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1992;52:5104-5109.Cancer ResRainy Umbas, Jack A. Schalken, Tilly W. Aalders, et al.Reduced or Absent in High-Grade Prostate CancerExpression of the Cellular Adhesion Molecule E-Cadherin Is

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(CANCER RESEARCH 52, 5 10 4- 51 09 , S ep tembe r 1 5. 1 99 2|

Adva nces in B riefExpression of the C ellular A dhesion Molecule E-Cadherin Is R educed or A bsentin H igh-G rade Prostate C ancer1Rainy Um bas, Jack A. Schalken, T illy W . Aalders, Bob S. Carter, H erbert F. M . K arthaus,H . E wout Schaafsm a, Frans M . J. D ebruyne, and W illiam B . Isaacs2D epa rtm ent of V rology/L'rological R esearch Laboratories [R . U ., T. W . A ., F . M . J. D ., J. A . S.] and D epartm ent of P athology H .E . S.J, U niversity H ospitalNijm egen, N ijm egen, the Netherlands; Jam es B uchanan B rady U rological Institute, Johns H opkins H ospital, Baltim ore, M aryland (W . B . l., B . S. C .J; anaD ep ar tm en t o f U ro lo gy , C an is iu s W il he lm in a H os pit al, N ij me ge n, t he N et he rl an ds [ H. F . M . K .]AbstractE -cadherin is a ( 'a- *-dependent cell adhesion m olecule w hich plays

an important role in normal growth and development via mediation ofh om otyp ic, h om op hilic cell-cell in ter action . R ece nt stu dies su ggest th atE -cadherin m ay be im portant in neoplastic progression as w ell, particularly as a suppressor of invasion. W e have previously dem onstratedth at th e in vasive p hen otyp e of rat p rostate can cer cells is a ssociated w iththe decreased expression of E-cadherin (M . J. G . Bussemakers, R . J. A.Van Moorselaar, L. A. Giroldi, T. Ichikawa, J. T. Isaacs, F. M . J.D ebruyne, and J. A . Schalken, Cancer Res., 52:2916-2922,1992). T hisis of particular interest, since the locus to which the hum an E -cadheringene is mapped is frequently involved in allelic loss in prostate cancer(B. S. Carter, C. M . Ewing, W . S. W ard, B. F. Treiger, T. W . Aalders,J. A . Schalken, J. 1. Epstein, and W . B. Isaacs, Proc. Nati. Acad. Sci.USA, 87:8751-8755,1990; U. S. Bergerheim, K . Kunimi, V. P. Collins,and P. Ekman, Genes, Chromosomes Cancer, 3: 215-220, 1991). Impaired E -cadherin function is likely to be associated with aberrant exp ressio n of th e p rote in . W e th erefore an alyzed E -cad herin exp ression insitu by immunohistochemistry in nonmalignant and malignant specim ens of hum an prostatic tissue. O f 92 tum or sam ples of either prim aryor metastatic deposits of prostate cancer, 46 had reduced or absentE -cadherin staining w hen com pared to nonm alignant prostate, w hichu nifo rm ly sta in ed s tr on gly p ositiv e. T he re w as a s ta tist ic ally s ig nific an tcorrelation between the decreased expression of E -cadherin and loss oftu mor d ifferen tiation . A dd ition ally, certain tumors w ith in a h istologi-cally similar group could be distinguished by the presence of mixedp op ulation s of E -cad herin -n egative an d -p ositive cells. T he p ercen tageof tu mo rs w ith ab erran t E -cad he rin stain in g in creased w hen clin icallylocalized tumors were compared to either tumors with extensive localprogression or m etastatic deposits of prostate cancer, suggesting a correlation between loss of E-cadherin and tumor progression. Taken together, these findings suggest that further exploration of E-cadherin asa candidate invasion suppressor m olecule in hum an prostate cancer iswarranted.IntroductionThe clinical course of men w ith prostate cancer may varyw idely, even in m en w hose tum ors are of sim ilar clinical stageand histological grade. At present there is no reliable way topredict w hich m en w ith prostate cancer w ill progress and even

tually die of their disease. C urrent system s of staging and grading prostate cancers provide adequate predictive value for tum ors at eith er en d o f th e d ifferen tiation spec trum (i.e., w ell an dpoo rl y d if fe re nt ia te d) b ut a re p ar ti cu la rly d ef ic ie nt a t p re dic tin gRece iv ed 6 /2 2/ 92 ; a ccep ted 7 /2 7/ 92 .T he c os ts o f p ub lic atio n o f th is a rtic le w ere d efra ye d in p art b y th e p ayme nt o fp ag e cha rg es . Th is a rt ic le mu st t he re fo re b e h er eby ma rk ed adv er ti semen t i n a cco rda nc e w ith 1 8 U .S .C . S ec tio n 1 73 4 so le ly to in dic ate th is fa ct.1 S u pp or te d b y g ra nts f rom t he N eth er la nd s U ni ve rs it ie s F ou nd at io n f or I nte rnationa l C oopera tion, van D eventer-M aasstichting (R .U .), and the U SP HS(CA5523101)(W.B.I.).2 T o whom r eq ue sts f or r ep rin ts s ho ul d b e a dd re ss ed , a t D ep ar tm e nt o f U ro lo gy ,M arburg 105, Johns Hopkins H ospital, 600 N. W olfe Street, Baltim ore, M D21205.

the outcom e of patients w hose tum ors lie in betw een these tw oe xtrem es (1, 2 ). U nfo rtu na tely , this latter class o f p ro state cancers is the m ost com mon (2). To address this problem , w e haveb eg un to an aly ze m olecu la r g en etic a lteratio ns in p ro sta te cancer with the goal of identifying changes w hich may be of predictive value. In a previous study of prim ary prostate cancers(3), chrom osom e 16q w as the m ost frequent location of allelicloss, suggesting this chrom osom al arm as the possible site of atum or suppressor gene w hich becom es inactivated in this disease. A subsequent study by Bergerheim et al. (4) also foundfrequent allelic loss on chrom osom e 16q in both prim ary andm etastatic deposits of prostate cancer. Interestingly, recentstu dies o f b reast can cer, h epa to cellu lar c arc inoma, an d W ilm s'tum ors have also observed frequent loss of al elesfrom chromosome 16q (5-7). M ultiple genes are known to reside in theregion of chrom osom e 16q com monly deleted in prostate cancer (4). O f particular interest is E-cadherin, a cell adhesionmolecule which has been shown to have characteristics of asup presso r o f inv asiv e ph en oty pe (8-1 2). T o assess the po ssib lerelevance of changes in E -cadherin to prostate cancer, w e examined the expression of E-cadherin in both normal and malig na nt p ro sta te t is su e.C adherins are cell surface glycoproteins involved in hom oty pic C a2 +-d ep en de nt c ell-c ell a dh esio n (1 3). T he se m ole cu le splay an essential role in em bryonic developm ent and m orphogenesis and in the maintenance of the normal structure andfunction of adult tissues (14, 15). M ore than ten subclasses ofcadherins have been identified (16-21). T hree of them , E -, N -,and P-cadherin, share a com mon basic structure and m ediatecell-cell b ind in g in a h om op hilic an d su bclass-spe cific m an ner(22). E -cadherin is also called uvom orulin (23), L -C AM (24),c ell-CAM 120 /8 0 (2 5), o r A rc -1 (2 6). Its e xp re ssio n is re stric te dto e pith elia l tis su es (2 7, 2 8). C on sid erin g th e im po rta nt g uid in gro le o f E -c adh erin in n orm al d evelopmen t, v ario us au th ors su ggested that im paired function of this m olecule could be im portant in the acquisition of invasive potential (8, 9, 22). Indeed,Behrens et al. (10) showed that M adin-Darby canine kidneycells, w hic h fo rm tigh t ep ith elial m ono la yers, acq uire d th e ab ility to invade collagen gels and embryonal heart tissue whenth eir in tercellu lar ad hesion is in hib ited b y the ad dition o f an ti-E-cadherin antibodies. Sim ilarly, in a study on a variety ofhum an cancer cell lines, F rixen et al. (11) found that noninva-sive cell lin es ex pressed E -cad he rin p ro tein , w hereas inv asiv ec arc in om a c ell lin es h ad lo st E -c ad he rin e xp re ssio n. Mo re ov er,th is stud y sh ow ed th at b y tran sfection w ith E -cad he rin comp lementary D NA , the invasive phenotype could be suppressed.From the study of these m odel system s it has becom e clear thatthere is a functional relation betw een the invasive phenotypeand decreased expression of E -cadherin. V arious studies nowsu gg est that a sim ilar co rrelatio n ex ists in some p rim ary h um an

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E-CA DHERIN EX PRESS ION [N HUMA N PROSTA TE CA NCER

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E-CA DHERIN EX PRES SION IN HUMA N PROSTA TE CA NCERpoorly differentiated tumors (Gleason scores 6-10), we obse rv ed a tre nd o f inc re asing pe rc entag e o f tumors w ith he te rogeneous o r abs ent s taining f or E- cadhe ri n. Spe ci fic ally , in moderately differentiated tumors (Gleason score 6 and 7), mostc ontinued to exhibit the normal patte rn o f E- cadhe ri n s taining ;how ever, 5 of 29 (17%) of these tumors exhibited heterogene ous staining (Fig . 2 ). In c ontrast, the majo rity (6 9%) o f moderate to poo rly differentiated tumors (Gleaso n sco re 8 ) and allo f poorly dif fe rentiated and undif fe rentiated tumors (Gl eas ons co re s 9 and 10) had de creas ed E-cadhe rin expre ss ion. Subs tantial frac tio ns o f tumor sample s in the se latte r g ro ups w ere c ompletely devoid of E-cadherin staining (19%, 50%, and 45% ofG le as on sc ore s 8 , 9 , and 1 0 tumo rs , re spe ctiv ely ). Ov erall, 5 2%o f all tumo rs analy zed had unifo rm po sitiv e staining, 1 6% hadabsent staining, and 3 2% had hetero geneo us staining. The decreasing expression of E-cadherin w ith increasing Gleasonsco re is hig hly statistically sig nificant by x2 analy sis (x 2 = 5 0.157; 12 df; P < 0.001).Ex pressio n of E-Cadherin in Pro state Cancer M tastases.S inc e metas tati c le si ons o f pro state c anc er are rare ly surg ic allyresected, w e w ere able to o btain o nly a limited number o f thesespe cim ens fo r analy sis . S ix o f e ig ht pro state c anc er m tas tase sshowed e ithe r ne gativ e o r he te ro ge ne ous staining w ith anti-E-cadherin antibodies (Table 1; Fig. 2, 7 and J). Those w ith hete ro ge ne ous s taining s howed a low-inte ns ity , diffuse stainingpatte rn in whic h the c ell bo rde rs w ere o nly bare ly marke d. Twometas ta ti c deposi ts cons is ted of we ll -d if ferenti ated prostati c ad-enocarc inoma cel ls which s tained s trong ly f or E- cadhe rin.A c orre latio n be tw ee n de cre as ed E-c adhe rin e xpre ss io n andtumor progress ion i s sugges ted when c lini cal ly l ocal ized tumorsare compared to eithe r more ex tensiv e primary tumo rs (tran-s ure thral re se ctio n s pe cim ens) o r metastatic de po sits o f pro state cancer. Forty % (19 of 47), 57% (21 of 37), and 75% (6 of8) of the tumors in these three groups, respectively, show edreduc ed or abs ent E- cadhe rin s taining .Expre ss ion o f E-Cadhe rin in Pro state Canc ers w ith Chromosome 16q D eletions. In a previous study (3) w e identified sixprimary pro static tumors in whic h the majo rity o f c anc er c ellshad lo st al eles rom the lo ng arm of chromo some 1 6. S ince theE-cadherin gene is located on this chromosomal arm, we examined the expression of this gene by staining sections fromthe se tumors w ith anti-E-c adhe rin antibo die s. The se tumorshad Gleason scores ranging from 6 to 9. Interestingly, five ofthe se s ix tumors showed alte re d E-c adhe rin staining , w ith fo urshowing hetero geneo us staining and o ne showing no staining(Fig . 3 ).DiscussionE-c adhe rin has be en demons trate d to play an impo rtant ro lei n normal g row th and deve lopment. A lte rnativ ely , when de regulated, i t can contribute to the invas ive potenti al o f trans formedc ells and c an the re fo re be c ons ide re d as an inv asio n suppre sso rgene (8, 9, 22). Moreover, the fact that the locus to which theE-c adhe rin g ene is mappe d (1 6q2 2.1 ) is fre que ntly inv olv ed inalle ile lo ss in pro state c anc ers (3 ,4 ,1 2) prompte d us to e xam inethe ex pression o f E-c adherin in nonmalignant and malig nanthuman prostate tissues. Reasoning that loss of invasive sup-

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E-CA DHERIN EX PRES SION IN HUMA N PROS TA TE CA NCERhighly metastatic ovarian tumor cell lines contained both Ic adhe rin-po sitiv e and E-c adhe rin-ne gativ e c ells. In the hig h-g rade pro state c anc ers e xam ined he re , w e neve r f ound a normalstaining patte rn, i.e ., tumors w ere e ithe r he te ro ge ne ous o r ne gative for E-cadherin. None of the Gleason score 9 and 10 tumors had strong expression of E-cadherin. From this w e canconclude that as in the D unning R-3327 rat prostatic cancermodel system (31) and several other human cancers (29, 30),E-c adhe rin expre ss ion is de creas ed in high-g rade malignant lesions o f the prostate. S ix o f the metastatic depo sits, w hich arepo orly diffe re ntiate d, showed he te ro ge ne ous o r abse nt E-c adhe rin expre ss ion, whil e the two wel l- di ff erentiated mtas tas esstained homogeneously positive. This indicates that eithero the r mec hanism s c an o ve rc ome the inv as iv e suppre ss or functio n o f E-c adhe rin (3 4) o r that E-c adhe rin c an be tempo rarilydown-regulated, re su lting in transi ent express ion of the invas ivephe no ty pe . Ev ide nc e from the Dunning rat pro state tumor sy stem supports this latte r po ss ibility ; e .g ., Bus semakers e t al. ( 31 )fo und E-c adhe rin-po sitiv e pro state c anc er c ells in s ome metas tatic lung depo sits de riv ed f rom anaplas tic E- cadhe ri n- negativ e primary tumor c ells .The mechanisms that le ad to aberrant e xpressio n o f E-cadherin are still unclear. Obviously , it is tempting to speculatethat loss of heterozygosity of 16q22 is one of the steps associate d w ith the lo ss o f s uppre ss iv e func tio n. Class ic al tumor s uppre ss or g ene the orie s (3 5) the n would pre dic t that the remaining al e leis mutate d, thus abo lis hing c omple te func tio ning o fE- cadhe rin. A lte rnativ ely , the reduc ed do sage o f the g ene due toalle lic lo ss may re sult in the re duc ed e xpre ss io n o f E-c adhe rinto a level below a critical threshold, which by itself could besuf fi cie nt to impai r f unc ti oning o f E- cadhe rin. Ev idenc e fo r thispossibility comes from the study of V leminckx et al. (9), w hoshowed that a reduc tion, no t e lim ination, o f E- cadhe rin expre ssio n w as sufficient to induce the inv asiv eness of kidney c arc inoma cells. In the study presented here, w e ex amined a limitednumbe r o f pro static tumors pre vio us ly ide ntifie d as hav ing alle lic lo ss o f se que nc es o n c hromo some 1 6q. Inte re sting ly , o ve r80% (5 of 6) of these primary tumors show ed either heterogeneous o r abs ent E- cadhe ri n s taining , s ugge sting a po ss ible c ausativ e link betw een these tw o alteratio ns. The se o bserv atio nsprovide a rationale for a more extensive search for possibleg ene tic alte rations ( e.g ., po int mutati ons , de le tions ) in bo th thecoding and regulatory regions of the E-cadherin gene w hichmay le ad to the inac tiv ation o f E- cadhe rin f unc tion. In addition,furthe r s tudie s w ill be ne ce ss ary to more pre cis ely quantitatethe de gree o f E-cadherin down-re gulatio n and to determinewhe the r a re duc ed le ve l o f the no rmal pro te in alo ne is s uffic ie ntto induc e invas iv e behav io r in expe rimental mode ls o f pro statecancer.With respect to the clinical value of these findings it is ofparticular interest to no te that w ithin the gro ups o f patientsw ith moderate ly di ff erenti ated tumors , compri sing the majori tyof cases observed clinically, a discrimination could be madebe tw ee n no rmally staining and abe rrantly staining (i.e ., he te ro ge neo us and neg ativ e) tumors. D ue to the lo ng fo llow -up nece ssary , it is no t y et c le ar whe the r the se finding s hav e pre dic tiv ev alue fo r the c linic al c ours e in te rm s o f s urv iv al. It is the re fo reimportant that antibodies be developed that can be used onarc hiv al mate rial in o rde r to te st the pro gno stic v alue o f E-c adhe rin staining re tro spe ctiv ely . On the o the r hand pre lim inarydata o n the re latio n be tw ee n de cre as ed E-c adhe rin e xpre ss io nand shortened surv ival in bladde r tumors indi cate the po tential

of this marker.4 We sug ge st that the v alue o f de cre ased E-cadhe rin e xpre ssio n in pro state c anc er be te ste d pro spe ctiv ely o n alarge scale .AcknowledgmentsThe autho rs would li ke to thank Dr. S . H iro has hi (T oky o, Japan) f orthe k ind g if t o f the monoc lonal an tibody agains t E -c adhe rin, HECD-1 ;and w e are g rateful to A nja de Ruijter, John Ro binso n, and Charle sEwing for their exce llent technical ass is tance .

References1 . Partin, A . W ., W al sh, A . C., Pitc oc k, R . V ., M ohle r, J. L., Eps te in, J. I., andC offe y, D . S . A c ompari so n o f nuc le ar m orphome try and G le as on g rade as apredi ctor o f p rognos is in s tage A2 pros ta te c ance r: a c ri ti ca l ana ly s is . J. Uro l. ,1 42 : 1 25 4- 12 58 , 1 98 9.2 . Carter, H. B ., and Co ffey , D . S . Predictio n o f tumo r behav io r in pro statec anc er. In: J. P. K arr and H . Y amanak (e ds .). Pro state C anc er: The S ec ondTo ky o S ympo sium , pp. 1 9- 27 . N ew Y ork: El se vi er, 1 98 9.3. Carter, B. S., Ew ing, C. M., Ward, W. S., Treiger. B. F., A alders, T. W.,S chal ke n, J. A ., Eps te in, J. I. , and Is aac s, W . B . A l le li c l os s o f c hromo some s16q and lOq in human prostate cancer. Proc. N ati. A cad. Sci. U SA , 87:8 75 1-8 75 5, 1 99 0.4 . B erg erheim, U . S . R., Rimimi, K., Co llins , V . P., and Ekm an, P. 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E -C AD HE RIN E XP RE SS IO N IN H UM AN P RO ST AT E C AN CE Re vi de nc e f or e ig ht n ew c ad he rin s in n erv ou s t is su e. C ell R e gu lati on , 2 : 2 61 -2 70 , 1 99 1.2 2. T ak eic hi, M . C ad he rin c ell ad he sio n re ce pto rs as a m o rp ho ge ne ti c re gu lato r.S cien ce (W a sh in gto n D C), 2 51 : 1 45 1-1 45 5, 1 99 1.2 3. H yaf il, F., B ab in et, C , an d Jaco b. F. C ell-cell in teractio ns in early em b ry o-g en es is : a m o le cu lar ap pro ac h t o th e ro le o f c al ci um . C ell , 2 6:4 47 -4 54 . 1 98 1.

24. G allin, W . J.. E delm an, G . M ., and Cun ningham , B . A . C haracteriz ation ofL -C AM , a m ajo r c ell ad hesio n m o lecu le f ro m em bry on ic liv er cells. Pro c.N ati. A cad. S ci. U SA , 80: 1038-10 42, 1983.25. D am sk y, C . H ., R icha, J., S olter, D ., K nudsen, K ., and B uck , C . A . Identif ic at io n an d p uri fi cat io n o f a c el l s urf ac e g ly c op ro te in m e di at in g i nt erc el lu larad hesio n in em bry on ic an d ad ult tissu e. C ell, 3 4: 4 55 -4 66 , 1 98 3.2 6. Im ho f, B . A . , V o llm ers, H . P., G oo dm an , S . L ., an d B irch meier, W . C ell-cell

i nt erac ti on an d p ol ari ty o f e pi th el ial c el ls : s pe ci fi c p ert urb at io n u si ng a mono clo nal an tib od y. C el l, 5 5:6 67 -6 75 , 1 98 3.2 7. B eh ren s, J., B irc hm eier, W . , G oo dm an , S . L ., an d Im ho f, B . A . D iss ociatio no f M ad in -D arb y can in e k id ney e pith elial cells b y th e m on oclo nal an tib od yan ti-A n - I: m ech an istic as pects an d id en tif icatio n o f th e an tig en as a co m

p on en t re lated to u vo mo ru lin . J. C ell B io l., 1 01 : 1 30 7-1 31 5, 1 98 5.28. S him oy am a, Y ., H irohashi, S ., M irano, S ., N oguchi, M ., S him osato, Y .,T ak eich i, M ., an d A b e, O . C ad herin cell-ad hesio n m o lec ules in h um an ep it he li al ti ss ue s an d c arc in om as . C an ce r R e s., 4 9: 2 12 8-2 13 3, 1 98 9.

2 9. S h im o y am a, Y . , an d H iro has hi , S . C ad he ri n in te rc el lu lar ad he si on m o le cu lei n h ep at oc el lu lar c arc in om as : lo ss o f E -c ad he ri n e xp re ss io n in an u nd if f er-e nti ate d c arc in om a. C an ce r L et t., 5 7: 1 31 -1 35 , 1 99 1.30. S chipper, J. H., Frix en, U . H ., B ehrens, J., Unger, A ., Jahnk e, K ., andB irc hm e ie r, W . E -c ad he ri n e xp re ss io n i n s qu am o us c el l c arc in om as o f h ead

an d n ec k: in ve rs e c orre lat io n w ith tu m or d ed if f ere nti ati on an d ly m p h n od em e tas tas is . C an ce r R e s., 5 7: 6 32 8-6 33 7, 1 99 1.31 . B ussem ak ers, M . J. G ., V an M oorselaar, R . J. A ., G iroldi, L . A ., Ichik aw a,T ., Isaacs, J. T ., T ak eichi, M ., Debruyne, F. M . J., and S chalk en, J. A .D e cre as ed e x pre ss io n o f E -c ad he ri n i n t he p ro gre ss io n o f rat p ro st at ic c an ce r.C an cer R es ., 5 2: 2 91 6-2 92 2, 1 99 2.3 2 . G le as on , D . F . H is to lo gi e g rad in g an d c li ni ca l s tag in g o f p ro st at ic c arc in oma.I n: M . Ta nn en ba um (e d.) , U ro lo gie P a th olo gy: Th e P r osta te , p p. 1 71 -1 97 .

Phi lad el ph ia: L e a an d F eb ig er, 1 97 7.3 3. H ash im oto , M ., N iw a, O ., N itta, Y . , T ak eic hi, M ., an d Y o k oro , K . U nstab lee xp ress io n o f E -cad herin ad hesio n m o lecu les in m etas tatic o varian tu mo rc ells. Jp n. J. C an cer R es ., 8 0: 4 59 -4 63 , 1 98 9.34. L igtenberg, M . J. L ., B uijs, F., V o s, H . L ., and H ilk en s, J. S uppression ofc el lu lar ag gre ga ti on b y h ig h l ev e ls o f e pi si al in . C an ce r R e s. , 5 2: 2 31 8- 23 24 ,

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