Trophoblast invasion the extracellular matrix and cell adhesion molecules

Cell adhesion molecules (CAMs) expressed on the surface of invasive cytotrophoblasts interact with the extracellular matrix (ECM) in the decidua to control invasion. The ECM of tissues is composed of a variety of proteins and polysaccharides assembled into an organized meshwork and are mainly produced by cells within the matrix (Alberts et al., 1994; Birk et al., 1991; Kreis and Vale, 1993). In most connective tissues, matrix molecules are secreted by fibroblasts or overlying epithelial sheets. The two main classes of molecules that make up the matrix are (i) polysaccharide chains of the glycosaminoglycan (GAG) class and (ii) fibrous proteins of two functional types: those which are mainly structural, e.g. collagen and elastin, and those which mainly play a role in attachment, e.g. fibronectin and laminin.

Cell adhesion molecules

The adhesion of cells to each other, to other cell types and to the ECM relies on the expression of CAMs and their ligands. At implantation, the trophoectoderm attaches to the uterine epithelial surface and CAMs play a major role. Interstitial and intravascular invasion of maternal tissue by trophoblast requires a new repertoire of CAM expression. Understanding the part played by adhesion molecules in pregnancy is paramount because pre-eclampsia as well as several pregnancy-associated disorders including fetal growth restriction, miscarriage and infertility problems have been linked to abnormalities in expression of particular CAMs and/or their ligands (Lyall, 1998). The majority of CAMs fall into one of four families: the immunoglobulin superfamily, the integrins, the selectins and the cadherins.

The cadherins include E-, N-, P-, R-, B- and VE-cadherins. The integrins bind to extracellular matrix proteins (fibronectin, fibrinogen, laminin, collagen, thrombospondin, vitronectin and von Willebrand factor) and to members of the immu-noglobulin superfamily such as intercellular adhesion molecule (ICAM)-1, 2 and 3, and vascular cell adhesion molecule (VCAM). All integrins are made up of two subunits, a and p. The ap pairing determines the binding specificities. The immunoglobulin family can act as calcium-independent intercellular adhesion molecules, signal-transducing receptors, or both. This family includes platelet endothelial cell adhesion molecule (PECAM-1), VCAM-1 and ICAM-1, 2 and

3. Although interactions between identical and non-identical family members are common amongst members of the immunoglobulin super-family, non-members have also been identified as ligands. These include LFA-1 and Mac-1 which bind ICAM-1 and VLA-4 and a4p7 which bind VCAM-1. Additional receptors include components of the ECM including collagen, heparin and heparan sulfate. Selectins are a group of cell adhesion molecules that bind to carbohydrates expressed on cells. The three members of this family, E, P and L-selectin, are involved in leukocyte extravasation.

Cytotrophoblast invasion and cell adhesion molecules

Cytotrophoblast invasion is analogous to tumor progression. It is accompanied by a reduction in proliferation as well as expression of specific proteinases (Fisher et al., 1989; Vicovac and Aplin, 1996). All highly invasive cells have altered expression of CAM phenotypes and matrix-degrading enzymes (Alexander and Werb, 1991). This is also the case for invasive cytotrophoblast.

In vivo studies suggest cytotrophoblast invasion is associated with switching of integrins and altered extracellular matrix expression

Much of the information on the mechanisms of human trophoblast invasion has come from studies on placental bed biopsies; these contain basal decidua and underlying myometrium with one or more uteroplacental (spiral) arteries. Immunohistochemical approaches have been used to study adhesion molecules and ECM components on first-trimester implantation sites. It is important to note that adhesion by integrins can also be mediated by switching from high- to low-affinity states without altered expression (Mould et al., 1995). Such studies suggest that marked changes in the expression of adhesion molecules and ECM components occur in parallel to the spatial distribution of cytotrophoblasts from the chorionic villi through to the uterine wall; however, the exact timing of these changes is unknown.

In the villi, where cytotrophoblasts exist as an epithelial monolayer anchored to the trophoblast basement membrane, trophoblast cells express integrin ECM receptors typical of many polarized epithelia (Carter et al., 1990; Larjava et al., 1990). a6/ß4 is the major integrin expressed by cytotro-phoblasts in villi (Aplin, 1993; Burrows et al., 1994; Damsky et al., 1992, 1994; Korhonen et al., 1991), while about a third of villous cytotrophoblasts weakly express a3/ß1. Within cell columns, where cytotrophoblasts are no longer associated with the basement membrane, fibronectin and collagen IV are no longer expressed. There is also a selective down-regulation of laminin production by cytotrophoblast (Church et al., 1997; Damsky et al., 1992; Leivo et al., 1989). The a3 integrin is no longer detectable; however, a6/ß4 remains intensely expressed (Damsky et al., 1992). Absence of proteins may also be due to the activity of matrix-degrading enzymes.

In the distal regions of the columns, cellular fibronectin (A+B+) and collagen IV expression increases (Damsky et al., 1992), moreover, onco-fetal fibronectin can be found (Feinberg and Kliman, 1993). The source of these is probably the cytotrophoblast. Matching the increase in fibronectin is a marked increase in the a5/ß1 subunits of the fibronectin receptor on cytotropho-blast cells (MacCalman and Chen, 1998), while the laminin receptor a6/ß4 decreases (Aplin, 1993; Damsky et al., 1992), although one study identified a6 in at least some cytotrophoblasts infiltrating the decidua (Aplin et al., 1990).

Within the placental bed cytotrophoblast cells exist as single cells or clusters of cells. Here they express a1/ß1 and a5/ß1 integrins (Damsky et al., 1992). In this area, decidual cells express a1/ß1 and a6/ß1 integrins (Damsky et al., 1992) and they interact primarily with matrix associated with maternal cells, i.e. fibronectin A+B+, collagen IV and laminins A (a1), B1 (ß1), B2 (g1) and M (a2). Different from the basal layer of stem cells, secretion of the ECM is not polarized but appears all over the surface of the cells (Castellucci et al., 1991; Huppertz etal., 1996). The matrix is no longer homogenous but shows a patchy mosaic pattern. Collagen IV laminin, heparan sulfate, fibronectins and vitronectins can be detected but not collagens I, III, VI or fibrin.

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