Cell adhesion molecules and adhesion abnormalities in prostate cancer

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Science Ireland Ltd. All rights reserved. Keywords: b-catenin; Cadherin; Prostate cancer; ...... Science 1993;262:1731–4. [48] Su LK, Vogelstein B, Kinzler KW.
Critical Reviews in Oncology/Hematology 41 (2002) 11 – 28 www.elsevier.com/locate/critrevonc

Cell adhesion molecules and adhesion abnormalities in prostate cancer Malcolm D. Mason a,*, Gaynor Davies b, Wen G. Jiang b a

Department of Clinical Oncology, Uni6ersity of Wales College of Medicine, Health Park, Cardiff CF14 4XN, UK b Department of Surgery, Uni6ersity of Wales College of Medicine, Health Park, Cardiff CF14 4XN, UK Accepted 28 May 2001

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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2. Cell adhesion molecules . . . . . . . . . . . . . . . . 2.1. Cell–matrix adhesion molecules . . . . . . . . . 2.2. Selectins and Immunoglobulin superfamily . . . 2.3. Cadherins . . . . . . . . . . . . . . . . . . . . . . 2.4. Other cellular adhesive molecules and adhesion

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4. Cadherin adhesion complex and regulation of cell growth . . . . . . . . . . . . . . . . . . . . . . .

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5. Regulation of cadherin mediated cell–cell adhesion . . . . . . . . . . . . . . . . . . . . . . . . . . .

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6. Abnormalities of cadherin mediated cell adhesion in cancer . . . . . . . . . . . . . . . . . . . . . .

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3. Cadherin adhesion complex and signalling events . . . . . . . . . . . . . . . . . . 3.1. Main components of the cadherin complex . . . . . . . . . . . . . . . . . . . 3.2. Cadherin complex mediates cell–cell adhesion . . . . . . . . . . . . . . . . . . 3.3. Catenins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. b-catenin is a central player in intracellular signalling . . . . . . . . . . . . . 3.4.1. b-catenin interacts with a number of intracellular molecules . . . . . . 3.4.2. Degradation of b-catenin is regulated by Wnt signalling pathway . . . 3.4.3. p120 catenin family, another expanding family of cadherin associated 3.5. b-catenin and its role in gene expression . . . . . . . . . . . . . . . . . . . . .

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7. Cell adhesion molecules, disease progression and prognosis in urological tumours . . . . . . . . .

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8. Soluble adhesion molecules and cancer invasion/metastasis . . . . . . . . . . . . . . . . . . . . . . .

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9. Summary and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author. Tel.: + 44-29-2031-6964; fax: + 44-29-2052-9625. E-mail address: [email protected] (M.D. Mason). 1040-8428/01/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 0 4 0 - 8 4 2 8 ( 0 1 ) 0 0 1 7 1 - 8

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Abstract Prostate cancer, the leading male cancer in Western countries, has accelerated in its incidence in the past decade. Patients with prostate cancer frequently have a poor prognosis as a result of local or distant spread of cancer. This review summarises some of the recent progress made in understanding the biology of cancer metastasis with a special emphasis on the role of cell adhesion molecules and adhesion abnormalities. The molecular and cellular function of cell adhesion molecules, their role in cancer and cancer progression, the clinical impact of these molecules, and therapeutic considerations are also discussed. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: b-catenin; Cadherin; Prostate cancer; Cell adhesion

1. Introduction Despite the steady decline in the incidence of, and mortality from, many cancers, the incidence of prostate cancer has overtaken lung cancer in many Western countries. The mortality of patients with prostate cancer has increased at a rate of 1 and 1.8% in white and black males, respectively, in recent years. This stems from an incidence rate of prostate cancer of 121.2 per 100 000 in white males and 163.1 in black males in the USA [1,2]. Lymph node metastasis, capsule penetration and seminal vesicle invasion are some of the factors associated with the prognosis of these patients. Most prostate cancer deaths are due to metastatic disease, but we do not have an effective means to combat metastasis in prostate cancer. Although the biological basis of progressive and metastatic behaviour of prostate cancer is yet to be fully established, aspects of the molecular and cellular biology underlying the metastatic process are increasingly recognised. The metastatic cascade is composed of a number of separate but important steps, including detachment of cancer cells from the primary tumour, adhesion to and degradation/invasion of the extracellular matrix, invasion of blood vessels, homing, extravasasion, re-establishment of secondary foci, and angiogenesis [3– 5]. One of the prominent features of the development and progression of prostate cancer is the development of abnormalities in cell adhesion in prostate epithelium and prostate cancer cells. These abnormalities extend to inter-cellular adhesion structures and cell– matrix adhesion molecules. This article will focus on cell– cell adhesion molecules in prostate cancer, with special emphasis on cadherin and related molecules.

tions [6–9]. These molecules form the key structures that maintain the normal structure, integrity and function of cells and tissues. They act as key mediators in a variety of processes such as cell motility, tissue integrity and the maintenance of tissue differentiation [6,7]. In addition, these molecules are involved widely in morphogenesis [10], embryogenesis and organogenesis by mediating adhesive processes [7,11,12].

2.1. Cell–matrix adhesion molecules Adhesion of cells to matrix components is mediated by a large family of proteins known as integrins. Integrins are transmembrane proteins formed by heterodimerisation of an a- and b-subunit. The extracellular domain of integrins has binding sites for extracellular proteins and, upon interacting with the matrix, they form links between the cell and matrix components. The intracellular domain of integrins has binding sites for a range of molecules that will coordinate intracellular events (by mediating extracellular signals into and/or intracellular signals out of the cell). The specificity of action of integrins on matrix components is mainly determined by the different combination of its subunits. Currently, there are at least 18 a units and nine b units known. These subunits form a number of different integrins which interact with various matrix components. Integrins are the key proteins in the formation of hemidesmosomes and focal adhesion complexes, the two main cell –matrix adhesion structures. These topics have been extensively reviewed elsewhere [13 –16] and are not covered by the current article.

2.2. Selectins and immunoglobulin superfamily 2. Cell adhesion molecules Cell adhesion molecules, also known as CAMs, are divided into four major categories: cadherins, integrins, selectins and members of the immunoglobulin superfamily. Adhesion molecules mediate the process of cell adhesion through either cell– matrix or cell– cell interac-

Selectins (endogenous lectins) are calcium-dependent carbohydrate binding proteins and are members of the lectin cell adhesion molecule family. They are found on leukocytes, platelets and endothelial cells as well as tumour cells. They are also shown to be involved in tumour adhesion to other cells, such as endothelial cells.

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2.3. Cadherins Cadherins belong to a family of transmembrane glycoproteins that mediate intercellular cell– cell adhesion in the presence of extracellular calcium [7]. Cell–cell adhesion in cadherins is mainly mediated by homotypic interactions. However, heterotypic interactions are also possible between different cadherin molecules [11]. Cadherins are classified according to the structural and functional similarities which they share. Typically, classical cadherins are composed of five tandem repeats in the N-terminal extracellular domain, and a single transmembrane segment containing a carboxy terminal in the intracellular domain [20,21]. Cell– cell adhesion is mediated by the N-terminal portion of the extracellular domain [22]. The anchorage of cadherins to the cytoskeleton is mediated by the carboxy terminal portion of the intracellular domain, via interactions with a group of cytoplasmic proteins known as catenins [23]. There are about 20 or so different cadherin molecules currently classified, with additional family members continuously being added to this growing superfamily of cell adhesion molecules [24,25]. The most extensively studied cadherins are: E- (epithelial), N- (neural) and P-(placental) cadherin. Although cadherins are mainly tissue type specific, they have been found transiently expressed in various other tissues during development. For example, the presence of E-cadherin is confined to the epithelium, but it has also been shown to exist in glia and some types of neurone cells [7]. In addition, N-cadherin is found in local regions of epithelial cells [6], and P-cadherin is expressed in the basal and lower layers of stratified epithelial and mesothelium cells [7,26].

2.4. Other cellular adhesi6e molecules and adhesion structures Tight junction proteins, such as occludin and claudin family members, are transmembrane proteins. Their role in the formation and function of tight junction has been firmly established [18,19]. However, it has been shown that these molecules also have the ability to mediate cell– cell adhesion in epithelial and endothelial cells, and therefore may find themselves in the front line during the invasion of endothelial structure by tumour cells [17].

3. Cadherin adhesion complex and signalling events Although cadherins and their associated molecules were initially thought to function solely as cell adhesion molecules, recent developments in this area have demonstrated that the function of these molecules go well beyond regulation of cell adhesion. This is reflected

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by the increasing number of molecules associated with the complex, the pathways that are mediated by the complex, and the increased number of cellular events as a result of the adhesion complex.

3.1. Main components of the cadherin complex The cadherin complex is composed of the following components: cadherin, intracellular components associated with cadherin (such as catenins), and the cytoskeleton (such as actin) (Fig. 1). Catenins are a group of cytoplasmic proteins which interact with the intracellular domain of the cadherin molecule, providing anchorage to the microfilament cytoskeleton and regulate the function of cadherins [10,27–29]. The three main catenin types identified according to their electrophoretic mobility on SDS-PAGE are: a-, b- and g-catenins [27–30]. a-catenin has been reported to provide direct mechanical linkage to the actin cytoskeleton, as it shares partial homology with the actinbinding protein vinculin [31,32]. In addition, a protein molecule called p120cas has also been identified as another catenin family member [33–35]. Furthermore, this cadherin-associated src (Rous Sarcoma virus gene family) substrate (p120cas) has also been implicated as a tyrosine kinase substrate, after phosphorylation by several receptor tyrosine kinases, such as: epidermal growth factor, platelet-derived growth factor and colony stimulatory factor-1 [36,37]. In addition, p120cas shares partial homology with: b-catenin, plakoglobin (g-catenin) and the Drosophila segment polarity gene product armadillo [33,38–40].

3.2. The cadherin complex mediates cell–cell adhesion The biochemical basis by which cadherins mediate cell–cell adhesion is perhaps best demonstrated by that of E-cadherin (Figs. 1 and 2). E-cadherin, widely expressed in epithelial cells, is a protein of 120 kDa in size that has three domains, the extracellular, the transmembrane, and the intracellular. The extracellular domain of E-cadherin has five cadherin repeats (Fig. 2). These repeats allow cadherins to form homotypic interactions in the presence of extracellular calcium, thus forming a zip-like structure between two cells (Fig. 2) and offering the strongest cell–cell adhesion mechanism in the epithelium. When cells contact each other, they use E-cadherin molecules already on the cell surface to rapidly form an adhesion structure. E-cadherin has a short half-life once synthesised (5–10 h). The subsequent assembly and turnover of the adhesion structure are processes regulated by complex biochemistry, which involve cadherin synthesis, degradation and the generation of other external or internal signals. Furthermore, it has been demonstrated that the homotypic binding capacity is conferred by the HAV

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sequence, a domain located in the first cadherin repeat of E-cadherin. Disruption or mutations of the HAV domain results in damage to cell adhesion [41,42]. High resolution crystal analysis has shown the formation of

cis/trans dimmers of E-cadherin (Fig. 2). The formation of the cadherin–cadherin dimers is dependent upon the existence of extracellular calcium. When calcium concentrations increase from 0 to 1 mM, a shift is seen

Fig. 1. Cadherin complex. Fig. 2. E-cadherin structure and binding sites. E-cadherin molecules have binding sites for catenins and p120cas. E-cadherin uses its HAV domain to form cis and trans links.

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from a disordered cadherin structure to a rigid and rod-like structure (cis dimer), followed by a trans dimer of multiple cis dimers, where the trans dimers formed a ‘zipper’ structure (Fig. 2). The HAV domain is involved in the formation of trans dimers. The p120cas family may also be involved in the formation of trans dimers (discussed in later sections). A number of methods can be used to disrupt E-cadherin mediated cell– cell adhesion, including antibodies to E-cadherin, antisense to E-cadherin, mutation of HAV and the intracellular domain of the molecule, and disruption of cadherin associated molecules (Fig. 3). Disruption to the cadherin complex results in the dissociation of cancer cells, and a gain in invasiveness (Fig. 3). These events and their implications in cancer are discussed later in this article

3.3. Catenins Both b-catenin and plakoglobin associate directly with cadherin, and can be substituted for each other within the cadherin– catenin complex [43– 46]. In addition, plakoglobin, b-catenin, and armadillo share partial homology with the protein product of the tumour suppressor gene, APC [47– 50]. APC can stabilise the level of either b-catenin, or plakoglobin, by complexing with glycogen synthase kinase-3b (GSK3b) [51]. Such complexes form part of the signalling pathway driven by the secreted glycoprotein wingless (Wg/Wnt) in Drosophila [52]. Alterations in the expression of catenin proteins in vivo may play important roles in the initiation of metastatic spread of tumour cells [53]. Reduced level, or loss of a-catenin expression is likely to result in an impairment in E-cadherin function [54,55]. Furthermore, deletion of the a-catenin gene in vitro results in the inactivation of E-cadherin-mediated cell– cell adhesion in prostate cancer cells [56]. Dysfunction or mutation of b-catenin may also result in cell– cell disengagement, and in subsequent invasion [57]. Tyrosine phosphorylation of b-catenin affects the cadherin/catenin complex in metastatic fibroblasts [58], and breast cancer cells [59], respectively. b-catenin has recently been identified as an oncogene, while its homolgue g-catenin (plakoglobin) appears to suppress tumorigenicity [60].

3.4. i-catenin is a central player in intracellular signalling 3.4.1. i-catenin interacts with a number of intracellular molecules b-catenin was initially discovered as an associated protein of the cadherin complex. However, it was soon realised to be a central player in a chain of complex signalling events. This was manifested by the presence of binding domains, and by its interactions with an

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array of other molecules important in signalling and gene expression including cadherin, a-catenin, axin, GSK3b, and APC (Figs. 4 and 5). The formation of the cytoplasmic b-catenin complex with these molecules is a regulated event that is determined by the other intra- or extracellular signals. The complex not only decides the fate of b-catenin, but also directly influences a number of cellular events and gene transcription (Fig. 4). It is well established that b-catenin interacts with glycogen synthase kinase 3b (GSK3b) (Fig. 4). Upon binding to b-catenin, GSK3b phosphorylates b-catenin on serine and threonine residues, which is subsequently targeted for ubiquination for rapid degradation in the proteosome [61,62]. However, it was soon discovered that the cytoplasmic interaction of b-catenin occurs in a more complex pattern, involving molecules seemingly unrelated to the complex. These molecules are discussed in later sections. APC is a large protein of approximately 300 kDa, encoded by the adenomatous polyposis coli gene. A number of 15 amino-acid and 20 amino-acid repeats in the protein molecule of APC are found at the location which allows b-catenin to interact (Fig. 5) [47– 50,63]. These amino acid repeats form the main basis of APC’s interaction with b-catenin. Within the APC protein there are also repeats where other molecules can bind, notably the SAMP repeats. These are critical sites for meditating the interaction of the APC molecule with another small group of proteins known as axin and conductin (Fig. 5). Axin, encoded by AXIN1 was cloned from a mouse mutant with body-axis duplication and was found to have a direct interaction site with b-catenin (Fig. 5) [63–65]. Axin homologues include conductin and an axin-like protein (Axil). b-catenin and GSK3b bind simultaneously to axin, as these interact at different locations. It appears that axin acts as a docking platform for APC, GSK3b and b-catenin [66]. When these proteins form a complex, axin increases the phosphorylation of b-catenin by GSK3b and accelerates the degradation of b-catenin [66]. GSK3b is able to phosphorylate APC and this phosphorylation is further enhanced by the binding of axin/ conductin to APC. Perhaps the most interesting feature of APC in cancers, particularly in colon cancer, is the frequent mutation in regions including the binding site for b-catenin and GSK3b. These mutations eventually lead to damage of the b-catenin complex and prevent effective phosphorylation of b-catenin. This would lead to accumulation of b-catenin in the nucleus, a feature frequently seen in cancer cells. Recently, another APC like protein was identified known as APCL or APC2 [67]. The overall structure of APC2 is similar to that of APC. It is smaller in size (approximately 550 amino acids shorter than APC) and has retained the 20 amino

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Fig. 3. Damage of the function or the structure of E-cadherin leads to the dissociation of cancer cells. Fig. 4. Interaction of b-catenin with other molecules and its regulation of gene expression.

therefore, a down-regulator of the cytoplasmic bcatenin [67]. Changes in APC2 in cancers, particularly mutations in the b-catenin and GSK3b binding sites, require extensive study in future.

3.4.2. Degradation of i-catenin is regulated by Wnt signalling pathway As already discussed, the interaction of APC, GSK3b, and axin decides the fate of b-catenin. How-

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ever, the activation of the degradation process is itself highly regulated. This is achieved by a pathway known as the Wnt signalling pathway. Wnt proteins are a family of cysteine rich secreted ligands that control embryonic development. These molecules are known to participate in the regulation of

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cell growth, proliferation, morphology, motility and organ development [51,68,69]. Wnt proteins are now known to bind to another group of transmembrane proteins, the Frizzled or the Wg receptor. The Wnt signalling pathway is an important feature in cell–cell adhesion since it regulates the degradation of b-catenin.

Fig. 5. Binding domains of b-catenin and partners. Fig. 6. Wnt signalling pathways and b-catenin.

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As indicated in Fig. 6, when the Wnt signal is absent (or is off), APC and axin family members form a complex, bind to and activate glycogen synthase kinase 3b (GSK3b). GSK3b goes on to interact with and to phosphorylate APC. The phosphorylated APC has an increased affinity to b-catenin. This would allow the addition of phosphate groups to bcatenin (phosphorylated). Phosphorylated b-catenin is able to bind to a protein known as bTrCP (Fig. 4). As a consequence of its interaction with bTrCP, bcatenin acquires the ability to interact with ubiquitin (Fig. 6). Complexes of b-catenin-ubiquitin are degraded by processing through the proteosome (cell protein recycling centre) [70]. However, when the Wnt signal is active (or is on) (Fig. 6), Wnt proteins first interact with its receptor, the Frizzled family (Fig. 4) and then activates another protein known as Dishvelled. The activation of Dishvelled results in the dephosphorylation of GSK3b and antagonises the action of APC-axin-GSK3b on the phosphorylation of b-catenin. This deactivation prevents the ubiquinous degradation of b-catenin and leads to the accumulation of b-catenin in the cytosol. Cytoplasmic b-catenin eventually translocates to the nucleus and participates in the regulation of gene expression (see later). Other molecules may also play a role in the degradation of b-catenin. Casein kinase 1o (CK1o), is a seriene/threonine kinase, downstream of Dishvelled, and upstream of GSK3b, and has been shown to stabilise b-catenin [65,71]. PP2A, a protein phosphatase can dephosphorylate axin and thus regulate the stability of b-catenin (Figs. 4 and 5) [72]. Chemicals that activate or deactivate GSK3b, such as LiCl, may also have an impact on the fate of b-catenin. E-cadherin, b-catenin, and g-catenin (plakoglobin) are found to be concentrated at caveolae membranes [73]. b-catenin/Lef-1 signalling by Wnt-1, or by overexpression of b-catenin itself, is inhibited by caveolin1 expression. Recombinant expression of caveolin-1 in caveolin-1 negative cells is sufficient to recruit bcatenin to caveolae membranes, thereby blocking bcatenin-mediated transactivation. Thus, caveolin-1 expression can modulate Wnt/beta-catenin/Lef-1 signaling by regulating the intracellular localisation of b-catenin.

3.4.3. p120 catenin family, another expanding family of cadherin associated molecules p120 protein is an onco-protein found to be associated with cadherin [33,40,89]. However, the exact role of the molecule in the cadherin complex was not clear until recently [90]. A large number of molecules have been identified belonging to the p120 catenin family, including p120cas (cadherin-associated src, or p120ctn, p120 catenin), ARVCF (Armadillo repeat gene

deleted in velo-cardio-facial syndrome), d-catenin/ NPRAP/neurojungin, plakophilin 1, plakophilin 2 and plakophilin 3, and p0071 [90– 92]. ARVCF and lcatenin/NPRAP/neurojungin share over 40% homology with p120cas, all three bind to classical cadherins. Plakophilins shares 30% homology with p120cas and possibly interacts with the desmosomal cadherins. In contrast to b-catenin which binds to the catenin-binding domain (CBD), p120cas binds to the juxtamembrane domain of cadherins. Juxtamembrane domain of cadherins has been implicated in the regulation (suppression) of the invasive and motile behaviour of cancer cells (Fig. 7). The exact role of p120cas in cadherin mediated cell adhesion is yet to be clarified. However, Reynolds and collegues [90] have proposed that p120cas may be involved in both ‘positive (activation)’ and ‘negative (inhibition)’ regulation of cell adhesion, possibly depending on the function status of the protein. Interestingly, p120cas is found to be able to mediate nuclear signalling, similar to that of b-catenin. This is perhaps achieved by direct interaction with a transcription factor Kaiso [91,92] (Fig. 7).

3.5. i-catenin and its role in gene expression Perhaps one of most exciting discoveries regarding b-catenin’s functions is that, in addition to acting as a adhesion regulator [28,74], it plays an essential role in the transcription of a number of genes. Cytoplasmic b-catenin, once dissociated from the axin complex and entering the nucleus, interacts with TCF and LEF-1 (T cell factor/lymphoid enhancer factor). TCF/LEFs are quite different from the classic transcription factors, and are unable to activate transcription by themselves. The TCF/LEF-b-catenin complex will, however, enable Tcf/Lef to bind to DNA and initiate gene transcription. The following genes are traditional targets of TCF: c-myc, c-jun, fra-1, PPARd, uPA, and cyclins [75–79]. Fibronectin and metalloproteinase 7 (MMP-7) are the new targets of b-catenin that have been recently identified [83– 85]. Interestingly, activation of b-catenin has been found to suppress the expression of monocyte chemotactic protein-3 (MCP-3), a chemokine known to reduce tumorigenicity [86–88]. The interaction of b-catenin with TCF is negatively regulated by the TCF-binding proteins including NLK (NEMO-like kinase) and CBP, and transcriptin repressor, the Groucho family [80–82]. The interaction may, however, be enhanced by other nuclear proteins such as pontin52 and duplin [75–77]. It is interesting to note that pontin52 and its interacting partner reptin52 may act as repressors of pontin52 in the b-catenin transcription complex [83]. p300, a transcriptional coactivator, is also known to regulate b-

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Fig. 7. p120cas and cell adhesion. Fig. 8. E-cadherin mediate cell cycle progression and the possible role of p27kip1.

catenin/TCF transcription, by interacting with the Nterminus domains in b-catenin [78]. This interaction and activation has also been indicated in b-catenin neoplastic transformation. Taken together, b-cateninmediated neoplastic transformation and tumour progression involve not only the activation of oncogenes and tumour enhancer genes, but also suppression of tumour inhibitor genes, such as MCPs.

4. Cadherin adhesion complex and regulation of cell growth In normal epithelial cells, when the density of the cell exceeds a certain limit, there is a reduction of the rate of growth and proliferation, a phenomenon frequently referred to as ‘contact’ inhibition. This is one of the key mechanisms whereby normal (epithelial) cells control

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their own fate and is one of the fundamental difference between normal epithelial cells and epithelium-derived tumour cells (cancer cells). In cancer cells, there has been a lack of contact inhibition, which leads to uncontrolled growth and piling-up cells on top of one another thus forming a tumour mass. The growth of a cell is controlled by a vast number of extra- and intracellular events and mechanisms. Many reasons why and how cancer cells have lost the contact inhibition have been postulated. However, a link between E-cadherin and a cell cycle regulator has been recently established. p27kip1 protein is one of the first molecules discovered that regulates cell cycle progression. The molecule is able to interact with cell cycle regulators, including cyclins and CDKs (cyclin-dependent kinases). These cycle regulators coordinate the progression of cell cycle from one phase to the following phase. The interaction of p27kip1 with these regulators results in the formation of a p27kip1-CDK complex and deactivation of CDKs. The result of the deactivation is blockade of cycle progression. Cells with deactivated CDK/cyclin thus have a reduced drive to proliferation and growth. Recently, it has been shown that contact inhibition and the lost of the contact inhibition in epithelial cell linage is linked to E-cadherin and p27kip1 (Fig. 8). In E-cadherin-positive cells, the formation of confluent cells with close cell–cell contact is mainly mediated by Ecadherin. Closely connected cells are seen with high level of p27kip1 in the nucleus. When the function of E-cadherin is disturbed, by such methods as netralising antibodies or calcium chelating, the cells exhibit diminished p27kip1 [96]. It is presently unclear how E-cadherin mediates the accumulation of p27kip1 in the cells. However, the phenomenon presents an important message when considering cell adhesion and cell growth. Furthermore, p27kip1 has been demonstrated to be an important regulator in tumour progression and is a prognostic factor in patients with cancer. Reagents that increase the level of p27kip1 are frequently seen to up-regulate the level of E-cadherin [93–96]. Cell– cell adhesion mediated cell growth arrest may also be dependent on the function and integrity of E-cadherin in the cell [97]. The loss of the b-catenin binding region of E-cadherin has been found to signal the process of apoptosis in prostate epithelial cells.

5. Regulation of cadherin mediated cell – cell adhesion A number of pathways have been demonstrated to lead to either enhanced or reduced cell– cell adhesion. They are briefly summarised as follows. 1. Change of composition of the cadherin complex. Activation of wnt pathways leads to a higher level of b-catenin and enhanced cell–cell adhesion, medi-

2.

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ated by E-cadherin [44]. Alteration of interaction of the cadherin complex may also impact on cell– cell adhesion. For example, binding of ZO-1 to acatenin may affect the strength of E-cadherin [98]. Tyrosine phosphorylatin of the cadherin complex. Phophsophorylation of E-cadherin, b-catenins and a-catenins has been shown to alter E-cadherin mediated adhesion [99,100]. Interplay between cadherin-associated molecules. A typical example here is p120cas. The interaction of p120cas with the juxtamembrane region of cadherin alters the function of E-cadherin. Intracellular signalling mediators. Rac, Rho and CDC42, a group of GTPases, are shown to regulate E-cadherin-mediated cell–cell adhesion, by either increasing the level of E-cadherin, directly binding to cadherin complex members, or possibly regulating the catenin–actin binding [101–104]. a-catenin has been shown to be a key molecule in linking the E-cadherin complex with other adhesion molecules, such as ALCAM (activated leukocyte cell adhesion molecule [105]. It has been demonstrated that in prostate cancer cells expressing both E-cadherin and a-catenin, ALCAM is located at the cell–cell contact region, whereas in cells expressing E-cadherin but not a-catenin, both E-cadherin and ALCAM are located cytoplasmically.

6. Abnormalities of cadherin mediated cell adhesion in cancer The importance of the cadherin complex in cell–cell adhesion and in the development and progression of cancer has prompted a large number of studies both scientifically and clinically, to determine abnormalities of these molecules in cancer. The following is a summary of the reported changes of the cadherin complex in cancer, with detailed studies in prostate cancer discussed in the following sections: 1. Reduced levels of cadherin. Lower level of E-cadherin (than normal tissues) has been reported in a majority of human solid tumours and in many cases the level is closely correlated with patients’ prognosis. 2. Abnormal location of E-cadherin. Cadherin mediates homotypic cell–cell adhesion only when the molecules are located at the cell–cell junction area. However, it has been shown that in cancer cells, E-cadherin can be located at the apical area or areas that do not confer cell adhesion. 3. Mutation of E-cadherin. E-cadherin mutation has been shown in a number of solid tumours, such as gastric cancer. However, it does not appear to be a common feature in other tumour types.

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4. Shedding of E-cadherin. Cadherin molecules can be degraded by proteolytic enzymes. Degraded proteins can be shed and be found in the circulation, referred to as soluble adhesion molecules. The shedding undoubtedly damages the adhesive property of the molecule. The clinical impact is discussed in detail in a later part of the article. 5. Mutation and abnormal level of a-catenin. Reduced levels, mutation, and alternative splicing variants of a-catenin have been reported in cancer cell lines and tissues. 6. Abnormalities of b-catenin. This has been discussed earlier. The abnormalities of b-catenin have been widely seen in cancer. The types of changes includeg mutation, alternative spliced variants, over-phosphorylation, and abnormal level. 7. Changes of b-catenin binding partners. As discussed previously, the function of b-catenin is regulated by a number binding partners, including APC, Axin, GSK3b. Any abnormalities of these proteins will lead to excess levels of b-catenin. APC is known to be frequently mutated in cancer, particularly in GI cancer. However, data from other proteins including TCF/LEF are not widely available.

7. Cell adhesion molecules, disease progression and prognosis in urological tumours The importance of the biological function of cadherins and their associated proteins has prompted extensive clinical studies on the role of these molecules in human cancer. The most extensively studied cancers include breast cancer, gastrointestinal cancer, lung and liver cancers and some of the neurological tumours. Although studies on prostate cancer are rather limited in number, there is strong evidence indicating a pivotal role of E-cadherin and catenins in the development and progression of human prostate cancer. A number of studies to date have shown that a reduction or a loss of the E-cadherin/catenin complex was related to clinicopathological data in urological tumours [106–110]. The conclusions drawn from such studies were that E-cadherin may constitute a prognostic factor. In an effort to evaluate the possible prognostic value of E-cadherin in bladder cancer, Mialhe et al. [111], investigated both the level of E-cadherin and the three catenin types in 99 bladder tumours using immunohistochemistry. It was found that both E-cadherin and its full catenin compliment (a-, b- and g-catenin) were strongly expressed in normal urothelium. However, upon examination of tumour tissue, histopathological data revealed disrupted expression for E-cadherin, a-catenin and b-catenin, respectively. This study showed a statistically significant association between abnormal a-catenin expression, and poor sur-

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vival for patients with carcinoma of the bladder, thereby indicating that a-catenin has prognostic value in patient outcome. However, in a more recent study, Morita et al. [112], examined the E-cadherin/catenin complex using immunohistochemistry in tumour tissues obtained by radical prostatectomy. Histopathological data in 45 prostate specimens examined showed an association between aberrant expression of each adhesion molecule with high grade. Their findings suggested, that all three catenin types (a-, b- and g-catenin), may be useful in the prognosis of biologically aggressive prostate cancers. In contrast, a study by Aaltomaa et al. [113], revealed that only a-catenin expression had prognostic value in both local and locally advanced prostate cancer. In this study, the E-cadherin/catenin complex was examined using immunohistochemistry in 215 males with cancer of the prostate. Their results showed that, a-catenin was the only adhesion molecule to be downregulated in 19% of the cases investigated. In addition, 3% of the tumours were found to lack expression of a-catenin altogether. The abnormality in a-catenin expression was found to be associated with high Gleason score, perineural growth and poor survival outcome. In contrast, a study of 87 prostate cancer patients treated by radical prostatectomy, a-catenin was found to have no relationship with seminal vesicle invasion and Gleason score [116]. In a further recent study, using multiplex real time quantitive RT-PCR, paired tumor and nonneoplastic primary prostate cultures were examined for the level of cadherins and associated catenins. Tumour tissues were demonstrated to exhibit moderately-to-markedly decreased levels of E-cadherin, P-cadherin, a-catenin and b-catenin [118]. In addition to E-cadherin, prostate cancer cells express a variety of cell adhesion molecules and cadherins, including P- and N-cadherin (Fig. 9). N-cadherin has also been found to play an important role in prostate cancer progression. N-cadherin is not expressed in normal prostate tissue; however, in prostatic cancer, N-cadherin is expressed in the poorly differentiated areas, which showed mainly aberrant or negative E-cadherin staining. Cadherin-11 is expressed in the stroma of all prostatic tumors, in the area where stromal and epithelial cells are found. In addition, cadherin-11 is also expressed in a dotted pattern or at the membrane of the epithelial cells of high-grade cancers. In a number of metastatic lesions, N-cadherin and cadherin-11 are expressed homogeneously. Richmond et al. [119], reported that abnormal expression of the E-cadherin/a-catenin complex was significantly correlated with Gleason score, and with a lower survival rate in patients with carcinoma of the prostate, thus indicating that disruption to the cell–cell adhesion complex leads to subsequent prostate cancer progression. Furthermore, the analysis of both E-cad-

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herin and a-catenin expression may be of clinical use in the detection of prostate cancer. However, it is unlikely that E-cadherin, b-catenin or a-catenin, individually, can be used as a prognostic marker in prostate cancer. A combination of these proteins may provide a better marker, as reported in other tumour types, such as colorectal and liver tumours [115,117,120,121]. Using the TRAMP animal model (Transgenic adenocarcinoma mouse prostate), dietary alpha-difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ODC (ornithine decarboxylase), was found to reduce the distant metastasis of prostate cancer [122] and restore the abnormal level of E-cadherin and a- and b-catenins. In prostate cancer cells, b-catenin significantly enhanced androgen-stimulated transcriptional activation by the androgen receptor (AR). b-Catenin also increased AR transcriptional activation by androstenedione and estradiol and diminished the antagonism of bicalutamide, Coimmunoprecipitation of b-catenin with AR from LNCaP prostate cancer cells showed that the two molecules are present in the same complex. The amount of b-catenin in the complex with AR was

increased by androgen. These findings implicate bcatenin in the regulation of AR function and support a role for b-catenin mutations in the pathogenesis of prostate cancer [123]. These two latter studies also indicates a tantalising possibility of regulating E-cadherin/catenin function and expression using therapeutic means.

8. Soluble adhesion molecules and cancer invasion/metastasis Soluble cell adhesion molecules, complete or partial adhesion molecules detectable in the circulation or the extracellular space, have been documented to play essential roles in the loss of cell adhesion in cancer and tumour invasion and metastasis by mediating a variety of cell–cell and cell–extracellular matrix interactions [134–138]. It adds further to the saga that E-cadherin is a metastasis suppressor [139–148]. The presence of soluble E-cadherin has been detected in biological specimens, such as serum [135,136,149– 152] and urine [153–155]. The size of circulating soluble

Fig. 9. Expression of cell adhesion molecules in prostate cancer [114].

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E-cadherin detected in these biological specimens was 80 kDa, and this is consistent with that found by Damsky et al. [156] using MCF-7 cells. Damsky et al. [156], reported that full length E-cadherin (120 kDa) had a cleavage site near its transmembrane domain which artificially produced a soluble 80 kDa amino terminal fragment in the culture medium from MCF-7 cells, upon trypsin digestion. In addition, enzymatic cleavage of cell surface adhesion molecules, or secretion of alternatively spliced forms lacking the transmembrane domain, have also been suggested as possible mechanisms for the elevation of circulating soluble cell adhesion molecules [157]. Furthermore, metalloproteinases have also been implicated in the cleavage of VE-cadherin (Vascular Endothelial-cadherin) after growth deprivation-induced apoptosis [158]. In addition, soluble forms from several other adhesion molecules have also been identified, such as: b-1 integrin [159], vascular cell adhesion molecule-1 (VCAM-1) [135,136,151,154], intercellular adhesion molecule-1 and E-selectin (ICAM-1) [151,160,135,136], and CD44 [161]. The presence of these soluble cell adhesion molecules, have been detected using the enzyme-linked immunosorbent assay (ELISA), and their levels have been compared to a number of clinicopathological parameters. However, the utility of a single soluble cell adhesion molecule, to act as a prognostic marker for patients with cancer remains debatable. The shedding of adhesion molecules in cancer has been shown to be the result of proteolytic enzymes, such as MMPs [124– 132] and adamylysin. Details of the ectodomain shedding of adhesion molecules have recently reviewed by Noe and colleagues [42]. Luo et al. [133], reported that the up-regulation of E-cadherin by transfection lead to down regulation of metalloproteinase-2 activity in prostatic adenocarcinoma. Furthermore, restoration to the E-cadherin/ catenin complex promoted: stronger cell– cell adhesion, a return to an epithelial phenotype and a reduction of cellular invasion. Elevated levels of soluble VCAM-1 have been reported in patients with gastric cancer and were found to be associated with poor survival outcome, compared to patients with normal serum levels [135]. In addition, elevated levels of both soluble ICAM-1 and VCAM-1 were found to be associated with local and metastatic disease in patients with colon cancer [136]. Furthermore, the detection of high levels of soluble ICAM-1 have been reported to be associated with liver metastasis, in cancers of the gall bladder, pancreas, gastrointestinal and colon [162]. Other reports suggest that soluble levels of circulating E-cadherin serve as an excellent tumour marker with high sensi-

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tivity in patients with gastric cancer [150,152], hepatocellular cancer [150], and bladder cancer [134,151].

9. Summary and perspectives As the biological roles of cell adhesion molecules in the development and progression of prostate cancer have become established, the role of these molecules in cancer progression and prognosis begins to unfold, as evident from the available clinical studies. However, the complex nature of these biological markers means that the part that these molecules play in prostate cancer may be more complicated than simply acting as adhesion regulators and prognostic markers. This has been clearly indicated in some of the very recent studies that the expression of E-cadherin and catenins in prostate cancer is associated with metastasis, but may also be complicated by the diverse pattern of the expression and re-expression at different locations and the stage of cancer development and progression [163,164]. To fully establish the clinical relevance and value of these molecules in prostate cancer, studies with much larger number of patients are required. Furthermore, it will be important to co-examine Ecadherin together with its associated molecules in prostate cancer, as most of the reported studies have been concentrating on one or a very small number of the molecules. A number of molecules that are important in the chain of events in E-cadherin/catenin function, have not been explored in clinical studies of prostate cancer, such as TCF/LEF, GSK3b, APC, and axin. It is also desirable to examine the pattern of the expression of these molecules in primary tumours as well as in metastatic tumours, as they may play different roles at different stage of tumour development. Furthermore, a combination of histological and molecular evaluation of these molecules in tumour tissues may enhance their clinical value, when combined with studies on the soluble form of these adhesion molecules. Finally, the therapeutic value of E-cadherin and its associated molecules should be explored. Although there is evidence that therapeutic agents may regulate either the function or the expression of E-cadherin and enhance the adhesiveness of tumour cells, there are no clinical studies to indicate that this can be translated into clinical practice. Studies of this kind may further enhance our capability to suppress the spread of cancer. Acknowledgements The authors would like to thank Cancer Research Wales and Prostate Research Campaign for supporting their research work.

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Biographies Professor Malcolm Da6id Mason, MB, B.S., MD, is Professor of Clinical Oncology at the University of Wales College of Medicine. His main specialist interests lie in the clinical management of urological cancers with laboratory interests in cancer vaccines and cell adhesion. He is the UK co-ordinator of several ongoing multi-centre clinical trials in prostate, testis and bladder cancers. Dr Gaynor Da6ies, BSc, MPhil, PhD, is a Research Fellow based at the University of Wales College of Medicine (Cardiff, UK), and an active member of the Metastasis Research Group within the University Department of Surgery. Her main interests include; the molecular and cellular mechanisms of cancer invasion/ metastasis, cell–cell adhesion mechanisms and bcatenin signalling pathways in prostate cancer cells. Dr Wen G. Jiang, MB, BCh, MD, is a Senior Lecturer in the University Department of Surgery, University of Wales College of Medicine in Cardiff. Previously he was a Senior Research Fellow in University of Wales College of Medicine. His main research interest is the molecular and cellular mechanism of cancer metastasis and methods to inhibit cancer invasion and metastasis. He is particularly interested in the role cell adhesion molecules and hepatocyte growth factor/scatter factor in cancer metastasis and angiogenesis.