the role of cell adhesion molecule in cancer progression ... · pdf filereview the role of...

Review

The role of cell adhesion molecule in cancer progression andits application in cancer therapy��

Takatsugu Okegawa�, Rey-Chen Pong, Yingming Li and Jer-Tsong Hsieh�

Department of Urology, The University of Texas Southwestern Medical Center, Dallas, Texas,U.S.A.

Received: 05 May, 2004; accepted: 26 May, 2004

Key words: cell adhesion molecules, tumor progression, tumor suppressor, gene, cancer gene therapy

Multiple and diverse cell adhesion molecules take part in intercellular andcell-extracellular matrix interactions of cancer. Cancer progression is a multi-stepprocess in which some adhesion molecules play a pivotal role in the development ofrecurrent, invasive, and distant metastasis. A growing body of evidence indicatesthat alterations in the adhesion properties of neoplastic cells play a pivotal role in thedevelopment and progression of cancer. Loss of intercellular adhesion and the des-quamation of cells from the underlying lamina propria allows malignant cells to es-cape from their site of origin, degrade the extracellular matrix, acquire a more motileand invasion phenotype, and finally, invade and metastasize. In addition to partici-pating in tumor invasiveness and metastasis, adhesion molecules regulate or signifi-cantly contribute to a variety of functions including signal transduction, cell growth,differentiation, site-specific gene expression, morphogenesis, immunologic function,cell motility, wound healing, and inflammation. Cell adhesion molecule (CAM), a di-verse system of transmembrane glycoproteins has been identified that mediates the

Vol. 51 No. 2/2004

445–457

QUARTERLY

�Presented as invited lecture at the 29th Congress of the Federation of European Biochemical Societies,Warsaw, Poland, 26 June 1–July 2004.�This work is sported in part by National Institute of Health CA95730.�Current address: Department of Urology, Kyroin University School of Medicine, 6-20-2 Shinkawa,Mitaka, Tokyo 181-8611, Japan.

�To whom requests for reprints should be addressed: Department of Urology, University of Texas South-western Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9110, U.S.A.; phone: (214)648 3988; fax: (214) 648 8786; e-mail: [email protected]

Abbreviations: BGP, bilary glycoprotein; CAM, cell adhesion molecule; CAR, coxsackie and adenovirusreceptor; DCC, deletion in colon carcinoma; PCa, prostate cancer; PIN, prostate intraepithelial neopla-sia; TCC, transitional cell carcinoma.

cell–cell and cell–extracellular matrix adhesion and also serves as the receptor fordifferent kinds of virus.We summarize recent progress regarding the role of CAM, particularly, immuno-

globulin-CAMs and cadherins in the progression of cancer and discuss the potentialapplication of CAMs in the development of cancer therapy mainly on urogenital can-cer.

More than 50 cell adhesion molecules(CAMs) have been identified; several largeCAM superfamilies include the immunoglobu-lin (Ig)-like CAMs, cadherins, selectins, andintegrins. The Ig superfamily, a largest familyof CAM, is a calcium independent CAM com-posed of variable numbers of Ig-like repeats(ranging from 4–6 U) on the ligand-bindingdomain and fibronectin-like repeats (up to 5U) on the extracellular domain, transmem-brane domain, and intracellular domain (ex-cept N-CAM). The cadherin family, a calciumdependent CAM, contains 3–5 internal re-peats on the extracellular domain, trans-membrane domain, and intracellular domain.All integrins consist of two noncovalently as-sociated subunits-� and -�, which are typicaltransmembrane proteins. Integrins are themajor receptor for many extracellular matri-ces. For selectins, the extracellular domaincontains three domains: a calcium dependentlectin domain, an epidermal growth fac-tor-like domain, and a variable number of re-peats homologous to complement regulatoryprotein.Cell adhesion is essential in all aspects of

cell growth, cell migration and cell differenti-ation in vertebrate cells. Cellular adhesionmolecules (CAMs) are important participantsin cell–cell interactions and interactions be-tween cells and components of the extra-cellular matrix (Cohen et al., 1997). Thesemolecules have been implicated in a wide vari-ety of cellular functions including signaltransduction, cellular communication andrecognition, embryogenesis, inflammatoryand immune responses, and apoptosis (Cohenet al., 1997). For metastatic tumor cells, theymust enter into the blood or lymphatic circu-lation, which presumably involves the loss ofintercellular adhesion and makes CAMs likely

participants in the development of metastaticdisease. Evidence to date suggests that theCAMs may be associated with invasion andmetastasis in a variety of human malignan-cies. In addition, some virus utilizes CAM asits own specific receptor. Such diverse func-tion of CAMs makes them become valuabletargets for cancer therapy. In this review, wesummarize recent progress regarding 3unique CAMs in biology and discuss itspotential application on the management ofurogenital cancers.

COXSACKIE AND ADENOVIRUSRECEPTOR (CAR)

Coxsackie and adenovirus receptor (CAR),first identified as the high affinity receptorfor both coxsackie and adenovirus (type 2 and5) (Bergelson et al., 1997; Tomko et al., 1997)is a typical Ig-like molecule with two Ig do-mains that may have adhesion activity(Okegawa et al., 2001). The first Ig domain ofCAR interacts with adenoviral fiber protein(van Raaij et al., 2000). Structurally, CAR is atransmembrane protein containing extra-cellular Ig loop (2 U), transmembrane do-main, and intracellular domain (Bergelson etal., 1997; Tomko et al., 1997).It is known that some differentiated normal

epithelia, such as polarized airway epithelia,are resistant to adenovirus because CAR pro-tein is located in the lateral part of cells(Zabner et al., 1997), where the tight junction,a barrier for the paracelluar transit of liquidand/or immune cells, prevents virus from ac-cessing the receptor. To study the physio-logical role and cellular localization of CAR,we recently show that CAR is localized intight junction when cells (such as Chinese

446 T. Okegawa and others 2004

hamster ovary cells and Madin-Darby caninekidney (MDCK) cells) become polarized. Inpolarized cells, CAR and ZO-1 (a protein intight junction complex) could be co-precipi-tated from cell lysates and soluble CAR caninhibit the formation of functional tight junc-tions (Cohen et al., 2001). Thus, CAR is acomponent of the tight junction and may playa role in the process of cell polarization.Recently, we demonstrate a strong correla-

tion between CAR levels and the viral sensi-tivity of any given cells (Li et al., 1999b;Okegawa et al., 2000). Furthermore, we ob-served a heterogeneous expression of CARamong several bladder and prostate cancer(PCa) cell lines (Okegawa et al., 2000; 2001;Rauen et al., 2002; Sachs et al., 2002). Simi-lar results were also observed in differentcancer types such as glioma, melanoma andbreast cancer (Miller et al., 1998; Hemmi etal., 1998; Li et al., 1999a; Lucas et al., 2003).We demonstrated that by increasing theirCAR levels, resistant cells could becamehighly sensitive to adenoviral infection.Thus, we believe that CAR can not only be asurrogate marker to monitor the outcome ofgene therapy, but also facilitate transgene de-livery. Several groups including us alsofound that down-regulation of CAR is oftenseen in TCC lesions but not in adjacent nor-mal tissue (Okegawa et al., 2001), which sug-gests that CAR may play a pathophysiologicrole in the progression of TCC. Our resultsindicate that increased CAR gene expressioncan inhibit the in vitro and in vivo growth oftumor cells (Okegawa et al., 2000; 2001). Al-ternatively, decreasing CAR expression (us-ing antisense vector) in several TCC cell linescan facilitate the in vitro and in vivo growthrate (Okegawa et al., 2001). These data indi-cate that CAR is a tumor inhibitor in TCCcells.To further elucidate the underlying mecha-

nism of CAR in TCC cells, we have demon-strated that: (1) CAR is able to elicithomophilic cell adhesion ability; (2) CAR

causes cell cycle arrest in TCC cells accompa-nied by p21 and hypophosphorylated Rb accu-mulation; (3) adhesion activity of CAR paral-lels its growth inhibitory function; (4) theintracellular domain of CAR is critical for in-ducing its growth inhibitory signal in TCCcells (Okegawa et al., 2001). Based on theseresults, we believe that CAR can inhibit can-cer growth by reestablishing intercellular in-teraction. Also, CAR behaves like a mem-brane receptor and conveys its signal into thenucleus, which results in suppressing cell pro-liferation. Therefore, unveiling this pathwayelicited by CAR may also help us explain whyinvasive TCC exhibits significant decreasedp21 levels in compared to superficial TCC(Malkowicz et al., 1996).Obviously, the decreased CAR expression

in many cancer types may also impose an ob-stacle for adenovirus based gene therapy. Inorder to circumvent this obstacle, one couldchange virus tropism by altering the fiberprotein of virus (Miller et al., 1998) or in-crease endogenous CAR expression by genetransfection. Alternatively, increased en-dogenous CAR expression in target cellscould also enhances their viral sensitivity.Several findings including our laboratory(Lee et al., 2001; Kitazono et al., 2001;Hemminki et al., 2003; Pong et al., 2004) in-dicate that some histone deactylase (HDAC)inhibitors could potentially turn on endoge-nous CAR gene expression in cancer cells invitro, suggesting that the down regulation ofCAR gene may be due to the epigenetic con-trol. By analyzing CAR gene promoter, datafrom our laboratory indicate that the CpG is-lands in the CAR promoter are unmethyl-ated. Thus, the decreased expression of CARis due to histone deacetylation at the CARpromoter (Pong et al., 2004). Several HDACinhibitors are in the clinical trials (Marshallet al., 2002). Thus, combining HDAC inhibi-tors with recombinant adenovirus could leadto a more effective treatment regimen forcancer patients.

Vol. 51 The role of CAM and its application in cancer 447

CELL–CELL ADHESION MOLECULE1 (C-CAM1 or CEACAM1)

This molecule has a homophilic interaction.Recently, we studied C-CAM1, an epithelialCAM with a relativer molecular mass of105000. C-CAM1 is highly homologous toBGP1, a biliary glycoprotein that cross reactswith antibodies against carcinoembryonic an-tigen (CEA) (Lin & Guidotti, 1989). C-CAM1was originally identified by Ocklind andObrink who studied the ability of papain-solubilized plasma membrane components toneutralize the inhibition of cell aggregationby antibodies generated against cell surfaceproteins (Ocklind & Obrink, 1982). In our re-cent study, we demonstrated that the expres-sion of C-CAM1 in rat ventral prostatic epi-thelium was repressed by androgen (Hsieh &Lin, 1994). A similar regulatory pattern wasobserved in the seminal vesicle, but not inother organs (liver and kidney), which sug-gests that regulation of C-CAM1 expressionby androgen is tissue specific.During development of human prostate, the

spatial-tempo expression of C-CAM1 corre-lates with basal cell differentiation. It isknown that the human prostate arises fromthe urogenital sinus and the vesicourethralcomponents of cloaca as solid buds. The budstage (20- to 30-week gestation) is character-ized by the appearance of solid cellular budsat the ends of ducts without a recognizable lu-men. C-CAM1 can be detected in the multiplecell layers of the acinar bud of a 30-week fetalprostate, but not in the surrounding stromalcomponent (Kleinerman et al., 1995a). By36-week, when tubular morphogenesis of theepithelial bud has occurred, the staining ofC-CAM1 is localized predominantly in thebasal cell layer of these tubular structures. Ina 13-yr old juvenile prostate, C-CAM1 can beclearly found in the basal cell layer of allglands examined (Kleinerman et al., 1995a).And, the basal cell in the prostate has beensuggested to represent a stem cell population(Coffey & Walsh, 1990; Bonkhoff & Rem-

berger, 1996). Therefore, we believe C-CAM1may play an important role in controllingprostate development.On the other hand, we have studied a series

of benign and malignant human prostate tis-sues, including prostate intraepithelial neo-plasia (PIN). An overall decrease in C-CAM1staining was detected in both BPH and PIN.Also, C-CAM1 is not detected in well, moder-ately, or poorly-differentiated carcinoma(Kleinerman et al., 1995a). Similar resultswere observed using the transgenic adeno-carcinoma of mouse prostate (TRAMP) model(Pu et al., 1996). These results indicate thatthere is an inverse correlation betweenC-CAM1 expression is clinical grades of PCa,which suggests that loss of C-CAM1 expres-sion is an early event in the development ofPCa. Similarly, several investigators showthat decreased C-CAM1 expression is foundin several other tumor types (Hixson et al.,1985; Neumaier et al., 1993; Rosenberg et al.,1993).To examine the functional role of C-CAM1 in

the prostate tumor, C-CAM1 expression vec-tor was transfected into human metastaticPCa cell in PC-3 cells. The C-CAM1 expres-sion clones had a significantly reduced in vi-tro growth compared to control cells. Theseclones formed significantly fewer clonesgrown in soft agar. These results clearly dem-onstrated that expression of C-CAM1 couldmarkedly suppress the in vitro tumorigenicproperty of PC-3 cells. Alternatively, anotherapproach for validating the tumor suppres-sive role of C-CAM1 in prostate was to reduceC-CAM1 expression in a nontumorigenicprostatic epithelial cell line (i.e., NbE) usingan antisense expression vector. In vivotumorigenic data indicate that antisenseclones could induce tumors in nude mice; theparental cells remained nontumorigenic(Hsieh et al., 1995). Furthermore, the condi-tioned medium collected from C-CAM1-trans-fected cells is able to induce endothelialapoptosis and inhibit endothelial migrationup to a gradient of vascular endothelial


growth factor, indicating that C-CAM1-medi-ated tumor suppression in vivo, at least inpart, is due to the inhibition of tumorangiogenesis (Volpert et al., 2002). These re-sults are consistent with the reduced expres-sion of C-CAM1 in malignant cells seen inhuman prostate specimens, indicating thatC-CAM1 is a potent tumor suppressor inprostate carcinognesis.Little is known about the functional domain

of C-CAM1 in modulating its tumor suppres-sion activity in PCa. We demonstrated thatboth the first Ig domain and the tyrosinephosphorylation site (i.e., amino acid 488) didnot play any significant role in modulatingthe suppression function of C-CAM1 in vivo(Hsieh et al., 1999). Further study indicatedthat serine 503 phosphorylation is critical formaintaining the tumor suppressive functionof C-CAM1 (Estrera et al., 2001). Theintracellular domain of C-CAM1 may also in-teract with other soluble factors to transduceits negative signal. An 80-kDa protein was re-cently identified as a potential interactionprotein involved in growth inhibitory cascade(Luo et al., 1998). The potential interactiveproteins associated with C-CAM1 warrantfurther investigation.We further explored the possibility of apply-

ing C-CAM1 as a potential therapeutic agentfor developing cancer gene therapy using anadenoviral delivery system. We found that de-livery of a single dose of C-CAM1 adenovirusrepressed the growth of PC-3-induced tumorsin nude mice for at least 3 weeks (Kleinermanet al., 1995b). Also, C-CAM1 adenovirus inhib-ited tumor growth of human TCC using anorthotopic model (Kleinerman et al., 1996).Therefore, we believe that C-CAM1 is a poten-tial candidate for both PCa and TCC therapy.

DCC

Deletion in colon carcinoma (DCC) shares asimilar Ig-like structure with C-CAM1 andwas first cloned from colon carcinoma cells as

a potential tumor suppressor gene (Fearon etal., 1990). Recent studies demonstrate thatDCC is a receptor for netrin, a critical factorinvolved in the development of central ner-vous system (Kolodziej et al., 1996; Fazeli etal., 1997). Interestingly, data from a knock-out mouse model indicate that loss of DCC islethal during fetal development because thelittermate has an impairment in the axonalformation of the spinal cord (Hedrick et al.,1994). In addition to its physiological role,DCC is often found to be missing in variouscancers, including prostate, bladder, gastricand colon (Hedrick et al., 1994; Cho &Fearon, 1995).We generated a recombinant adenoviral ex-

pressing DCC that has a high efficiency ofgene delivery into target cells. With this tech-nique, we demonstrated that the expressionof DCC can induce apoptosis in a variety ofcancer cell lines (Chen et al., 1999). The tim-ing of the appearance of the apoptotic pheno-type coincided with the cleavage of poly(ADP-ribose) polymerase (PARP), which isthe substrate of caspases and is a hallmark ofthe biochemical pathway of apoptosis.DCC-induced apoptosis can not be abrogatedby the antagonistic effect of Bcl-2, suggestingthat a different apoptotic signal induced byDCC is operated via a Bcl-2 independent path-way (Chen et al., 1999).Although DCC is considered to be a tumor

suppressor gene for colorectal adenocarci-noma, allelic loss at the DCC gene (five chro-mosome 18q loci) has also been confirmed in36% of TCCs (Brewster et al., 1994; Miyamotoet al., 1996). This loss has been associatedwith muscle invasive disease and an in-creased recurrence rate.

CADHERIN

Cadherin are transmenbrane Ca2+-depend-ent homophilic adhesion receptors that playimportant roles in cell recognition and cellsorting during development (Takeichi, 1991).


Cadherin genes are considered as tumor sup-pressor genes (Hedrick et al., 1993) and de-fects in their expression or function havebeen associated with tumor progression(Behrens et al., 1989). The expression ofcadherin in tumor cells can serve to trace thehistologic origin of tumors and can be used asdifferential diagnostic markers between tu-mors of similar phenotype but differenthistogenesis (Peralta et al., 1995; 1997). Cad-herin are localized in specialized cell–cell ad-hesion sites that are termed adherence junc-tions: at these sites cadherins establish link-ages with the actin-containing cytoskeleton.The classical cadherins include E-, N-, andP-cadherin. E-cadherin mediates cell contactand acts as an important suppressor of epi-thelial tumor cell invasiveness and metastasis(Birchmeier & Behrens, 1994). N-cadherin isexpressed in neuroectodermal and meso-dermal-derived tissues (Hatta et al., 1987).P-cadherin is found in mouse placenta, lungepithelial, basal cells of the skin, andmyoepithelial cells of the mammary gland(Hirai et al., 1989; Daniel et al., 1995). The ex-pression of P-cadherin in epithelial tissues ischaracteristic of cell populations with pro-liferative potential, and its expression de-creases as cells differentiate (Shimoyama etal., 1989).Cadherins associate with a group of intra-

cellular proteins termed catenins, which linkthe cadherin molecules to the actin micro-filaments and mediate signal transductionmechanisms that regulate cell growth and dif-ferentiation (Ozawa et al., 1989). Threecatenins have been identified: �-, �-, �-catenins. �- and �-catenins form mutually ex-clusive complexes with �-catenins and bind tothe carboxy-terminal cytoplasmic domain ofcadherin molecules (Jou et al., 1995). The as-sociation of catenins to cadherins is a keystep in the function of intact adhesion com-plexes, and alterations in catenin moleculescan lead to disruption of the cell–cell adhe-sion, resulting in tumor aggressiveness andinvasiveness in neoplastic disease. Recent

data unveiled that several potential signalingpathways could be modulated by E-cadherincomplex. First, E-cadherin can recruit epider-mal growth factor receptor and induces itsligand independent activation (Kovacs et al.,2002). Second, non-sequestered, free �- and�-catenin are rapidly phosphorylated by glyco-gen synthase kinase 3� (GSK-3�) in adenoma-tous polyposis coli (APC)-axin complex andsubsequently degraded by ubiquitin-pro-teasome pathway (Cavallaro & Christofori,2004). If APC is absent as in colon cancers orif GSK-3� activity is blocked by WNT-signal-ling pathway, which leads to the accumula-tion and translocation of �-catenin into nu-cleus then �-catenin further activate T cell fac-tor/lymphoid enhancer factor-1 (TCF/LEF-1)transcription factors-mediated gene expres-sion implicated in cell proliferation and tu-mor progression (Cavallaro & Christofori,2004; Wong & Gumbiner, 2003). Third,E-cadherin adhesion junction can recruitphosphatidylinositol-(3,4,5)-3-kinase (PI3K)to generate PIP3 resulting in the activation ofthe RHO GTPase-mediated pathways (Norenet al., 2003) that affects the organization ofactin cytoskeleton and possibly the migrationbehavior of tumor cells.In a normal prostate gland, E-cadherin is lo-

calized in the lateral side of the luminalepithelia. However, in a Dunning prostate tu-mor, Bussemakers et al. (1992) demonstratedthat there is an inverse correlation of E-cad-herin mRNA and metastatic ability of tumorcells, which suggests that E-cadherin may beinvolved in tumor progression by disruptingcell–cell communication. A possible cause ofaltered E-cadherin expression may be the lossof heterozygosity at the 16.1q chromosomeband, which is often detected in human PCa(Suzuki et al., 1996). Clinically, decreased orabsent E-cadherin expression in PCa is asso-ciated with tumor grade, advanced clinicalstage, and poor survival (Cheng et al., 1996).The regulation of E-cadherin gene expressionin PCa is still not fully understood; however,some evidence indicates that hypermethyl-


ation of the E-cadherin promoter region incancer cells may reduce its gene expression(Graff et al., 1995).In highly invasive breast tumors, N-cadherin

was shown to replace E-cadherin at cell–cellcontacts, and it has been proposed that N-cad-herin mediates carcinoma cell interactionwith mammary stromal cells. It has also beensuggested that this cadherin is involved in thepromotion of breast cancer metastasis by fa-cilitating carcinoma cell migration throughthe mammary stroma and in reestablishinghomophilic cell–cell adhesion in metastasis(Hazan et al., 1997). This assertion may notbe generalized for most tumor. In prostate tis-sue, Arenas and coworkers observed a de-creased expression of N-cadherin in both PCaand benign prostatic hyperplasia (Arenas etal., 2000).P-cadherin is present in the cell–cell bound-

ary of basal epithelia of the normal prostategland, suggesting that P-cadherin can be a po-tential basal cell marker. The expression ofP-cadherin is down regulated in PIN tissueand is absent in cancer lesions ranging fromwell to poorly-differentiated tumors (Jarrardet al., 1997). Soler et al. (1997) further ob-served that all P-cadherin-positive cells arenegative for prostate-specific antigen (PSA).In addition to the loss of P-cadherin expres-sion in the majority of PCa cells, some tumorthat are P-cadherin positive are frequently lo-cated close to ejaculatory ducts and are nega-tive for PSA, suggesting that P-cadherin maybe a useful diagnostic marker for patientswith low PSA levels.In some cases, not every patient with nor-

mal E-cadherin expression had a better sur-vival. This suggests that the downstreameffector of E-cadherin may be impaired inthese cancer cells. It is known that E-cadherincan form a complex with catenin proteins(i.e., �, �, and �) that serve as an anchor pointto the microfilament cytoskeleton (Cavallaro& Christofori, 2004) The �-catenin serves asa bridge between E-cadherin and �-catenin,which connect with the microfilament

cytoskeleton. Morton et al. (1993) demon-strated that loss of �-catenin expression inE-cadherin-positive human PCa cells iscaused by homozygous deletion. Clinically,about 25% of PCa specimens analyzed hadloss of heterozygosity in the �-catenin gene(5q21-22) (McPherson et al., 1994). An in-creased expression of �-catenin in PC-3 cellsresults in the suppression of tumorigenicityin athymic mice by microcell-mediated trans-fer of the entire chromosome 5 (Ewing et al.,1995), indicating the potent role of �-cateninin PCa progression.Alternatively, altered expression of �-cate-

nin can disassemble the adherent junction,which can make the cell become more inva-sive (Sommers et al., 1994). Furthermore,�-catenin can form a complex with TCF/LEF-1 and this complex can bind to the 5� endof the E-cadherin gene and also can activateseveral genes involved in cell proliferation,which further suggests that �-catenin may beinvolved in cancer progression (Daniel &Reynolds, 1997).With �-catenin, levels of protein have been

found to correlate with the tumorigenicity ofseveral tumor types. Transfection of�-catenin into tumor cells significantly de-creases their tumorigenicity in vivo. A recentimmunostaining study using 45 PCa speci-mens obtained from radical prostatectomy in-dicates that aberrant expression of threetypes of catenin are associated with capsularinvasion, although the significant relation-ship is retained only for �- and �-catenin whenrestricted to moderately differentiated(Gleason’s score 5–7) tumors (Morita et al.,1999). Arenas et al. (2000) reported that thedecrease in E-cadherin expression was not as-sociated with the loss of �-catenin: �-cateninexpression was higher in PCa specimens thanin those with a normal prostate or BPH.Therefore, the functional role of both �- and�-catenin in the progression of PCa warrantsfurther investigation.Several in vitro studies of human TCC cell

lines demonstrate a correlation between ab-


normal expression of E-cadherin and an ag-gressive phenotype. Loss of E-cadherin ex-pression is associated with loss of cellular dif-ferentiation and increased cellular invasi-veness and infiltration in collagen gel assaysand transfection of these cell lines withE-cadherin cDNA is able to suppress thisinvasiveness (Frixen et al., 1991). Investiga-tion of the expression of E-cadherin inhistopathologic material from human TCCsdemonstrates that aberrant expression ofE-cadherin correlates with lack of differentia-tion, muscle invasion, and distant metastasis.Loss of normal E-cadherin expression has

also been shown to correlate with decreasedrecurrence-free and overall survival, althoughmultivariate analysis suggests that it has noindependent prognostic value over the gradeand stage of the tumor (Shimazui et al.,1996).Increased levels of soluble E-cadherin can be

detected in the serum of patients with TCC,and their role in the follow-up of these pa-tients is currently under investigation, withvery promising preliminary results. The in-creased levels correlate with advanced gradeand with the number of superficial lesions,and patients with elevated levels of serumE-cadherin have an increased risk of havingrecurrent disease at follow-up cystoscopy(Griffiths et al., 1996). Soluble forms ofE-cadherin have also been detected in theurine of patients with TCC and may reflectshedding from the urinary epithelium as partof the normal turnover of this molecule(Banks et al., 1995).Loss of membranous �-, �-, and �-catenin

immunoreactivity has been associated withadvanced tumor grade and stage, and loss ofnormal membranous �-catenin has also beenassociated with a worse prognosis of patientswith TCC. In addition, the presence of multi-ple abnormalities in the E-cadherin–catenincomplex was correlated with advanced gradeand stage and with poor survival of patientswith TCC (Shimazui et al., 1996).

A number of possible mechanisms havebeen proposed to account for the documentedreduction in E-cadherin function in bladdercells undergoing malignant transformation.These include suppression or mutation of theE-cadherin gene (Taddei et al., 2000), transla-tion disorder (Frixen et al., 1991), or in-creased protease-mediated degradation(Katayama et al., 1994). Nevertheless, thecommonly observed heterogeneous pattern ofE-cadherin expression might be caused by tu-mor heterogeneity or unstable expression ofE-cadherin in vivo.Loss of immunoreactivity of the normal,

membranous E-cadherin–catenin complex oc-curs frequently in transitional bladder carci-nomas and correlates with high grade, ad-vanced stage, and poor prognosis. In addi-tion, the involvement of APC with thecatenins, together with the tumor suppressivefunction of E-cadherin, suggests that theseproteins play a role in bladder tumorigenesis.Study of the interactions of these proteinswith the adhesion and signaling pathways willcontribute to our better understanding thisfundamental area of TCC biology.

CONCLUSIONS

CAMs play a major role in morphogensisand organogenesis in vertebrates becausethey are the key factors in mediating cell–cellinteraction and cell–matrix interaction.CAM not only can elicit its specific signal butalso can interact with growth factor receptorand other membrane protein and participatetheir signal cascade, which form a complexsignal network leading to growth, differentia-tion and survival. However, aberrant expres-sion of CAMs is often associated with carcino-gensis since cancer cells have lost normal dif-ferentiated phenotype leading to the abnor-mal growth pattern. Understanding theunique mechanism of CAM in different can-cer type could provide new diagnostic or prog-


nostic markers or more strategies of cancergene therapy. In addition, CAMs also serve asthe receptor for certain virus; some virus hasbeen utilized as a backbone for virus-basedgene therapy. Thus, knowledge about CAMbecomes an integral part in cancer patientmanagement.

R E F E R E N C E S

Arenas MI, Romo E, Royuela M, Fraile B,Paniagua R. (2000) E-, N- and P-cadherinand �-, �-, and �-catenin protein expressionin normal, hyperplastic and carcinomatoushuman prostate. Histochemical J.; 32:659–67.

Banks RE, Porter WH, Whelan P, Smith PH,Selby PJ. (1995) Soluble forms of the adhe-sion molecule E-cadherin in urine. J ClinPathol.; 48: 179–80.

Behrens J, Mareel MM, Van Roy FM,Birchmeier W. (1989) Dissecting tumor cellinvasion: epithelial cells acquire invasiveproperties after the loss of uvomorulin-medi-ated cell–cell adhesion. J Cell Biol.; 108:2435–47.

Bergelson JM, Cunningham JA, Drouguett G,Kurt-Joned EA, Krithivas A, Hong JS,Horwitz MS, Crowell RL, Finberg RW.(1997) Isolation of a common receptor forcoxsackie B viruses and adenoviruses 2 and5. Science.; 275: 1320–3.

Birchmeier W, Behrens J. (1994) Cadherin ex-pression in carcinomas: role in the formationof cell junctions and the prevention ofinvasiveness. Biochim Biophys Acta.; 1198:11–26.

Bonkhoff H, Remberger K. (1996) Differentia-tion pathways and histogenetic aspects ofnormal and abnormal prostatic growth: astem cell model. Prostate.; 28: 98–106.

Brewster SF, Gingell JC, Browne S, Brown KW.(1994) Loss of heterozygosity on chromo-some 18q is associated with muscle-invasivetransitional cell carcinoma of the bladder. BrJ Cancer.; 70: 697–700.

Bussemakers MJ, van Moorselaar RJ, GiroldiLA, Ichikawa T, Isaacs JT, Takeichi M,Debruyne FM, Schalken JA. (1992) De-creased expression of E-cadherin in the pro-gression of rat prostatic cancer. Cancer Res.;52: 2916–22.

Cavallaro U, Christofori G. (2004) Cell adhesionand signalling by cadherins and Ig-CAMs incancer. Nat Rev Cancer.; 4: 118–32.

Chen YQ, Hsieh JT, Yao F, Fang B, Pong RC,Cipriano SC, Krepulat F. (1999) Induction ofapoptosis and G2/M cell cycle arrest byDCC. Oncogene.; 18: 2747–54.

Cheng L, Nagabhushan M, Pretlow TP, AminiSB, Pretlow TG. (1996) Expression ofE-cadherin in primary and metastatic pros-tate cancer. Am J Pathol.; 148: 1375–80.

Cho KR, Fearon ER. (1995) DCC: linking tumorsuppressor genes and altered cell surface in-teractions in cancer? Curr Opin Genet De-velop.; 5: 72–8.

Coffey DS, Walsh PC. (1990) Clinical and exper-imental studies of benign prostatic hyperpla-sia. Urol Clin North Am.; 17: 461–75.

Cohen MB, Grieblin TL, Ahaghotu CA, RokhlinOW, Ross JS. (1997) Cellular adhesion mole-cules in urologic malignancies. Amer J ClinPath.; 107: 56.

Cohen CJ, Pickles RJ, Okegawa T, Hsieh JT,Bergelson J. (2001) The coxsackie virus andadenovirus receptor (CAR) is atransmembrane component of the tight junc-tion. Proc Natl Acad Sci USA.; 98:15191–96.

Daniel JM, Reynolds AB. (1997) Tyrosinephosphorylation and cadherin/catenin func-tion. Bioessays.; 19: 883–91.

Daniel CW, Strickland P, Friedmann Y. (1995)Expression and functional role of E- andP-cadherins in mouse mammary ductalmorphogenesis and growth. Develop Biol.;169: 511–9.

Estrera VT, Chen DT, Luo W, Hixson DC, LinSH. (2001) Signal transduction by theCEACAM1: phosphorylation of serine 503 isrequired for growth-inhibitory activity. J BiolChem.; 276: 15547–53.


Ewing CM, Ru N, Morton RA, Robinson JC,Wheelock MJ, Johnson KR, Barrett JC,Isaacs WB. (1995) Chromosome 5 sup-presses tumorigenicity of PC3 prostate can-cer cells: correlation with re-expression of al-pha-catenin and restoration of E-cadherinfunction. Cancer Res.; 55: 4813–7.

Fazeli A, Dickinson SL, Hermiston ML, TigheRV, Steen RG, Small CG, Stoeckli ET,Keino-Masu K, Masu M, Rayburn H, SimonsJ, Bronson RT, Gordon JI, Tessier-LavigneM, Weinberg RA. (1997) Phenotype of micelacking functional deleted in colorectal can-cer (DCC) gene. Nature.; 386: 796–804.

Fearon ER, Cho KR, Nigro JM, Kern SE,Simons JW, Ruppert JM, Hamilton SR,Preisinger AC, Thomas G, Kinzler KW.(1990) Identification of a chromosome 18qgene that is altered in colorectal cancers. Sci-ence.; 247: 49–56.

Frixen UH, Behrens J, Sachs M, Eberle G, VossB, Warda A, Lochner D, Birchmeier W.(1991) E-cadherin-mediated cell–cell adhesionprevents invasiveness of human carcinomacells. J Cell Biol.; 113: 173–85.

Graff JR, Herman JG, Lapidus RG, Chopra H,Xu R, Jarrard DF, Isaacs WB, Pitha PM,Davidson NE, Baylin SB. (1995) E-cadherinexpression is silenced by DNA hypermethyl-ation in human breast and prostate carcino-mas. Cancer Res.; 55: 5195–9.

Griffiths TR, Brotherick I, Bishop RI, WhiteMD, McKenna DM, Horne CH, Shenton BK,Neal DE, Mellon JK. (1996) Cell adhesionmolecules in bladder cancer: soluble serumE-cadherin correlates with predictors of re-currence. Br J Cancer.; 74: 579–84.

Hatta K, Takagi S, Fujisawa H, Takeichi M.(1987) Spatial and temporal expression pat-tern of N-cadherin cell adhesion moleculescorrelated with morphogenetic processes ofchicken embryos. Develop Biol.; 120: 215–27.

Hazan RB, Kang L, Whooley BP, Borgen PI.(1997) N-cadherin promotes adhesion be-tween invasive breast cancer cells and thestroma. Cell Adhes Commun.; 4: 399–411.

Hedrick L, Cho K, Vogelein B. (1993) Cell adhe-sion as tumor suppressors. Trends Cell Biol.;3: 36–9.

Hedrick L, Cho KR, Fearon ER, Wu TC,Kinzler KW, Vogelstein B. (1994) The DCCgene product in cellular differentiation andcolorectal tumorigenesis. Genes Develop.; 8:1174–83.

Hemmi S, Geertsen R, Mezzacasa A, Peter I,Dummer R. (1998) The presence of humancoxsackie virus and adenovirus receptor isassociated with efficient adenovirus-mediatedtransgene expression in human melanomacell cultures. Human Gene Ther.; 9:2363–73.

Hemminki A, Kanerva A, Liu B, Wang M,Alvarez RD, Siegal GP, Curiel DT. (2003)Modulation of coxsackie-adenovirus receptorexpression for increased adenoviraltransgene expression. Cancer Res.; 63:847–53.

Hirai Y, Nose A, Kobayashi S, Takeichi M.(1989) Expression and role of E- andP-cadherin adhesion molecules in embryonichistogenesis. II. Skin morphogenesis. Devel-opment.; 105: 271–7.

Hixson DC, McEntire KD, Obrink B. (1985) Al-terations in the expression of a hepatocytecell adhesion molecule by transplantable rathepatocellular carcinomas. Cancer Res.; 45:3742–9.

Hsieh JT, Lin SH. (1994) Androgen regulationof cell adhesion molecule gene expression inrat prostate during organ degeneration.C-CAM belongs to a class of androgen-re-pressed genes associated with enrichedstem/amplifying cell population after pro-longed castration. J Biol Chem.; 269:3711–16.

Hsieh JT, Luo W, Song W, Wang Y,Kleinerman DI, Van NT, Lin SH. (1995) Tu-mor suppressive role of an androgen-regu-lated epithelial cell adhesion molecule(C-CAM) in prostate carcinoma cell revealedby sense and antisense approaches. CancerRes.; 55: 190–7.

Hsieh JT, Earley K, Pong RC, Wang Y, Van NT,Lin SH. (1999) Structural analysis of the


C-CAM1 molecule for its tumor suppressionfunction in human prostate cancer. Prostate.;41: 31–8.

Jarrard DF, Paul R, van Bokhoven A, NguyenSH, Bova GS, Wheelock MJ, Johnson KR,Schalken J, Bussemakers M, Isaacs WB.(1997) P-Cadherin is a basal cell-specific epi-thelial marker that is not expressed in pros-tate cancer. Clin Cancer Res.; 3: 2121–8.

Jou TS, Stewart DB, Stappert J, Nelson WJ,Marrs JA. (1995) Genetic and biochemicaldissection of protein linkages in thecadherin–catenin complex. Proc Natl AcadSci USA.; 92: 5067–71.

Katayama M, Hirai S, Kamihagi K, NakagawaK, Yasumoto M, Kato I. (1994) SolubleE-cadherin fragments increased in circulationof cancer patients. British J Cancer.; 69:580–5.

Kitazono M, Goldsmith ME, Aikou T, Bates S,Fojo T. (2001) Enhanced adenovirustransgene in malignant cells treated with thehistone deacetylase inhibitor FR901228.Cancer Res.; 61: 6328–30.

Kleinerman DI, Troncoso P, Lin SH, Pisters LL,Sherwood ER, Brooks T, von EschenbachAC, Hsieh JT. (1995a) Consistent expressionof an epithelial cell adhesion molecule(C-CAM) during human prostate develop-ment and loss of expression in prostate can-cer: implication as a tumor suppressor. Can-cer Res.; 55: 1215–20.

Kleinerman D, Zhang WW, von Eschenbac AC,Lin SH, Hsieh JT. (1995b) Application of atumor suppressor gene, C-CAM1, in andro-gen-independent prostate cancer therapy: apreclinical study. Cancer Res.; 55: 2831–6.

Kleinerman D, Diney C, Zhang WW, Lin S-H,Van NT, Hsieh JT. (1996) Suppression of hu-man bladder cancer growth by increased ex-pression of C-CAM1 gene in an orthotopicmodel. Cancer Res.; 56: 3431–5.

Kolodziej PA, Timpe LC, Mitchell KJ, Fried SR,Goodman CS, Jan LY, Jan YN. (1996) fraz-zled encodes a Drosophila member of theDCC immunoglobulin subfamily and is re-quired for CNS and motor axon guidance.Cell., 87: 197–204.

Kovacs EM, Ali RG, McCormack AJ, Yap AS.(2002) E-cadherin homophilic ligation di-rectly signals through Rac andphosphatidylinositol 3-kinase to regulate ad-hesive contacts. J Biol Chem.; 277: 6708–18.

Lee C, Seol JY, Park K, Yoo C, Kim YW, AhnC, Song Y, Han SK, Han JS, Kin S, Lee J,Shim Y. (2001) Differential effects ofadenovirus-p16 on bladder cancer cell linescan be overcome by the addition of butyrate.Clin Cancer Res.; 7: 210–4.

Li D, Duan L, Freimuth P, O'Malley W Jr.(1999a) Variability of adenovirus receptordensity influences gene transfer efficiencyand therapeutic response in head and neckcancer. Clin Cancer Res.; 5: 4175–81.

Li Y, Pong RC, Bergelson JM, Hall MC,Sagalowsky AI, Tseng CP, Wang Z, Hsieh JT.(1999b) Loss of adenoviral receptor expres-sion in human bladder cancer cells: a poten-tial impact on the efficacy of gene therapy.Cancer Res.; 59: 325–30.

Lin SH, Guidotti G. (1989) Cloning and expres-sion of a cDNA coding for a rat liver plasmamembrane ecto-ATPase. The primary struc-ture of the ecto-ATPase is similar to that ofthe human biliary glycoprotein I. J BiolChem.; 264: 14408–14.

Lucas A, Kremer EJ, Hemmi S, Luis J, VignonF, Lazennec G. (2003) Comparativetransductions of breast cancer cells by threeDNA viruses. Biochem Biophys Res Commun.;309: 1011–6.

Luo W, Earley K, Tantingco V, Hixson DC,Liang TC, Lin SH. (1998) Association of an80 kDa protein with C-CAM1 cytoplasmic do-main correlates with C-CAM1-mediatedgrowth inhibition. Oncogene.; 16: 1141–7.

Malkowicz SB, Tomaszewski JE, Linnebach AJ,Cangiano TA, Maruta Y, McGarvey TW.(1996) Novel p21WAF1/CIP1 mutations in su-perficial and invasive transitional carcinomascell. Oncogene.; 13: 1831–7.

Marshall JL, Rizvi N, Kauh J, Dahut W,Figuera M, Kang MH, Figg WD, Wainer I,Chaissang C, Li MZ, Hawkins MJ. (2002) Aphase I trial of depsipeptide (FR901228) in


patients with advanced cancer. J Exp TherOncol.; 2: 325–32.

McPherson JD, Morton RA, Ewing CM,Wasmuth JJ, Overhauser J, Nagafuchi A,Tsukita S, Isaacs WB. (1994) Assignment ofthe human �-catenin gene (CTNNA1) tochromosome 5q21-q22. Genomics.; 19:188–90.

Miller CR, Buchsbaum DJ, Reynolds PN,Douglas JT, Gillespie GY, Mayo MS, RabenD, Curiel DT. (1998) Differential susceptibil-ity of primary and established human gliomacells to adenovirus infection: targeting viathe epidermal growth factor receptorachieves fiber receptor-independent genetransfer. Cancer Res.; 58: 5738–48.

Miyamoto H, Shuin T, Ikeda I, Hosaka M,Kubota Y. (1996) Loss of heterozygosity atthe p53, RB, DCC and APC tumor suppres-sor gene loci in human bladder cancer. JUrol.; 155: 1444–7.

Morita N, Uemura H, Tsumatani K, Cho M,Hirao Y, Okajima E, Konishi N, Hiasa Y.(1999) E-cadherin and �-, �- and �-catenin ex-pression in prostate cancers: correlationwith tumour invasion. Br J Cancer.; 79:1879–83.

Morton RA, Ewing CM, Nagafuchi A, Tsukita S,Isaacs WB. (1993) Reduction of E-cadherinlevels and deletion of the alpha-catenin genein human prostate cancer cells. Cancer Res.;53: 3585–90.

Neumaier M, Paululat S, Chan A, Matthaes P,Wagener C. (1993) Biliary glycoprotein, a po-tential human cell adhesion molecule, isdown-regulated in colorectal carcinomas.Proc Natl Acad Sci USA.; 90: 10744–8.

Noren NK, Arthur WT, Burridge K. (2003)Cadherin engagement inhibits RhoA viap190RhoGAP. J Biol Chem.; 278: 13615–8.

Ocklind C, Obrink B. (1982) Intercellular adhe-sion of rat hepatocytes. Identification of acell surface glycoprotein involved in the ini-tial adhesion process. J Biol Chem.; 257:6788–95.

Okegawa T, Li Y, Pong RC, Zhou J, BergelsonJM, Hsieh JT. (2000) The impact of coxsackie

and adenovirus receptor on human prostatecancer gene therapy. Cancer Res.; 60:5031–6.

Okegawa T, Pong RC, Li Y, Bergelson JM,Sagalowsky AI, Hsieh JT. (2001) The mecha-nism of growth inhibitory effect of coxsackieand adenovirus receptor (CAR) on humanbladder cancer: a functional analysis of CARprotein structure. Cancer Res.; 61:6592–600.

Ozawa M, Baribault H, Kemler R. (1989) Thecytoplasmic domain of the cell adhesion mol-ecule uvomorulin associates with three inde-pendent proteins structurally related in dif-ferent species. EMBO J.; 8: 1711–7.

Peralta Soler A, Knudsen KA, Jaurand MC,Johnson KR, Wheelock MJ, Klein-Szanto AJ,Salazar H. (1995) The differential expressionof N-cadherin and E-cadherin distinguishespleural mesotheliomas from lungadenocarcinomas. Human Pathol., 26:1363–9.

Peralta Soler A, Knudsen KA, Tecson-Miguel A,McBrearty FX, Han AC, Salazar H. (1997)Expression of E-cadherin and N-cadherin insurface epithelial-stromal tumors of theovary distinguishes mucinous from serousand endometrioid tumors. Human Pathol.,28: 734–9.

Pu YS, Luo W, Lu HH, Greenberg NM, Lin SH,Gingrich JR. (1996) Differential expressionof C-CAM cell adhesion molecule in prostatecarcinogenesis in a transgenic mouse model.J Urol.; 162: 892–6.

Rauen KA, Sudilovsky D, Le JL, Chew KL,Hann B, Weinberg V, Schmitt LD,McCormick F. (2002) Expression of thecoxsackie adenovirus receptor in normalprostate and in primary and metastaticprostate carcinoma: potential relevance togene therapy. Cancer Res.; 62: 3812–8.

Rosenberg M, Nedellec P, Jothy S, Fleiszer D,Turbide C, Beauchemin N. (1993) The ex-pression of mouse biliary glycoprotein, acarcinoembryonic antigen-related gene, isdown-regulated in malignant mouse tissues.Cancer Res.; 53: 4938–45.


Sachs MD, Rauen KA, Ramamurthy M, DodsonJL, De Marzo AM, Putzi MJ, SchoenbergMP, Rodriguez R. (2002) Integrin �(v) andcoxsackie adenovirus receptor expression inclinical bladder cancer. Urology.; 60: 531–6.

Shimazui T, Schalken JA, Giroldi LA, JansenCF, Akaza H, Koiso K, Debruyne FM,Bringuier PP. (1996) Prognostic value ofcadherin-associated molecules (�-, �-, and�-catenins and p120cas) in bladder tumors.Cancer Res.; 56: 4154–8.

Shimoyama Y, Hirohashi S, Hirano S, NoguchiM, Shimosato Y, Takeichi M, Abe O. (1989)Cadherin cell-adhesion molecules in humanepithelial tissues and carcinomas. CancerRes.; 49: 2128–3.

Soler AP. Harner GD. Knudsen KA. McBreartyFX. Grujic E. Salazar H. Han AC.Keshgegian AA. (1997) Expression ofP-cadherin identifies prostate-specific-anti-gen-negative cells in epithelial tissues ofmale sexual accessory organs and in pros-tatic carcinomas. Implications for prostatecancer biology. Am J Pathol.; 151: 471–8.

Sommers CL, Gelmann EP, Kemler R, Cowin P,Byers SW. (1994) Alterations in beta-cateninphosphorylation and plakoglobin expressionin human breast cancer cells. Cancer Res.;54: 3544–52.

Suzuki H, Komiya A, Emi M, Kuramochi H,Shiraishi T, Yatani R, Shimazaki J. (1996)Three distinct commonly deleted regions ofchromosome arm 16q in human primary andmetastatic prostate cancers. Genes Chromo-somes Cancer.; 17: 225–33.

Taddei I, Piazzini M, Bartoletti R, Dal Canto M,Sardi I. (2000) Molecular alterations ofE-cadherin gene: possible role in humanbladder carcinogenesis. Int J Mol Med.; 6:201–8.

Takeichi M. (1991) Cadherin cell adhesion recep-tors as a morphogenetic regulator. Science.;251: 1451–5.

Tomko RP, Xu R, Philipson L. (1997) HCARand MCAR: the human and mouse cellularreceptors for subgroup C adenoviruses andgroup B coxsackieviruses. Proc Natl AcadSci USA.; 94: 3352–6.

van Raaij MJ, Chouin E, van der Zandt H,Bergelson JM, Cusack S. (2000) Dimericstructure of the coxsackievirus andadenovirus receptor D1 domain at 1.7 � res-olution. Structure Fold Des.; 8: 1147–55.

Volpert O, Luo W, Liu TJ, Estrera VT,Logothetis C, Lin SH. (2002) Inhibition ofprostate tumor angiogenesis by the tumorsuppressor CEACAM1. J Biol Chem.; 277:35696–702.

Wong AS, Gumbiner BM. (2003) Adhesion-inde-pendent mechanism for suppression of tu-mor cell invasion by E-cadherin. J Cell Biol.;161: 1191–203.

Zabner J, Cheng SH, Meeker D, Meeker D,Launspach J, Balfour R, Perricone MA, Mor-ris JE, Marshall J, Fasbender A, Smith AE,Welsh MJ. (1997) Lack of high affinity fiberreceptor activity explains the resistance ofciliated airway epithelia to adenovirus infec-tion. J Clin Invest.; 100: 1144–9.


the role of cell adhesion molecule in cancer progression ... · pdf filereview the role of...

Documents