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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Oncogene. Author manuscript; available in PMC Sep 17, 2009.
Published in final edited form as:
PMCID: PMC2745643
NIHMSID: NIHMS131677

Cadherins and cancer: how does cadherin dysfunction promote tumor progression?

Abstract

It has long been recognized that the cell–cell adhesion receptor, E-cadherin, is an important determinant of tumor progression, serving as a suppressor of invasion and metastasis in many contexts. Yet how the loss of E-cadherin function promotes tumor progression is poorly understood. In this review, we focus on three potential underlying mechanisms: the capacity of E-cadherin to regulate β-catenin signaling in the canonical Wnt path-way; its potential to inhibit mitogenic signaling through growth factor receptors and the possible links between cadherins and the molecular determinants of epithelial polarity. Each of these potential mechanisms provides insights into the complexity that is likely responsible for the tumor-suppressive action of E-cadherin.

Keywords: E-cadherin, β-catenin, Wnt, growth factor receptor, cell polarity, metastasis

Introduction

In this review, we aim to explore the relationship between cadherin adhesion molecules and tumor progression. Ever since the classic demonstration that tumor cells adhere to one another less avidly than do non-tumor cells (Coman, 1944; Brugmans et al., 1978), the question of how adhesive dysfunction contributes to cancer biology has been an active issue in cancer research. The discovery that cadherin cell–cell adhesion receptors are key regulators of tissue architecture during development and in tissue homeostasis (Takeichi, 1991) provided molecular candidates to link cell–cell adhesion, morphogenesis and cancer.

Classical cadherins are versatile cell–cell adhesion receptors. As type 1 membrane glycoproteins, they function as dynamic membrane-spanning macro-molecular complexes (Goodwin and Yap, 2004). The extracellular regions are responsible for adhesive recognition, binding to the ectodomains of other cadherins presented on neighboring cells (Leckband and Prakasam, 2006). On the other side of the plasma membrane, the cadherin cytoplasmic tails interact with a range of proteins that link the cadherin receptor to fundamental intracellular processes, including the actin cytoskeleton, cell signaling and trafficking (Yap and Kovacs, 2003; Bryant and Stow, 2004; Mege et al., 2006). Indeed, because classical cadherins lack intrinsic enzymatic activity, their interactions with intracellular events occur through these intermediary proteins. The best-understood of these associated proteins are β-catenin, which binds directly to the distal region of the cytoplasmic tail; α-catenin, which is indirectly coupled to the cadherin complex by association with β-catenin; and p120-catenin which binds to the membrane-proximal region of the cadherin cytoplasmic tail. The biochemistry and biology of the catenins have been thoroughly encompassed in a number of recent review articles (Anastasiadis and Reynolds, 2000; Scott and Yap, 2006; Daugherty and Gottardi, 2007).

However, it is important to emphasize that these core catenins are not the only proteins that interact, physically or functionally, with classical cadherins. Indeed, a host of other cytoplasmic effectors can bind the cadherin directly or indirectly. These include cell signaling molecules, among them protein tyrosine kinases and protein tyrosine phosphatases (Perez-Moreno et al., 2003; McLachlan and Yap, 2007); cytoskeletal regulators that affect nucleation, filament dynamics, crosslinking and myosin motors (Mege et al., 2006) and determinants of epithelial polarity (Laprise et al., 2004; Iden et al., 2006). Accordingly, it is perhaps not surprising that classical cadherins affect many aspects of tissue architecture. These include establishing and maintaining cell-to-cell cohesion, thereby linking isolated cells into cohesive populations; cell–cell recognition during sorting and tissue reorganization; cell-upon-cell locomotion and epithelial polarity.

It is unlikely, though, that cadherins interact with all these potential partners simultaneously. Instead, there is emerging evidence that associations may be transient and regulated. For example, the actin-based motor, Myosin VI, is recruited only to E-cadherin complexes relatively late in the biogenesis of epithelial monolayers, as cell–cell contacts mature (Maddugoda et al., 2007). The precise biological impact of cadherin receptors is therefore likely to be determined by the exact set of proteins that they associate with, something that is, in turn, likely to vary depending on cellular context and cell signaling. Additionally, it is important to emphasize that some proteins interact with the cadherin regardless of whether the receptor is bound to other cadherins on neighboring cells. This is the case for β-catenin, which binds the unoccupied receptor on the cell surface and during intracellular membrane transport (Chen et al., 1999). Conversely, other protein interactions appear to occur when the cadherin is engaged in a productive adhesive interaction. This is consistent with the observation that classical cadherins, such as E-cadherin, can behave as adhesion-activated signaling receptors (Yap and Kovacs, 2003), stimulating intracellular signal-transduction pathways that ultimately affect processes as diverse as the cytoskeleton (Mege et al., 2006) and cell proliferation (Perrais et al., 2007).

Their broad-ranging effects on physiological tissue organization make cadherins attractive targets during tumorigenesis, the disruption of which might contribute to the aberrant morphogenetic effects in cancer. Indeed, it is now clear that classical cadherin dysfunction is a major contributor to cancer progression (Birchmeier and Behrens, 1994; Thiery, 2002). Because the majority of solid tumors are carcinomas that arise from epithelial tissues, the key target is the prototypical epithelial cadherin, E-cadherin. This large literature has been thoroughly surveyed in several earlier reviews, to which we refer readers for more comprehensive discussion (Birchmeier and Behrens, 1994; Berx et al., 1998; Thiery, 2002).

Briefly, the major lines of evidence for this conclusion include: (1) the pathologic demonstration that advanced cancers often have abnormal E-cadherin expression. Tumor progression correlates with loss of overall E-cadherin expression or loss of its normal localization at cell–cell contacts (Birchmeier and Behrens, 1994; Yap, 1998). (2) Evidence from both cellular and animal models that cadherin dysfunction promotes tumor progression to invasion and metastasis (Vleminckx et al., 1991). One notable example was the demonstration that expression of a dominant-negative cadherin mutant in a mouse pancreatic β-cell tumor model accelerated the rate at which adenomas converted into carcinomas (Perl et al., 1998). Conversely, over-expression of E-cadherin in those cells retarded tumor progression. More recently, Derksen et al. (2006) demonstrated that conditional deletion of E-cadherin in p53-deficient mouse mammary epithelium promoted tumor initiation and progression to invasion and metastasis. Thus, experimental manipulation established an inverse relationship between E-cadherin function and tumor progression. It is important to emphasize, however, that in mouse models loss of E-cadherin alone is not sufficient to induce tumor formation (Tinkle et al., 2004; Tunggal et al., 2005; Derksen et al., 2006). (3) The identification of both somatic and germline E-cadherin mutations in a number of cancers (Berx et al., 1998). Somatic mutations have been most thoroughly characterized in lobular breast cancer, but have also been identified in other tumors (Berx et al., 1995, 1996). Characteristically, these mutations are accompanied by loss of heterozygosity of the remaining E-cadherin allele, and correlate with tumor progression toward an invasive and metastatic phenotype. Germline mutations have also been reported in a number of families with diffuse gastric carcinoma (Guilford et al., 1998), suggesting that for some cancers cadherin mutations may act early in the natural history of the disease, indeed behaving as a classic tumor suppressor gene.

Mutation of the coding sequence, however, probably accounts for only a minority of cases of cadherin dysfunction in cancer. More commonly, cadherin expression is reduced by transcriptional silencing, notably through a variety of transcription factors that target the E-cadherin promoter (Thiery, 2002). These include transcriptional repressors of the Snail/slug family that are overexpressed in advanced carcinomas (reviewed in Moreno-Bueno et al., 2008); and the transcriptional repressors SIP1 and ZEB1, the aberrant expression of which may, in turn, reflect loss of inhibitory microRNAs (Gregory et al., 2008). Interestingly, many of these transcriptional events also occur in development during epithelial-to-mesenchymal transitions, where E-cadherin expression is characteristically lost (Yang and Weinberg, 2008). Given increasing evidence that aberrant epithelial-to-mesenchymal transition participates in tumor progression, this lends additional weight to the general concept that physiological processes regulating cadherin expression during development may be pathogenetically active to perturb E-cadherin expression in carcinomas.

Overall, then, these several lines of evidence demon-strate that E-cadherin function is perturbed in many epithelial carcinomas, and that this cadherin dysfunction promotes cancer progression to invasion and metastasis. What is less clear, though, is what mechanisms allow E-cadherin dysfunction—especially loss of cadherin expression—to promote tumor progression. This question is the subject of our review. It remains an open issue and we focus on three major areas: the role for β-catenin signaling; the impact of cadherins on mitogenic signaling and the capacity for cadherins to regulate epithelial cell polarity.

Cadherin loss and β-catenin signaling

The elephant in the room is β-catenin. In vertebrate systems, β-catenin was first identified as a binding partner for classical cadherins that interacted directly with the distal portion of the cadherin cytoplasmic tail (Nagafuchi and Takeichi, 1989; Ozawa et al., 1989). That it played a vital role in cadherin function was suggested by the demonstration that cadherin mutants lacking the β-catenin-binding domain were often poorly adhesive (Nagafuchi and Takeichi, 1989). In contrast, the Drosophila homolog of β-catenin, armadillo, was first identified as a component of the Wnt signaling pathway (Peifer and Wieschaus, 1990; Peifer et al., 1991). Only subsequently was it discovered that armadillo makes a genetically distinct contribution to cadherin function in flies (Sanson et al., 1996).

β-Catenin/armadillo supports cadherin-adhesive function by acting as an adaptor for a range of cytoplasmic proteins, many of which potentially interact, functionally and/or physically, with the actin cytoskeleton. The best known is α-catenin, which incorporates into the cadherin molecular complex by binding directly to β-catenin. α-Catenin has a clear and significant contribution to cadherin-based cell–cell interactions (Vasioukhin et al., 2001), but its mechanism of action is poorly understood (Scott and Yap, 2006). Once commonly thought to anchor cadherin complexes directly to cortical actin filaments, this simple model has not been experimentally verified. Alternatively, α-catenin may indirectly couple cadherins to actin filaments through proteins such as EPLIN (Abe and Takeichi, 2008), though α-catenin can also modulate actin filament nucleation in a cadherin-independent manner (Drees et al., 2005). Functional interaction with the actin cytoskeleton is not the only way that β-catenin can contribute to cadherin function, however, as it can bind many other proteins and is implicated in other aspects of cadherin biology, including post-Golgi transport of newly synthesized cadherin to the cell surface (Chen et al., 1999).

In Wnt signaling, β-catenin acts independently of the cadherin (Daugherty and Gottardi, 2007). Briefly, β-catenin can function as a transcriptional co-regulator, cooperating with transcription factors of the TCF (T-cell factor) family to determine gene expression. One key to the role of β-catenin in Wnt signaling is regulation of the cytosolic pool of β-catenin that is available to enter the nucleus and thereby modulate transcription. In the absence of Wnt signaling, this cytoplasmic pool is tightly controlled by a destruction complex, the key components of which include axin and the adenomatosis polyposis coli (APC) protein. Axin binds to β-catenin directly, and through co-recruitment of CK1 and GSK3β promotes the phosphorylation of serine residues in the N terminus of cytosolic β-catenin required for polyubiquitylation and subsequent proteosomal destruction (reviewed in Luo and Lin, 2004) (Figure 1). APC is thought to out-compete Axin for β-catenin, promoting β-catenin flux through the phosphorylation complex (Ha et al., 2004), and thus facilitating the degradation process. Thus, under basal conditions free cytosolic β-catenin levels are kept low by rapid degradation. Wnt signaling inhibits this degradative process by phosphorylating and inhibiting GSK3β, thereby allowing β-catenin to accumulate in the cytosol and enter the nucleus.

Figure 1
Overview of β-catenin signaling and its regulation. Free cytosolic β-catenin is regulated by the combination of a destruction complex (adenomatosis polyposis coli (APC), Axin, GSK3β and CK1) and binding to the cytoplasmic domain ...

β-Catenin signaling is an essential element in this canonical Wnt pathway both during development and physiological tissue turnover in post-embryonic life (Cadigan and Nusse, 1997). Thus, the fact that in mammalian systems Wnts were first discovered in screens for oncogenes (Fung et al., 1985; Brown et al., 1986) suggested the attractive notion that the pathologic expression of these important developmental regulators might also contribute to tumor progression. And, by implication, that components of the canonical Wnt pathway might be implicated in tumor biology. Indeed, activation of canonical Wnt signaling is a key early event in the vast majority of sporadic and familial colorectal cancers (Fodde and Brabletz, 2007). In the majority of cases, this hyperactive signaling occurs either through inactivating mutations in APC or mutations in β-catenin itself that render it resistant to phosphorylation by GSK3β. Similar roles for β-catenin signaling have been identified in skin, breast and hemopoietic tumors (Fodde and Brabletz, 2007). Aberrant β-catenin signaling in the canonical Wnt pathway is thus a well-established contributor to tumor biology.

The fact that cells use this common component, β-catenin, for the transactivation of TCF-dependent target genes and to support cadherin function, has long suggested a relationship between cadherins and Wnt signaling. Intuitively, it has been attractive to postulate that cadherin loss promotes tumorigenesis by effectively releasing membrane-bound β-catenin into the cytosol, hence stimulating canonical Wnt signaling. The key foundation for this idea is the demonstration that binding to cadherins can antagonize Wnt signaling by sequestering β-catenin at the membrane, thereby preventing it from entering the nucleus to transmit Wnt signals. Thus, forced overexpression of cadherins antagonizes Wnt/β-catenin signaling in Xenopus, Drosophila and cell culture models (Heasman et al., 1994; Fagotto et al., 1996; Sanson et al., 1996; Orsulic et al., 1999). Conversely, reductions in cadherin levels have been shown to enhance β-catenin signaling events associated with fly and mouse development (Cox et al., 1999; Ciruna and Rossant, 2001). These phenotypic data are supported by biochemical evidence that β-catenin uses the same binding interface to engage TCF and cadherin ligands (reviewed in Gottardi and Gumbiner, 2001), and that the cadherin can preferentially compete with TCFs for binding to β-catenin through superior binding affinity of the cadherin–catenin interaction (Choi et al., 2006). Taken together, these data suggest that cadherins effectively serve as a ‘sink’ for Wnt/β-catenin signals, such that the level of cadherin expression in a cell sets a threshold over which β-catenin protein levels must rise to gain access to the nucleus, bind TCFs and drive transcription.

However, although these gain- and loss-of-function experiments clearly demonstrate that cadherin levels can affect β-catenin signaling, the notion that cadherin loss is sufficient to promote β-catenin signaling by releasing it from the cadherin-bound pool is largely incorrect. For example, cancer cell lines that lack E-cadherin do not manifest a corresponding upregulation of β-catenin signaling (Caca et al., 1999; van de Wetering et al., 2001). Moreover, depletion of E-cadherin in a mouse model for pancreatic cancer (using the Rip-Tag system) showed no role for β-catenin signaling in the progression of these tumors (Herzig et al., 2007). This is because although a cadherin can bind a newly synthesized β-catenin, compete for its association with the Axin/APC degradation complex, and stabilize it (Sadot et al., 1998; Herzig et al., 2007), cadherin loss appears to let this process work in reverse, allowing the once cadherin-bound β-catenin to be consumed by the degradation machinery. Simply, loss of the cadherin alone does not increase β-catenin stabilization and signaling when the degradation pathway is intact.

However, if cadherin loss alone is not sufficient to activate β-catenin signaling, loss of the cadherin ‘sink’ can certainly amplify the cellular response to Wnt or Wnt-like signals (Cox et al., 1999; Ciruna and Rossant, 2001). For example, colon cancer cells that manifest β-catenin signaling activation through mutations in the APC tumor suppressor gene show enhanced transcriptional activation in the absence of E-cadherin (Gottardi et al., 2001; Kuphal and Behrens, 2006). Similarly, mammary epithelial cells expressing an estrogen-inducible cFos estrogen receptor fusion protein (FosER) exhibit β-catenin/TCF-dependent proliferative activity that can be potently attenuated by the cadherin (Eger et al., 2000; Stockinger et al., 2001). Thus, it appears that the cadherin’s capacity to buffer β-catenin is most critical during times when the cell is actively engaged in signaling. Furthermore, canonical Wnt signaling is often upregulated in tumors (Fodde and Brabletz, 2007). Wnt expression may be increased either from tumor cells themselves or secreted from stromal cells (notably macrophages). Alternatively, paracrine factors in the tumor environment, especially cytokines secreted by stromal cells, can amplify the intracellular Wnt signal-transduction pathway. For example, tumor necrosis factorα secreted from macrophages stimulates Akt (protein kinase B) that in turn phosphorylates and inhibits GSK3β activity, which ultimately promotes the stabilization of β-catenin (Oguma et al., 2008).

Thus, when we consider E-cadherin’s role as a tumor suppressor and its relationship to β-catenin, it is perhaps most accurate to consider that E-cadherin sets a threshold for Wnt/β-catenin signaling: high cadherin expression—as is typically found in epithelial tissues—serves to keep Wnt signals off, whereas cadherin loss can potentiate Wnt signaling driven at many points in the pathway. There are, though, additional levels of complexity. Some intriguing studies revealed that cadherin-mediated cell–cell adhesion and polarity (rather than changes in cadherin expression) may affect the strength or duration of Wnt/β-catenin signals through a poorly defined mechanism (Greaves et al., 1999; Hamada and Bienz, 2002; McCartney et al., 2006). Further, in this discussion we have focused on the impact that overt loss of E-cadherin may have on β-catenin signaling. A more subtle alternative is that the high-affinity cadherin–β-catenin interaction may be disrupted during oncogenesis, thereby perturbing E-cadherin adhesion as well as releasing β-catenin to signal (Nelson and Nusse, 2004). It is particularly attractive to postulate that tyrosine phosphorylation of β-catenin and/or E-cadherin by oncogenic kinases, such as Src, may serve just this dual purpose. Both these proteins, and other cadherin-binding proteins, are targets for tyrosine phosphorylation in cells (McLachlan and Yap, 2007); tyrosine phosphorylation of recombinant β-catenin disrupts its binding to cadherin in vitro (Roura et al., 1999); and reduced binding of β-catenin to cadherin has been reported in growth factor- or oncogene-transformed cells (Piedra et al., 2003; Bamji et al., 2006). How extensive a mechanism this may be remains an open question: the cadherin–β-catenin interaction is not always perturbed despite phosphorylation of β-catenin (Piedra et al., 2003) and cadherin adhesion is often regulated without detectable changes in cadherin–β-catenin association (Gumbiner, 2005). Any increase in free β-catenin may also be transient unless accompanied by changes in β-catenin degradation through the destruction complex. Clearly, much remains to be learnt about the relationship between E-cadherin and β-catenin signaling in cancer.

Cadherin regulation of growth factor signaling

A second avenue for E-cadherin to influence tumorigenesis is by modulation of mitogenic signaling. This notion was first suggested by observations that cadherin adhesion could influence cell proliferation in the PC9 lung carcinoma cell line (Watabe et al., 1994). Although these cells possess E-cadherin and β-catenin, they adhere poorly to one another due to lack of α-catenin. Restoration of α-catenin induced cell–cell cohesion and also retarded cell proliferation, suggesting that functional E-cadherin adhesion might participate in contact inhibition of growth. Growth factor stimulation is a major drive for cell proliferation and often upregulated in tumors. Notably, many epithelial cancers display high levels of EGF receptor (EGF-R, ErbB1), which is implicated in cell proliferation, invasion and metastasis (Bublil and Yarden, 2007). Indeed, a number of recent studies point to the potential for E-cadherin to inhibit or modulate signaling through the EGF receptor.

Support for this idea comes from the following lines of evidence. First, E-cadherin co-accumulates with EGF-R at cell–cell contacts (Fedor-Chaiken et al., 2003) and can physically interact with the EGF receptor (Hoschuetzky et al., 1994; Fedor-Chaiken et al., 2003; Qian et al., 2004) and also with other members of the ErbB receptor tyrosine kinase family (Ochiai et al., 1994). EGF-R did not, however, interact with N-cadherin, suggesting a degree of selectivity among the classical cadherins (Fedor-Chaiken et al., 2003; Qian et al., 2004). The molecular basis for this interaction remains controversial. Recombinant EGF-R can bind β-catenin in vitro (Hoschuetzky et al., 1994); however, in cells neither the β-catenin- or p120-ctn-binding regions appeared to be necessary for E-cadherin and EGF-R to co-immunoprecipitate (Fedor-Chaiken et al., 2003; Qian et al., 2004). Instead, the interaction appeared to map to the extracellular domain of E-cadherin. Regardless, E-cadherin and EGF-R have the capacity to interact functionally with one another.

Second, E-cadherin can inhibit cell responsiveness to EGF stimulation (Qian et al., 2004; Perrais et al., 2007). This was first suggested by Qian et al. (2004) who observed that mitogenic responsiveness to EGF (measured by cell proliferation and activation of Ras signaling) decreased as cells grew to confluence. However, this desensitization was overcome by adding antibodies that block E-cadherin function. Interdicting the cadherin increased both EGF receptor autophosphorylation and EGF-induced DNA synthesis. This implied that E-cadherin exerted an effect at a receptor-proximal point in the signaling pathway with ramifications to downstream targets. Although these experiments identified a role for cadherin adhesion, they did not distinguish whether inhibition of EGF-R signaling occurred as a direct response to E-cadherin homophilic ligation or more indirectly through the many other juxtacrine events that occur when cadherin adhesion brings cell surfaces into contact with one another.

Perrais et al. (2007) addressed this issue directly, developing assays using recombinant cadherin ligands to test whether homophilic ligation of E-cadherin was sufficient to affect cell proliferation. They found that E-cadherin ligation inhibited serum-stimulated cell proliferation through a mechanism that required the ability of cadherin to bind β-catenin, but did not appear to involve the canonical Wnt/β-catenin signaling pathway. Further, they demonstrated that E-cadherin ligation inhibited EGF-induced cell proliferation. Interestingly, in their experiments, E-cadherin binding did not appear to affect either the ability of EGF-R to undergo autophosphorylation or to stimulate ERK signaling. Instead, homophilicligation disrupted the ability of EGF-R to activate the Stat 5b signaling pathway that leads to ERK-independent DNA synthesis.

Taken together, these recent studies suggest the broad capacity for E-cadherin to negatively regulate mitogenic signaling through EGF-R. It remains to be seen whether the differences between these two studies reflect the different experimental systems used or whether cadherin adhesion may affect EGF-R signaling by multiple pathways involving both direct pathways from homophilic ligation and possible juxtacrine effects. We do not have a clear picture of how cadherin adhesion inhibits EGF-R signaling. It is likely to be complex. Blocking cadherin function decreased receptor affinity for EGF and also increased the apparent surface mobility of EGF-R, as measured by FRAP (Qian et al., 2004). This would be consistent with the observation that cadherin modulated EGF-R autophosphorylation (Qian et al., 2004), though not with a more secondary effect on Stat 5b signaling (Perrais et al., 2007). An interesting alternative model is presented in endothelial cells, where VE-cadherin interacts with the VEGF-receptor 2 (VEGF-R2). Here, VEGF stimulation induces the clathrin-dependent internalization of VEGF-R2, which leads to sustained signaling from the internalized receptors (Lampugnani et al., 2006). It is noted that VE-cadherin can associate with VEGF-R2 and inhibit its internalization. This suggests that VE-cadherin may inhibit mitogenic signaling by VEGF-R2 by preventing its internalization and entry into an endomembrane compartment. Whether something similar occurs for E-cadherin and EGF-R is an interesting issue for future research.

E-cadherin, polarity and tumorigenesis

Finally, let us discuss the potential relationship between E-cadherin and polarity. Apico-basal polarization is a defining feature of epithelial cells—most apparent in simple transporting epithelia. Ultimately, the functional asymmetry of membrane composition and cytoskeletal and organellar organization supports many aspects of epithelial function, among them regulated transport across tissue barriers in the body (Rodriguez-Boulan and Nelson, 1989). Loss of normal plasma membrane polarization in epithelial cancers was an early observation when antibodies to polarized membrane markers became readily available (Molitoris and Nelson, 1990). However, it was the subsequent discovery in Drosophila of tumor suppressor genes that are physiological determinants of epithelial polarity (Bilder, 2004; Lee and Vasioukhin, 2008) that has catalysed recent interest in the regulation of polarity as a determinant of tumorigenesis.

It has long been recognized that E-cadherin is functionally linked to the generation of a polarized epithelial phenotype. Early studies that used inhibitory antibodies to acutely block E-cadherin function demonstrated that this adhesion receptor was necessary for isolated cells to make productive contacts with one another and for the subsequent processes of epithelial biogenesis, notably epithelial polarization (Gumbiner et al., 1988; Wheelock and Jensen, 1992). There is also genetic evidence to link E-cadherin and epithelial polarity: apical markers are mislocalized in the Drosophila neuroepithelium in DE-cadherin (Shotgun) mutant embryos (Tepass et al., 1996). These findings are complemented by the observation that E-cadherin supported assembly of tight junctions (Gumbiner et al., 1988), thought to assist in segregating membrane domains, and by the recent demonstration that E-cadherin adhesions may contribute to the polarized targeting of basolateral membrane components (Nejsum and Nelson, 2007). This emphasizes that a major impact of cadherin may be on biogenesis of the basolateral membrane domain; indeed, epithelial cells begin to segregate apical membrane markers in response to substrate, even in the absence of cell–cell adhesion (Vega-Salas et al., 1987). However, the precise mechanisms that allow E-cadherin adhesion to influence epithelial polarity remain incompletely understood.

The exciting advance has been the identification of highly conserved groups of polarity-determining factors that act as membrane proteins, scaffolds and signaling molecules to support polarized cellular asymmetry in many different contexts (Kemphues et al., 1988; Tepass et al., 1990; Bilder et al., 2000). There are three major groups of polarity determinants that function in epithelia; these are discussed in greater depth in other reviews in this issue. But briefly, the Crumbs/Stardust/Discs lost complex (Crb/Sdt/Dlt) localizes to the apical membrane and has a key function in apical membrane biogenesis (Tepass et al., 1990; Tepass and Knust, 1993; Bhat et al., 1999); the Par3/Par6/aPKC complex is found in the region of tight junctions at the apico-lateral interface (Kemphues et al., 1988; Tabuse et al., 1998; Petronczki and Knoblich, 2001) and the Scribble/Discs large/Lethal giant larvae complex (Scrib/Dlg/Lgl) is found at the lateral membrane (Bilder et al., 2000). Some of these were first identified as tumor suppressor genes in Drosophila (Bilder, 2004). Geneticand cellular studies have implicated all these molecules in the control of apico-basal epithelial polarity. They have also demonstrated functional interplay, by positive and negative feedback, between the different complexes to maintain their asymmetric localization within cells (Bilder and Perrimon, 2000; Benton and St Johnston, 2003; Tanentzapf and Tepass, 2003; Yamanaka et al., 2003). Further, loss of one protein in a complex often leads to mislocalization and disruption of the other proteins in the complex, indicating interdependence within complexes (Tabuse et al., 1998; Bilder et al., 2000).

The tantalizing question, then, is whether E-cadherin may influence epithelial polarity through one or several of these polarity factors. If this were the case, it would suggest the possibility that cadherin dysfunction might promote tumorigenesis by disrupting the action of a polarity determinant. There are, indeed, early hints of physical and functional links between E-cadherin and certain polarity factors. Consistent with their roles as basolateral determinants, members of the Scrib/Dlg complex are found at cadherin-based cell–cell contacts. Dlg colocalizes with E-cadherin both during cellularization of the Drosophila ectoderm (Harris and Peifer, 2004) and in cultured mammalian epithelial cells, where it can form a complex with the cadherin (Reuver and Garner, 1998; Laprise et al., 2004). Scribble, too, is found with E-cadherin at lateral membranes, though there is no evidence for a physical interaction to date (Navarro et al., 2005; Qin et al., 2005). Moreover, expression of E-cadherin in cadherin-null cells induced the relocalization of both Dlg and Scribble into those contacts (Reuver and Garner, 1998; Navarro et al., 2005), suggesting that cadherin adhesion can influence the subcellular localization of these polarity determinants.

E-cadherin also has links with elements of the Par complex. Although in mature mammalian epithelia, these proteins often show a restricted localization to the region of tight junctions, aPKC and Par3 can be found in MTD1-A cells after punctate adherens junctions had formed (Suzuki et al., 2002). In Drosophila, Bazooka (Par3) also localizes with DE-cadherin in apical adherens junctions (Harris and Peifer, 2004). Moreover, cadherins can interact physically with elements of the Par complex. VE-cadherin was reported to bind Par3 and Par6 (Iden et al., 2006), whereas chick N-cadherin formed a complex with Par3 (Afonso and Henrique, 2006). Whether similar interactions occur with E-cadherin remains to be determined.

Finally, genetic studies have provided perhaps the most striking evidence that places cadherin adhesion potentially upstream of polarity factors. In the early Drosophila embryo, disruption of adherens junctions in Armadillo mutant animals prevented Dlg from segregating from the apical to the basolateral domain (Harris and Peifer, 2004), and also perturbed the apical localization of Bazooka in some studies (Bilder et al., 2003), though not in others (Harris and Peifer, 2004). Indeed, in the latter case, Bazooka was necessary for the integrity of adherens junctions. This emphasizes the likely complexity of genetic inter-relationships between cadherins and polarity determinants. A requirement for a functioning cadherin–catenin complex is also suggested by studies in mice, where conditional knockout of α-catenin caused mislocalization of LGN, Par3 and aPKC (Lechler and Fuchs, 2005).

Overall, then, there are encouraging signs that E-cadherin may contribute to epithelial polarization by regulating the subcellular localization of some of the canonical polarity factors. The extent of such impact and the mechanisms responsible are important issues that need to be determined. Whether any such mechanism contributes to the impact of cadherin dysfunction on tumorigenesis is also an open question. It is important to emphasize that the relationship between E-cadherin and polarity is complex. Whereas acutely perturbing E-cadherin can prevent cells from effectively establishing a polarized phenotype, steady-state depletion of E-cadherin often does not overtly affect maintenance of polarity (Tunggal et al., 2005; Capaldo and Macara, 2007). Further, polarity factors may feedback on cadherin function (Qin et al., 2005), adding a level of complexity to their functional interrelationship.

Conclusions and future directions

Clearly, then, we cannot yet provide any simple answer to the question of how E-cadherin dysfunction promotes tumor progression. Indeed, the many recent advances in our knowledge would strongly suggest that there is no simple answer; the rich complexity of cadherin biology would perhaps make this an unreasonable ambition. Moreover, there are many other phenomena that we have not discussed in this short overview, among them the potential role of other catenins (Yanagisawa et al., 2008) and pathogenetic expression of other cadherins (notably N-cadherin) when E-cadherin is lost (Wheelock et al., 2008). E-cadherin dysfunction is likely to affect tumor cell biology in many ways. In this regard, how we frame the relevant problems in tumor cell biology will critically influence the analysis of cadherin dysfunction. Much of the current literature, and our discussion, focuses on how E-cadherin may regulate tumor cell proliferation. But a major physiological impact of E-cadherin and other cadherins occurs by regulating morphogenesis (Gumbiner, 2005). This morphogenetic impact involves cellular processes such as cell–cell recognition, regulation of the cytoskeleton, dynamic control of surface adhesion, many of these integrated through cell signaling. To what extent might dysregulation of mechanisms for morphogenesis contribute to tumor progression? The emerging notion that aberrant expression of epithelial-to-mesenchymal transitions contributes to tumor invasion and metastasis provides an example of how a morphogenetic process active in development may be pathogenetic when aberrantly expressed in tumors (Yang and Weinberg, 2008). Interestingly, the transcription factor Twist was recently observed to be upregulated when E-cadherin was depleted in cultured epithelial cells (Onder et al., 2008). As Twist can drive epithelial-to-mesenchymal transition (Yang et al., 2004), this provides a novel potential pathway for cadherin loss to drive morphogenetic changes in tumors. It is unlikely that this will be the last.

Acknowledgments

We thank our colleagues in our labs for their thoughtful comments and support. AJ and ASY were funded by the National Health and Medical Research Council of Australia, whereas CJG is funded by the NIH (GM076561).

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