cell architecture, and as such its expression is an indispensible element of epithelial differentiation. Importantly, its reduced expression has been associated with the induction of EMT, which is instrumental in pathologies such as carcinoma invasion [43], [49], as well as choriocarcinoma in the placental setting.

E-cadherin is structurally linked to β-catenin in epithelial, non-migratory cells. When E-cadherin-mediated adhesion is disrupted in epithelial cells, they adopt a migratory capacity. In addition, the aberrant regulation and continued stabilisation of β-catenin is characteristic to the early development of certain cancers [50]. This supports the contention that changes to E-cadherin expression may be a key factor in breast and other cancer biology. E-cadherin is absent or reduced in a range of tumours, including breast [51], lung [52], skin [53], pancreas [53] nasopharyngeal [54] and gastric cancers [55]. In addition, in vitro analyses have demonstrated E-cadherin is an invasion-suppressor gene. Specifically, the down-regulated expression of E-cadherin, and loss of heterozygosity analysis at 16q22.1 (site of E-cadherin) in breast cancer cells, implies it may be a putative tumour suppressor in these cancers [15]. Chen et al. [56] showed that rat astrocytoma cells had reduced migration when forced to express E-cadherin, suggesting a role for E-cadherin in controlling migration. Similarly, various carcinoma cells showed reduced malignancy after E-cadherin was expressed [57]. There is evidence to suggest that control of this expression is either through mutations in the E-cadherin gene, or altered E-cadherin protein expression through cadherin regulators such as Snail, Zeb-1, as well as the catenins [57]. More recently, epigenetic silencing of the E-cadherin gene has been identified in breast cancer cell lines [57].

Expression of E-cadherin was reported in both the first and second trimesters in cytotrophoblasts of early chorionic villi cytotrophoblasts cell columns [58]. As explained by Zhou et al. [58], E-cadherin was shown to reduce the invasive potential of cytotrophoblasts. These cells appeared highly epithelial, well attached to one another and retained polarity, all of these features being characteristic of epithelial cells. However, in cytotrophoblasts closer to the uterine wall, as well as those identified within the maternal decidua, E-cadherin was reduced. The question is what does this indicate for a role of EMT? Since cell columns lose their epithelial morphology and tight attachment to one another as they progress towards the maternal environment, it is likely that these cells are undergoing an EMT. Hence, these cells slowly acquire a mesenchymal, invasive phenotype coupled with reduced epithelial morphology and marker expression. E-cadherin is localised in cytotrophoblasts but absent in syncytiotrophoblasts [59], [60], [61]. Coutifaris et al. [61] reported E-cadherin expression by immunofluorescence and electron microscopy in trophoblast cell lines, whilst others have detected E-cadherin linking cytotrophoblast and syncytiotrophoblast [20], [61]. Floridon et al. [21] indicated the absence of E-cadherin in normal term interstitial trophoblasts and syncytiotrophoblast. They found that E-cadherin was localised in anchoring cells columns, but absent in distant trophoblasts. Expression of E-cadherin was reduced from first to third trimester [21], supporting the notion that E-cadherin-mediated invasion is more pronounced as trophoblast invasion peaks in the first trimester.

Another study showed that in normal human placentae, E-cadherin occurred in the membrane of villous trophoblasts, with a reduction of E-cadherin by third trimester [62]. In addition, E-cadherin has also been analysed in normal rodent placenta, with decreased expression shown in trophoblast giant cells [63].

Several studies link increased E-cadherin with PE. In Li et al. [62], PE tissues expressed E-cadherin at higher levels than that of normal placentae. Zhou et al. [58] showed that cytotrophoblasts of PE placentae expressed strong E-cadherin, including cells that had penetrated the uterine arterioles [58]. Brown et al. [64] also reported elevated E-cadherin in the cytotrophoblasts of PE placentae compared to syncytiotrophoblast, which suggests a significant role for E-cadherin-mediated increased proliferation of cytotrophoblast cells or poor differentiation of syncytiotrophoblast. These results are in contrast with a study by Blechschmidt et al. [65] who showed elevated Snail (a repressor of E-cadherin) coupled with reduced E-cadherin in PE pregnancies. All these studies suggest a role for E-cadherin in the placenta, with a difference in E-cadherin expression across normal and PE pregnancies. The controversy around the direction of difference needs to be resolved, but most studies favour a loss of E-cadherin as pregnancy develops, and a retention of E-cadherin in PE.

The pathways regulating cadherin expression are well characterised. The zinc-finger proteins Snail1, Snail2 (commonly known as ‘Slug’), ZEB-1 (EF1) and Smad-interacting proteins (SIP-1 or ZEB-2) bind to one of the three E-boxes of the E-cadherin promoter, repressing its expression [65], [66]. Regulation of the E-cadherin and β-catenin complex includes activation of Snail2 by β-catenin-TCF/LEF1 and activation of the ERK pathway. For example, when AJs are established in confluent cell cultures, the Erb-2, -3 and ERK pathways are inactivated. As a result, β-catenin is localised to AJs, Snail2 expression is reduced, and E-cadherin transcription is induced [50].

The coupled expression of E-cadherin and β-catenin has been shown to be critical for the stable assembly of a cytoskeleton structure, and maintenance of cell–cell contact in epithelial cells [68]. The cadherin intracellular domain interacts with the catenins, which are linked to the actin cytoskeleton. During the formation of AJs, β-catenin is sequestered to the junctions, initiating the expression of E-cadherin and stabilizing the cell–cell adhesion complex [50]. This is more clearly identified in dense cultures where cells are in close contact and maintain their attachment via this cadherin–catenin interaction [50]. Conversely, E-cadherin expression decreases dramatically from the cell cytoskeleton when cells become migratory. In normal cells, β-catenin is important in embryogenesis [69], and helps maintain the proliferative compartment of the adult epithelium in the intestine [70]. Interestingly, aberrant activation of β-catenin is a feature of colorectal cancer development [50].

Stabilisation of β-catenin through phosphorylation at tyrosine results in an association with transcription factors TCF/LEF1, and activation of several genes implicated in cell survival. In a study conducted by Hiscox et al. [71], breast cancer cells resistant to the anti-oestrogen tamoxifen were found to have elevated levels of the β-catenin-TCF/LEF1-dependent genes c-myc, cyclin D1, CD44 and cox-2 [71]. These findings showed that genes important in contributing to cell growth and/or oncogenesis are expressed when β-catenin is stabilised, tyrosine phosphorylated and translocated to the nucleus.

Interestingly, there is evidence to suggest that regulation of E-cadherin occurs similarly in the placental setting, suggesting a role for EMT in the human placenta. It is established that Snail family genes coupled with TCF/LEF processes, regulated by Wnt signaling, are important EMT in tumours. Trophoblasts, however, have shown to undergo invasion by growth factors, and Snail family genes are expressed by EVT. As such these may be important in regulating invasive or mesenchymal processes in of the placenta. It has been reported that elevated invasion of trophoblasts is coupled with reduced E-cadherin expression by anchoring villi [72]. Pollheimer et al. [72] also suggested a role for TCF’s in trophoblast invasive behaviour. These findings suggest a possible regulatory role for not only Wnt signaling and Snail gene expression in trophoblast invasion, but that EMT processes are happening in invasive trophoblast cells [72].

Overall, several studies have addressed the significance of the co-ordinate expression of β-catenin and E-cadherin for the development of a stable cell–cell adhesion network. The absence or altered expression of either one or both of these molecules results in two major physiological changes: a) reduced cell–cell contact and b) enhanced cellular mobility. Thus, the regulation of these molecules is central for the control of EMT and aberrant regulation of these events may contribute to pathologies such as FGR and PE in the placenta.

3.2. Neuronal (N)-Cadherin 

N-cadherin has recently been associated with accelerated EMT processes in certain tumours. Since invasive placental cells may operate using similar EMT events, future investigation of N-cadherin in placental trophoblasts may assist in identifying its role in these tissues. N-cadherin was originally identified in developing neural tissue, but has now been shown to be expressed in many mesenchymally derived cell types. One frequent hallmark of EMT is the switch from E-cadherin to N-cadherin when changing from an epithelial to a migratory capacity and N-cadherin expression may also be altered during MET [73]. During development, N-cadherin is involved in the organization and regulation of the nervous system, skeletal and cardiac muscles [74] and is often expressed by cells that are poised for EMT. A role for N-cadherin in malignancy has also been proposed, since it is frequently up-regulated in invasive cells where it functions as an invasion promoter [75]. Overall, recent studies have provided a great deal of evidence to suggest that N-cadherin is a marker for malignancy in many cancers and is an indication of EMT in many cells both normal and cancerous. However, the distribution, expression and functional role of N-cadherin are yet to be investigated in the human placenta. Thus, future studies describing the spatio-temporal distribution and identification of functional role on N-cadherin in the human placenta is warranted.

3.3. Placental (P)-cadherin 

Placental cadherin (P-cadherin) is also a member of the classical cadherin family. Originally defined in the murine placenta [76], P-cadherin was subsequently shown not to be expressed in the placenta of several other species, including human gestational tissues (Table 2; [58]). In the murine placenta it appears at early stages of pregnancy and may be involved in facilitating the binding of the placenta to the uterus [76], [77]. Interestingly, this group also reported that the human homologue of murine P-cadherin was well expressed in the mouse system [82]. Furthermore, P-cadherin expression is well described in mammary ducts and alveoli of the mouse. During pregnancy in the mouse, mammary ducts and alveoli form around a central luminal region. Myoepithelial cells surround the lumen and adhere to one another through P-cadherin. Cowin et al. [67] showed that in P-cadherin −/−mice, mammary development occurred early, indicating that loosening of myoepithelial cell junctions triggers ductal branching. In humans, on the other hand, E-cadherin is likely to be the main cadherin molecule expressed in the placenta, and not P-cadherin. Furthermore, in humans, P-cadherin expression and cancer progression is well documented in models of tumorigenesis [75]. Although some speculation exists as whether it may be a useful marker for poor prognosis, the mechanism regulating this association is yet to be elucidated.

3.4. Vascular endothelial (VE) cadherins 

Vascular endothelial (VE) cadherin appears in the human placenta, consistent with a role in cell adhesion. VE cadherin, (cadherin-5) facilitates the attachment of endothelial cells through calcium-dependent binding in blood vessel formation allowing consolidation of angiogenic sprouts [78]. Its localisation is specifically at the site of cell–cell contact [79]. Like all cadherins, VE cadherin structurally contains an extracellular region which is important for cell adhesion, whilst the cytoplasmic region is linked to β-catenin, connecting the actin cytoskeleton to cell–cell contacts. VE cadherin has been identified in human placentae, as summarized in Table 2. Zhou et al. [58] clearly point to the relevance of VE cadherin expression in the human placenta. Specifically, when VE cadherin was followed in second and third trimester tissues, positive expression was localised to cytotrophoblasts in cell columns and in the decidua, which were coupled with decreasing E-cadherin expression. Furthermore analysis of VE cadherin in decidual cells showed positive expression coupled with reduced E-cadherin [58], consistent with a role of VE cadherin in consolidation of extensions into the decidua comparable to the similar role in blood vessels.

This may help to explain the behaviour of cell columns which acquire a more invasive potential as they loosen their attachment to one another, gradually invading the maternal environment. The question remains, however, as to whether this apparent cadherin exchange is an EMT related process? Interestingly, the maternal decidua highly expresses the mesenchymal marker vimentin, which tends to be increased upon the reduced expression of E-cadherin. These findings suggest a role for an at least partial EMT-like process in the human trophoblast. Further examination of mesenchymal markers as well as epithelial EMT markers may help to establish and EMT profile in the process of trophoblast invasion. At term, VE cadherin is detected in placental vessels as well as in extravillous cytotrophoblasts [80]. VE cadherin is induced by vascular endothelial growth factor (VEGF), contributing to the assembly of endothelial cells [77]. In addition, N-cadherin (often up-regulated in EMT) is co-expressed in endothelial cells with VE cadherin, and can up regulate the levels of the latter [81]. VE cadherin is said to assist in the maternal and fetal interface, with particular relevance to remodeling of the vasculature. Specifically, a study by Bulla and others [82] reported the localisation of VE cadherin at the interface of extravillous trophoblasts and decidual endothelial cells, which suggest that these cadherins may be significant for this interaction. Interestingly, when assessing the expression of VE cadherin in confluent compared to less-attached cell populations, VE cadherin was not phosphorylated at tyrosine, a characteristic feature of these molecules in epithelial populations. Accelerated tyrosine phosphorylation was identified at VE cadherin in less-attached human vascular endothelial cells [83], correlated with the loosened adhesion of cells to one another. Although this has not been directly reported in the placenta, it is possible that this tyrosine phosphorylation interchange in trophoblasts may be indicative of an EMT phenotype. As such, the role of VE cadherin may be two-fold. It may be re-localised to facilitate cell migration and also be relevant for modulating calcium-dependent cell–cell adhesion when cells are in an organised polarized form during vascular regeneration of the placenta.

VE cadherin has also been studied in non-placental systems. For instance, VE cadherin was strongly expressed in arterial endothelial cells of human lung tissues, but its presence was not detectable in veins. Hence, VE cadherin appears vessel specific and may serve as a putative marker for arterial cells [84]. In a study by Tang et al. [79], which assessed tumour vasculature formation, inhibition of VE cadherin blocked the ability of VEGF to initiate microvascular tube formation. Moreover, this investigation also showed that green tea catechins inhibit angiogenesis by targeting VE cadherin. As such, these findings propose a role for VE cadherin in tumour vasculature formation.

VE cadherin 2 (proto-cadherin 12) has been reported in the murine placental endothelial cells as well as mesangial cells, kidney glomeruli and endothelial cells [85]. Furthermore, this same study described that this cadherin was expressed in glycogen-rich trophoblasts of the placenta, and might act as markers of these cells and mesangial cells [85]. During embryonic differentiation, VE cadherin 2 was identified in the vascular endothelium [85]. Rampon et al. [86] also showed that VE cadherin 2-deficient mice showed marked morphological changes, including reduced placental size and vascularisation, as well as defective segregation of the placental layer.

3.5. Cadherin-11 

Cadherin-11 may also be important in EMT events in the human placenta, as its expression has been identified in these tissues (Table 2). Cadherin-11 is a human cadherin belonging to the type-II family of cadherins. In normal development, cadherin-11 is associated with a number of early differentiation events. For instance, its expression was shown to be important for the regulation of mesoderm formation in rodent embryos. In addition, cadherin-11 is expressed by primary chondrocytes [87], cartilage and bone [88] and neuronal development [89], [90] Teratomas positive for cadherin-11 showed evidence of cartilage and bone formation, indicating a role for cadherin-11 in regulating differentiation of mesenchymal cells into both the osteocyte and chondrocyte cell types [88]. In the nervous system, Cadherin-11 promotes axon elongation in embryonic explant tissues [89] and in differentiation processes associated with motor neuron development and formation [90]. In addition, cadherin-11 is also believed to play a role as a tumour suppressor in retinoblastoma [91].

Cadherin-11 is another recognized cadherin molecule in the human placenta (Table 2). It has been associated with terminal differentiation of cytotrophoblasts into syncytiotrophoblasts [92], as well in the extravillous cytotrophoblast cell columns. Interestingly, cells expressing cadherin-11 showed reduced proliferation. Additionally, cadherin-11 positive placental cells show evidence of lowered E-cadherin, suggesting a role for cadherin-11 in placental EMT. These findings suggest that alternate expression of cadherin-11 and E-cadherin occurs when cells undergo a differentiating, and not proliferating potential. Localisation studies have confirmed cadherin-11 in epithelial cells of the human placenta. At term, however, cadherin-11 is absent in the decidua, as well as being absent in non-decidualised stroma, indicating that its expression is more important in early implantation, decidual development or decidualisation events. Cadherin-11 may also be important in endometrial and trophoblast interactions since cadherin-11 was shown to be expressed in glandular and surface epithelial cells of the maternal endometrium [93]. Furthermore, cadherin-11 is also localised to the stroma during decidualisation, and invading trophoblasts may interact with the decidual cells through cadherin-11. Regulation of these differentiation events in the human placenta appears to be through the expression of TGF-β1 signaling molecules, which increases mRNA and protein expression of cadherin-11 in cultured extravillous cytotrophoblasts [94].

One report investigated cadherin-11 in trophoblastic diseases, such as choriocarcinoma and hydatiform mole. Although the authors stated that no clear association existed with cadherin-11 and trophoblastic disease formation, the expression of cadherin-11 was reduced in choriocarcinoma [95]. This may be similar to the situation in retinoblastoma, where cadherin-11 expression is markedly lowered in aggressive tumour tissues [95]. In contrast, cadherin-11 was shown to be over-expressed in the hydatiform mole, and this may be explained by the fact that hydatiform mole tissue is not cancerous, but instead, a growing placental entity in the absence of a fetus. Hence, expression of cadherin-11 in these tissues may be similar to that observed in normal placentae. Overall, these findings implicate cadherin-11 in normal developing placentae. In addition, expression of cadherin-11 may also play a putative tumour-suppressive role in protecting the placenta since its absence has been shown to be prominent in choriocarcinoma development in gestational tissues.

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4. Overall conclusions 

This review outlines the expression and role of cadherins in the placental system. Comparisons were also made to other normal developmental systems and in cancer progression, particularly with respect to EMT. E-cadherin, VE and cadherin-11 were described with regards to their role in placentae compared to other normal and cancerous developmental tissues. Specifically E-cadherin is localised in more epithelial trophoblasts (i.e. cell columns and cytotrophoblasts) and reduced in third trimester tissues. For instance, evidence reporting the reduced expression of epithelial markers, elevated expression of mesenchymal markers and change in cell morphology reflect EMT-like processes in invading cell columns. These changes are similar to other developmental processes as well as the pattern shown in several tumours. As described in this review, first and second trimester epithelial cytotrophoblasts, express E-cadherin. These cells are arranged as an epithelial layer, which is polarized, therefore presenting with a more a cobble-stoned appearance, with clear cell–cell contact. Furthermore, cytotrophoblasts closer to the maternal environment, which is the region invaded by these cells, presented with reduced E-cadheirn and up-regulated VE cadherin. As stated by Zhou et al. [58], this is invasion ‘active’ region in early pregnancy. VE cadherin is recognized in vessels and extravillous cytotrophoblasts at term, and cadherin-11 is associated with terminal differentiation of trophoblasts. Thus, normal placentae express certain cadherins at differing stages of development. Interestingly, there is paucity of data describing the role of N-cadherin in human placentae, although this cadherin is related to EMT elsewhere. As such and we are in the process of establishing the role of N-cadherin with our collected human tissues. P-cadherin, on the other hand, is not expressed in human placental tissues. We, therefore, propose that regulation of certain cadherins, such as VE cadherin, Cadherin-11, and E-cadherin, are relevant in human placentation or placental development. In particular, it is likely that the regulation of these cadherins is important in maintaining cell–cell junctional complexes, as well as, when down-regulated, initiating events similar to developmental EMT, which lead to regulated migration and invasion of extravillous trophoblasts in the maternal environment. The question, however, yet remains as to what the role of cadherins specifically pose in two clinically relevant pregnancy disorders, PE and FGR. Since invasion of trophoblasts into the decidua is shallower than that of normal trophoblast cells, we hypothesise that compromised EMT and/or altered epithelial/mesenchymal balance may lead to this decreased invasion, and continued elevated cadherin levels may participate in this. Further analyses of EMT in the placenta may help explore this further in normal and diseased pregnancies such as PE and FGR, which present with reduced trophoblast invasion into the maternal environment. Our analyses of FGR and PE affected gestation tissues will, in future, help elucidate a role for specific cadherins in these diseases.

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PII: S0143-4004(10)00247-X

doi:10.1016/j.placenta.2010.06.017

Placenta
Volume 31, Issue 9 , Pages 747-755, September 2010

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