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Clinical Cancer Research Vol. 10, 1235-1240, February 2004
© 2004 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Epithelial-Cadherin and ß-Catenin Expression Changes in Pancreatic Intraepithelial Neoplasia

Maamoun M. Al-Aynati1, Nikolina Radulovich1, Robert H. Riddell2 and Ming-Sound Tsao1

1 Department of Pathology, University Health Network-Ontario Cancer Institute/Princess Margaret Hospital and2 Mount Sinai Hospital, Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

ABSTRACT

Purpose: Cadherins and associated catenins are important mediators of epithelial cell-cell adhesion, as well as the Wnt-signaling pathway. Significant changes in their expression or structure have been implicated in malignancy. This study aimed to investigate the epithelial-cadherin (E-cadherin) and ß-catenin expression changes during multistage, pancreatic ductal carcinogenesis.

Experimental Design: Ninety-four Whipple resection specimens were retrieved from the surgical pathology files of the University Health Network (Toronto, Canada), from which tissue microarray blocks containing 36 pancreatic ductal adenocarcinomas, 34 PanIN-1A lesions, 28 PanIN-1B lesions, 27 PanIN-2 lesions, 16 PanIN-3 lesions, and 32 normal ducts were constructed. The E-cadherin, ß-catenin, and the phosphorylated glycogen synthase kinase-3ß of the Wnt/ß-catenin pathway were immunohistochemically evaluated in these duct/PanIN lesions.

Results: There was marked increase in the cytoplasmic E-cadherin expression in PanIN lesions (P < 0.0001) and adenocarcinoma (P = 0.005) compared with normal pancreatic ducts. In contrast, reduced/loss of E-cadherin membranous expression was also significant in ductal adenocarcinoma compared with both the PanIN lesions (P < 0.0001) and normal ducts (P = 0.05). The ß-catenin expression showed significantly more frequent aberrant nuclear localization in high-grade PanIN lesions, particularly PanIN2 and in adenocarcinoma compared with normal ducts or low grade PanIN lesions (P < 0.0001). However, there was a lack of correlation between phosphoSer9-glycogen synthase kinase-3ß cytoplasmic expression and ß-catenin aberrant nuclear expression (P = 0.07).

Conclusions: Aberration in the expression of E-cadherin and its associated ß-catenin is evident in pre-invasive (PanIN) neoplastic pancreatic duct cells, suggesting involvement of pathways leading to ß-catenin stabilization during pancreatic duct cell carcinogenesis.

INTRODUCTION

Cadherins and catenins play important roles in epithelial cell-cell adhesion and signal transduction mechanisms. Epithelial-cadherin (E-cadherin) is one member of a developmentally regulated family of cell surface glycoproteins localized largely in the adherens junctions and mediates adhesion between epithelial cells (1 , 2) . The extracellular domain of E-cadherin between neighboring cells interacts in the presence of calcium ions to form tight cell-cell adhesion (2 , 3) . The cytoplasmic domain of E-cadherin is associated with catenins (3 , 4) . ß-catenin directly connects the E-cadherin to {alpha}-catenin, which, in turn, links up with the actin-based cytoskeleton. These associations are essential for the intercellular adhesive function of E-cadherin (5) . Any significant change in the expression or structure of one of these components may lead to adheren junction disassembly, which has been implicated in the loss of tumor differentiation and the development of invasive phenotype of tumor cells (6) . In addition to this role, increased cytoplasmic ß-catenin levels can also lead to the translocation of ß-catenin into the nucleus, where it binds to the T-cell factor 4 and activates genes with promoter regions containing the T-cell factor 4/ lymphoid enhancer-binding factor-binding sites (7) . Among such target genes are cyclin D1 and c-myc (8 , 9) . The level of ß-catenin is regulated by proteolytic mechanisms involving the phosphorylation and complex formation of ß-catenin with the protein product of the APC gene and axin (10 , 11) . The ß-catenin-T-cell factor transcription signaling also serves as the downstream target of Wnt path-way (12) . Several mechanisms for activating this pathway have been reported. These include mutations at the glycogen synthase kinase-3ß (GSK3ß) phosphorylation sites of ß-catenin, inactivation of the APC gene, and activation of the Wnt pathway (12 , 13) . All three mechanisms can lead to decreased degradation of ß-catenin and the cytoplasmic accumulation of ß-catenin. A recent report demonstrated that when using small interfering RNA directed against ß-catenin to decrease its cellular expression in colon cancer cell lines resulted in an inhibition of cellular proliferation in vitro and tumor growth in vivo (14) .

Expression of E-cadherin and ß-catenin has been studied in pancreatic adenocarcinomas (15, 16, 17, 18, 19, 20) . Consistently with E-cadherin and, less so, with ß-catenin, their reduced/absent expression or aberrant localization has been associated with a poorer differentiation, infiltrative growth pattern, higher stage, lymph node metastasis, and, in some studies, with cancer specific survival. However, molecular analysis has not confirmed a role for ß-catenin or APC inactivation in pancreatic ductal carcinogenesis, primarily because of the low frequency or lack of mutations involving these genes (21, 22, 23, 24, 25) . Nevertheless, direct evaluation of the ß-catenin signaling pathway activation in pancreatic carcinogenesis has not been reported. Furthermore, although there is an increasing number of genetic abnormalities in the pre-invasive PanIN lesions being reported (26 , 27) , there has been no report on alterations related to cell-cell adhesion signaling including E-cadherin and the associated catenins of E-cadherin in these lesions. We report here the results of immunohistochemical studies on the E-cadherin and ß-catenin expression during early stages of human pancreatic carcinogenesis using tissue microarray (TMA) constructed from normal pancreatic ducts, PanIN lesions of various grades, and pancreatic adenocar-cinoma.

MATERIALS AND METHODS

Tissue Materials.
After the approval of this study design by the University Health Network Research Ethics Board (Toronto, Canada), we searched the surgical pathology files of the Department of Pathology at the University Health Network for specimens of Whipple resection and partial pancreatectomy during the period of 1999–2002. Ninety-four cases were identified and their formalin-fixed paraffin embedded tissue blocks were retrieved. Among these, 36 cases were from pancreatic ductal adenocarcinoma patients, 28 cases from miscellaneous neoplastic conditions other than ductal cancer, and 30 cases were associated with benign or reactive conditions.

TMA.
The H&E slides of these cases were reviewed for the presence of normal ducts, PanIN lesions, and adenocarcinoma. The PanIN lesions were graded according to established criteria (26) . Using the manual tissue arrayer (Beecher Instruments, Silver Spring, MD), we constructed six TMA blocks containing cores of normal duct, PanIN duct lesions, and ductal carcinoma. Tissue cores of 1.0 mm were extracted from the 36 carcinoma cases and three to four cores were obtained from each cancer; these were fashioned into one and one-half recipient TMA blocks. The other four and one-half TMA blocks contained 1.5-mm tissue cores taken from 39 PanIN-1A lesions, 34 PanIN-1B lesions, 29 PanIN-2 lesions, 18 PanIN-3 lesions, and 35 normal ducts (Fig. 1A)Citation . Each lesion was represented by one or two tissue cores. Also included in each TMA block were nonpancreatic tissue cores used both as control samples and for orientation purposes; these were normal colonic mucosa and small bowel, prostate, liver, kidney, and tonsil. After sample loss, attributable to technical problems and/or tissue exhaustion, the number of lesions that were available for evaluation by immunohistochemistry included approximately 36 pancreatic adenocarcinomas, 34 PanIN-1A lesions, 28 PanIN-1B lesions, 27 PanIN-2 lesions, 16 PanIN-3 lesions, and 32 normal ducts. The final numbers assessed were slightly variable for different markers, as a result of additional losses suffered during block trimming and immunostaining procedures.



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  		Fig. 1. Tissue microarray (TMA) and epithelial-cadherin (E-cadherin) or ß-catenin immunohistochemistry of pancreatic ductal tissue. A, a representative field of tissue microarray that contained PanIN-2 and PanIN-3 duct lesions. B, normal pancreatic duct epithelium demonstrating lateral intercellular membrane staining for E-cadherin. C, aberrant E-cadherin staining showing increased cytoplasmic staining. D, paranuclear aberrant E-cadherin staining. E, adenocarcinoma (ADC) cell (TC) showing loss of membranous or cytoplasmic staining of E-cadherin, compared with preserved membranous staining in residual acinar cells (*). F and G, normal membranous staining for ß-catenin noted in normal duct and PanIN epithelia. H, aberrant nuclear staining for ß-catenin in a high grade PanIN lesion. I, an adenocarcinoma showing aberrant nuclear and increased cytoplasmic staining of ß-catenin.

 
Immunohistochemistry.
Serial 4-µm sections from the TMA blocks were cut and dried in a 60°C oven overnight. Sections were dewaxed in xylene and rehydrated through graded alcohol to water. Initial sections were stained for H&E to verify histology. Slides were subjected to microwave antigen retrieval in 10 mM Citrate buffer (pH of 6.0) in a pressure cooker, before incubation with the primary antibodies. The clone HECD-1 antibody to E-cadherin (Zymed Laboratories, South San Francisco, CA) was used at 1:500 dilution. The antibody to ß-catenin was clone 14 from BD Biosciences-PharMingen (San Diego, CA), which was used at 1:3000 dilution. The rabbit polyclonal antibody against phosphoSer9-GSK3ß (Cell Signaling, Beverly, MA) was used at 1:500 dilution after overnight incubation. Secondary antibody incubation was carried out with a multispecies link Ultra-streptavidin detection system (Signet Pathology System, Dedham, MA), followed by streptavidin-horseradish peroxidase for 20 min each. Immunoreactivities were revealed by incubation in Nova Red substrate (Vector Laboratories, Burlingame, CA) for 5 min. Slides were counterstained in Mayer’s hematoxylin and mounted with Permount.

Evaluation of Immunoreactivity.
We first determined the scoring criteria during a preliminary evaluation using a multiheaded microscope, as summarized in Tables 1Citation and 2Citation . Two pathologists then independently evaluated the slides and discordant cases were reviewed and agreed upon; the latter was done before data and statistical analyses. The staining was evaluated using the nonneoplastic pancreatic duct epithelium as a positive control and in accordance with previously published reports (15, 16, 17, 18, 19, 20 , 28, 29, 30, 31, 32, 33) . Immunoreactivity was assessed with respect to cellular localization (membranous, cytoplasmic, paranuclear, or nuclear), intensity, and distribution. The staining intensity was scored as 0 for absent, 1 for weak, and 2 for strong staining. The staining distribution was scored as 0 (absent) for <10%, 1 (focal) for 10 to <50%, and 2 (diffuse) for >=50% positive-stained areas noted. The sum of intensity and distribution scores were then used to determine the E-cadherin and ß-catenin immunoreactivity. For membranous or cytoplasmic staining, the sum score of 0 was considered as negative, 2 as weak, and 3 or 4 as strong immunoreactivity. For paranuclear/nuclear staining, score 0 was considered negative and 2–4 as aberrant. Immunostaining was interpreted as normal if strong membranous staining at the intercellular junctions and negative/weak cytoplasmic, paranuclear, or nuclear staining was observed. If immunostaining patterns outside these limits were observed, the expression of E-cadherin or ß-catenin was considered abnormal. For statistical analysis, PanIN-1A and PanIN-1B were considered low-grade PanIN lesions, whereas high-grade PanINs included PanIN-2 and PanIN-3. All correlations were evaluated using the Fisher’s two-tailed exact test.


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  		Table 1 The scoring criteria for immunostaining intensity and distribution patterns

 

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  		Table 2 The scoring criteria for overall expression based on staining intensity and distribution patterns

 
Quantitative Real-Time Reverse-Transcription PCR.
The pancreatic cancer cell lines were purchased from the American Type Culture Collection (Rockville, MD). The establishment of the near normal HPDE6c7 cell line from normal human pancreatic duct epithelium has been described previously (34) . Total cellular RNA was isolated from exponentially growing cells using previously described methods (34) , but was subjected to additional cleanup using the RNeasy Mini kit (Qiagen Canada, Mississauga, ON). First-strand cDNA was prepared from 2 µg of total RNA using the Taqman reverse-transcription reagents and random hexamer primer (Perkin-Elmer Applied Biosystems, Foster City, CA). Primer sets for PCR amplifications were designed using the Primer Express software (Perkin-Elmer Applied Biosystems). The primers for ribosomal 18S (GenBank accession no. X03205) were 5'-CGC-GGTTCTATTTTGTTGGTTT-3' (forward) and 5'-TTCGCTCTGGTCCGTCTTG-3' (reverse) and for ß-catenin (GenBank accession number NM 001904), 5'-CTGGTGAAAATGCTTGGT-TCA-3' (forward) and 5'-ACTGCCATTTTAGCTCCTTCT-TGA-3' (reverse). Real-time PCR amplification was performed in the SYBR Green PCR Master Mix (Perkin-Elmer Applied Biosystems) using an ABI PRISM 7700 Sequence Detection System (Perkin-Elmer Applied Biosystems). Assay for each sample and primer set was performed in duplicate, with each reaction using a reverse-transcription product equivalent to 10 ng of RNA and 0.4 µM primers. Thermal cycle condition was 50°C for 2 min, 95°C for 10 min, 40 cycles of 95°C 15 s, and 60°C for 1 min. The data were analyzed by the Comparative CT Method per the instructions of the manufacturer, using the values of ribosomal 18S as the calibrator for the amount of RNA. The ß-catenin RNA levels in tumor cell lines were expressed as percent changes compared with level expressed in the HPDE6c7 cell line.

RESULTS

E-Cadherin and ß-Catenin Expression in Normal Pancreas.
In normal and nonneoplastic pancreatic tissues, E-cadherin and ß-catenin immunoreactivity were localized uniformly along the lateral intercellular plasma membrane of the pancreatic acinar and ductal cells, as well as in pancreatic islet cells (Fig. 1, B and F)Citation . Stromal cells did not exhibit any staining.

E-Cadherin Expression Changes.
Departure from the normal E-cadherin expression pattern was seen in PanIN duct lesions and pancreatic adenocarcinoma. This was characterized by a marked increase in cytoplasmic E-cadherin expression (Fig. 1C)Citation in all grades of PanIN lesions (P < 0.0001) and adenocarcinoma (P = 0.005) compared with normal pancreatic ducts. Paranuclear staining (Fig. 1D)Citation appeared to parallel the cytoplasmic staining intensity, but there was no nuclear localization of E-cadherin. In ductal adenocarcinoma, however, loss of E-cadherin membranous staining was noted in 36% (13/36) of cases (Fig. 1E)Citation , which compared with 13% (4/32) in normal ducts, 0% (0/62) in low-grade PanIN lesions, and 9% (4/43) of high-grade lesions. The loss of E-cadherin membranous staining in adenocarcinomas (Fig. 2A)Citation was significantly more common than among normal duct epithelium (P = 0.05) and PanIN lesions (P < 0.0001).



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  		Fig. 2. The distribution of aberrant epithelial-cadherin (E-cadherin) and ß-catenin expression in normal pancreatic duct (NL) and neoplastic duct lesions. A, marked increase in E-cadherin cytoplasmic and paranuclear staining is apparent in PanIN and adenocarcinoma (ADC), but loss in membranous staining is significant only in adenocarcinoma. B, progressive increase in frequency of cytoplasmic and nuclear staining for ß-catenin is noted with increasing degree of duct cell transformation, but this occurs without significant changes in membranous staining. C, real-time reverse-transcription PCR demonstrates uniformly marked increase in ß-catenin mRNA expression in pancreatic cancer cell lines compared with an immortalized human pancreatic duct epithelial cell line established from a normal pancreas.

 
ß-Catenin Expression Changes.
There was no significant change in ß-catenin immunoreactivity in the low grade PanIN duct lesions compared with normal ducts (Fig. 1, F and G)Citation . However, we observed abnormal nuclear immunoreactivity of ß-catenin among high-grade PanIN lesions (particularly in PanIN-2) and adenocarcinoma (Figs. 1HCitation and 2BCitation ). There was also an abnormal increase in the ß-catenin cytoplasmic expression that paralleled the emergence of nuclear staining, which increased incrementally with higher PanIN grade and reached the highest in adenocarcinoma (Fig. 1I)Citation . The percentage of cases with aberrant ß-catenin expression (combined nuclear and cytoplasmic aberrations) was 0% (0/32) for normal ducts, 8% (5/62) for low grade PanINs, 14% (6/43) for high grade PanINs, and 31% (11/36) among adenocarcinoma.

Phospho-GSK3ß Expression.
The immunoreactivity for phosphoSer9-GSK3ß was cytoplasmic and was noted in 75% (24/32) of normal ducts, 29%(18/62) of PanIN-1 ducts, 49% (21/43) of PanIN-2/3, and 28% (10/36) of adenocarcinoma cases. There was a lack of significant association between the phosphoSer9-GSK3ß staining and aberrant expression of the ß-catenin (P = 0.07).

ß-Catenin mRNA Expression Levels in Cell Lines.
A quantitative real-time reverse-transcription PCR study revealed that ß-catenin mRNA was uniformly overexpressed in all six pancreatic cancer cell lines studied (Fig. 2C)Citation . The enhanced expression levels were 100–550-fold greater than that expressed in the HPDE6c7 near normal pancreatic duct epithelial cell line.

DISCUSSION

By exploiting the high-throughput nature of tissue microarray, we have demonstrated that during early stages of pancreatic ductal carcinogenesis, a significant increase in cytoplasmic E-cadherin immunoreactivity in PanIN lesions occurs compared with normal pancreatic ducts. Paradoxically, markedly reduced or absent E-cadherin membranous staining was noted in one-third of adenocarcinoma cases, but not in PanIN lesions. Furthermore, we observed a progressive increase in aberrant ß-catenin expression in the nuclei of higher grade PanIN and adenocarcinoma cells. To the best of our knowledge, this is the first report on expression changes involving the E-cadherin and ß-catenin in PanIN lesions. Our findings suggest that aberrations in E-cadherin expression and the ß-catenin activation pathway may also play some role in the molecular pathogenesis of pancreatic duct carcinoma.

Analysis of molecular aberrations in pancreatic cancer cells and their putative precursor lesions has led to the establishment of a novel paradigm for multistage and progressive carcinogenesis of pancreatic duct epithelium (26 , 27) . Early pre-invasive ductal changes are designated as PanIN lesions and the various grades (1A, 1B, 2, and 3) of PanIN are defined morphologically based on their progressive degree of nuclear dysplasia and aberrant cellular arrangement. Because of the focality, paucity, and microscopic nature of these lesions and the lack of appropriate in vitro/cell line models to study them, our understanding of the molecular changes occurring in PanIN lesions remains limited. The molecular aberrations that have been well established include mutations in the K-ras, p16INK4A, Smad4/DPC-4, and p53 genes, as well as aberrant expression of several other genes (27) . The results of our current study add further to the list of aberrant gene expression changes in this pancreatic duct carcinogenesis paradigm.

E-cadherin and catenins form part of the adherens junction complex. They play a critical role in regulating epithelial intercellular adhesion and control normal tissue morphogenesis, including segregation of cell types, differentiation, and the support of specific tissue architecture (1, 2, 3) . Aberrant expression of E-cadherin and its related catenins has been reported in a number of human cancers and their precursor lesions (28, 29, 30, 31, 32, 33) . Our result that revealed the loss of E-cadherin expression in 36% of pancreatic ductal cancers was consistent with previous reports, which reported rates that ranged from 42% to 60% (15, 16, 17, 18, 19, 20) . The marked increase in cytoplasmic E-cadherin immunoreactivity in PanIN lesions compared with normal pancreatic ducts signifies relocation of E-cadherin from the plasma membrane to the cytoplasm. This might represent one of the abnormalities that underlie the loss of cell polarity and differentiation in PanIN and invasive carcinoma cells, and could potentially lead to increased cell proliferation and altered differentiation, as has been suggested previously (7, 8, 9) .

In normal pancreatic duct epithelium, ß-catenin predominantly demonstrates plasma-membrane localization, suggesting that the main function of ß-catenin in these cells is cell-adhesion maintenance. However, in high-grade PanIN lesions and in invasive ductal cancer, frequent cytoplasmic/nuclear localization was observed; however, this occurred in the absence of a loss in its membranous distribution. This finding suggests additional roles for ß-catenin during multistage pancreatic duct cell carcinogenesis, possibly related to its transciptional and proliferative roles in neoplastic transformation. The aberrant localization is putatively caused by stabilization of the ß-catenin protein and its subsequent accumulation in the cytoplasm and nucleus, but increased ß-catenin protein level could also be caused by increased transcription. We have demonstrated that mRNA expression level of ß-catenin was significantly higher in several pancreatic cancer cell lines compared with a cell line derived from normal human pancreatic duct epithelium. Verma et al. (14) recently reported that a reduction in the ß-catenin levels using small interfering RNA against ß-catenin sequences resulted in the inhibition of growth of colon cancer cells that overexpress this protein, further supporting the role of ß-catenin in regulating cellular proliferation.

Several mechanisms have been implicated in the stabilization of the ß-catenin protein, including loss of APC gene function by mutations or lack of expression, mutations in the ß-catenin gene, and the activation of Wnt pathway (12 , 13) . The expression of Wnt proteins in pancreatic cancer and its role in ß-catenin accumulation has not been investigated. Central to the Wnt-signaling pathway activation is the phosphorylation of GSK3ß, which results in inhibition of GSK3ß-phosphorylation activity on ß-catenin and the stabilization of ß-catenin. We hypothesized that the levels of phosphorylated GSK3ß would correlate with the aberrant ß-catenin expression in PanIN and adenocarcinoma cells. However, our immunohistochemistry results failed to substantiate a correlation between phosphoSer9-GSK3ß immunoreactivity and ß-catenin aberrant expression. The GSK3ß Ser-9 residue is phosphorylation target for protein kinase B/Akt and integrin-linked kinase, which putatively inhibits GSK3ß activity leading to activation of the ß-catenin/T-cell factor4 transcription activation pathway. However, regulation of GSK3ß activity by the Wnt pathway appears to be more complicated, and the mechanism is currently not entirely resolved (35) . Among other things, GSK3ß kinase activity is inhibited when GSK3ß is phosphorylated at serine sites but is activated when phosphorylated at tyrosine sites (36) . Furthermore, Wnt signaling that results in ß-catenin accumulation does not appear to involve GSK3 phosphorylation of sites targeted by the protein kinase B and integrin-linked kinase (37) . Our observation of higher levels of phosphoSer9-GSK3ß cytoplasmic staining in normal compared with cancer cells, as well as the lack of association between phosphoSer9-GSK3ß and ß-catenin aberration, would support this.

In summary, we have demonstrated a powerful exploit of TMA in the high-throughput investigation of gene expression in PanIN lesions, which tend to be microscopic in size. Using immunohistochemistry, we have demonstrated aberrations in E-cadherin and ß-catenin expression or staining patterns in PanIN, as well as pancreatic ductal carcinoma, thus suggesting their possible involvement in the molecular mechanism of pancreatic duct cell carcinogenesis.

ACKNOWLEDGMENTS

We thank James Ho and Patricia Wegrynowski for assistance in performing the immunohistochemistry staining and Diana Birle for her valuable input during the preparation of this manuscript.

FOOTNOTES

Grant support: This work was supported by Grant MOP-49585 from the Canadian Institutes of Health Research. Dr. Al-Aynati is a Scholar of the College of American Pathologists (CAP) Foundation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Ming-Sound Tsao, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, M5G 2M9 Canada. Phone: (416) 946-4426; Fax: (416) 946-6579; E-mail: ming.tsao{at}uhn.on.ca

Received 8/25/03; revised 10/27/03; accepted 11/ 6/03.

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