Annals of Surgical Oncology 10:284-290 (2003)
© 2003 Society of Surgical Oncology
Dysregulation of ß-Catenin Expression Correlates With Tumor Differentiation in Pancreatic Duct Adenocarcinoma
Andrew M. Lowy, MD,
Cecilia Fenoglio-Preiser, MD,
On Ja Kim, MD,
Jennifer Kordich, MS,
Ana Gomez, MD,
Joy Knight, MS,
Laura James, MS and
Joanna Groden, PhD
From the Department of Surgery, Division of Surgical Oncology (AML, JJK, JK, LJ), the Department of Pathology and Laboratory Medicine (OJK, AG, CF-P), and the Department of Molecular Genetics, Biochemistry and Microbiology, Howard Hughes Medical Institute (JG), University of Cincinnati College of Medicine, Cincinnati, Ohio.
Correspondence: Address correspondence and reprint requests to: Andrew M. Lowy, MD, Division of Surgical Oncology, University of Cincinnati, 234 Goodman Street, Cincinnati, OH 45219-0772; Fax: 513-584-0459; E-mail: lowyam{at}healthall.com
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ABSTRACT
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Background: ß-Catenin functions as an integral part of the E-cadherin/catenin adhesion complex to maintain epithelial cell integrity. ß-Catenin also functions as part of the Wnt signal transduction pathway to transmit growth-promoting signals to the nucleus via its interactions with Tcf/Lef transcription factors. Previous reports have demonstrated altered ß-catenin expression in numerous tumor types; however, reports regarding ß-catenin expression in pancreatic cancer have been conflicting.
Methods: ß-Catenin expression was examined in 10 pancreatic cancer cell lines by Western and Northern analysis and by immunofluorescence. Expression was also examined by immunohistochemistry in 57 primary pancreatic cancers and 7 foci of carcinoma-in-situ.
Results: Reduced expression of ß-catenin was observed in 4 of 10 pancreatic cancer cell lines. Reduced membranous expression was noted in 32 pancreatic cancers (56%) and correlated with loss of tumor differentiation. Nuclear ß-catenin expression was identified in two tumors (4%). ß-Catenin expression was present in all seven foci of carcinoma-in-situ; however, nuclear expression was predominant in four of the seven cases.
Conclusions: Alterations in ß-catenin expression are common in pancreatic cancer; however, signaling and adhesion functions may be perturbed at different times during tumor progression. Therefore, dysregulation of ß-catenin may contribute to the development and progression of this disease through distinct mechanisms.
Key Words: ß-Catenin • Pancreatic cancer • E-cadherin • Adhesion • Wnt signaling
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INTRODUCTION
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ß-Catenin is a 92-kDa protein that functions as part of the cadherin/catenin adhesion complex and as part of the Wnt signaling pathway.1 Cellular levels of ß-catenin are tightly regulated via its phosphorylation by the GSK3-ß kinase and binding to the tumor suppressors adenomatous polyposis coli (APC) and axin.2 These interactions target ß-catenin for degradation via the ubiquitin/proteasome pathway. When mutations in APC, axin, or ß-catenin disrupt this equilibrium, ß-catenin levels increase, and the protein may translocate to the nucleus, where it binds to the Tcf/Lef family of transcription factors.3 The result is increased transcription of numerous genes, including c-myc and cyclin D.4,5 Thus, dysregulation of ß-catenin, resulting in its nuclear expression, has been shown to contribute to carcinogenesis in numerous tissues.
Reduced ß-catenin expression has also been described in many human tumors. Decreases in membranous expression have been shown to correlate with loss of differentiation and decreased survival in cholangiocarcinoma and gastric cancer, respectively.6,7 Loss of functional ß-catenin has been ascribed to chain-terminating mutations in two human gastric cancer cell lines. Loss of wild-type ß-catenin in the HSC69 gastric cancer cell line results in a dysfunctional cadherin/catenin complex and loss of cell/cell adhesion that can be restored only after reintroduction of functional ß-catenin.8 Our work has demonstrated that the restoration of ß-catenin and E-cadherin expression in pancreatic cancer cells results in decreased cell growth and apoptosis.9
Two published reports have investigated ß-catenin expression in pancreatic duct adenocarcinoma. The initial report examined ß-catenin expression in 40 tumors by immunostaining and found no changes in membranous expression.10 No nuclear expression was noted. A larger number of tumors were examined for mutations in ß-catenin, yet no mutations were identified. A more recent study examined ß-catenin expression in 43 pancreatic duct adenocarcinomas and found reduced membranous staining in 58%.11 This correlated with increased levels of cytoplasmic staining and with expression of cyclin D. Furthermore, tumors that expressed increased cytoplasmic ß-catenin and cyclin D were associated with a poorer prognosis. The goal of this study was to provide additional information regarding ß-catenin expression in pancreatic duct adenocarcinoma and to determine whether ß-catenin dysregulation correlates with clinicopathologic factors such as stage, grade, perineural and lymphovascular invasion, and survival. We observed that ß-catenin expression was frequently absent or decreased but that in instances of carcinoma-in-situ, ß-catenin localization was frequently nuclear, and we observed that these changes correlate with tumor differentiation. Our data suggest that dysregulation of ß-catenin expression is common in pancreatic cancer and may influence pancreatic carcinogenesis via two distinct mechanisms.
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MATERIALS AND METHODS
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Cell Lines and Tumors
All cell lines were obtained from the American Type Culture Collection (Manassas, VA). Pancreatic cancer cell lines were ASPC1, BxPc3, Capan-1, Capan-2, CFPAC, HPAFII, HS766T, MiaPaca-2, Panc-1, and Su8686. All cell lines had been previously classified by the American Type Culture Collection as well, moderate, or poorly differentiated according to the tumor from which they were derived and by their histological appearance in culture. Additional cell lines used in these experiments included the colon cancer cell lines SW480 and HCT116. Cells were maintained in recommended growth media. Pancreatic cancer specimens were obtained from the archives of the Division of Surgical Pathology in the Department of Pathology at the University of Cincinnati.
Immunofluoresence
Cells were plated on glass coverslips and incubated under normal culture conditions. When the cells reached 50% to 80% confluence, they were fixed and permeabilized with methanol. After incubating for 1 hour in blocking solution (triethanolamine-buffered saline [TBS] + 5% nonfat dry milk), the cells were incubated with a monoclonal antibody to ß-catenin (Transduction Laboratories) that recognizes the C terminus of the protein (Transduction Laboratories, Lexington, KY). After washing in TBS, the cells were incubated with a fluorescein isothiocyanate–conjugated anti-mouse antibody (Kirkegaard and Perry Labs, Inc., Gaithersburg, MD), rewashed in TBS containing 46'-diamidino-2-phenylindole-2 HCl (DAPI) to enable nuclear identification, and mounted onto slides by using fluromount. Subcellular localization of ß-catenin was visualized by fluorescent microscopy.
Western Analysis
Protein lysates were collected from each of 10 pancreatic adenocarcinoma cell lines, COS1 cells, and the colon cancer cell lines HCT116 and SW480. After quantitation (DC Protein Assay; Bio-Rad, Hercules, CA), total protein lysates (25 µg each sample) were resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and electroblotted onto nylon membranes (Amersham, Piscataway, NJ). The membranes were incubated for 90 minutes in blocking solution (TBS + 5% nonfat dry milk) and then for 2 hours with ß-catenin antibody (1/1000). After washing in TBST, the blots were incubated with goat anti-mouse peroxidase-labeled immunoglobulin G (H+L; Kirkegaard and Perry Labs, Inc.) for 1 hour and washed in TBST. Blots were then treated with chemiluminescent solutions (Renaissance; PerkinElmer, Boston, MA) and exposed to x-ray film at multiple time intervals. To assess for equal sample loading, membranes were reprobed with actin primary antibody (Sigma, St. Louis, MO).
Northern Analysis
Total cellular RNA was extracted from pancreatic cancer cell lines by using Trizol reagent (Gibco BRL, Grand Island, NY). Approximately 20 µg of RNA was separated on a 1.5% formaldehyde/agarose gel and transferred onto Hybond N+ Membrane (Amersham). The membrane was prehybridized for 4 hours and then hybridized overnight to 32P-labeled ß-catenin complementary DNA, washed, and exposed to film. The membrane was then stripped and rehybridized to a 32P-labeled glyceraldehyde phosphate dehydrogenase complementary DNA probe (base pairs 69–588) to enable quantitative analysis.
Immunohistochemistry
Formalin-fixed, paraffin-embedded tissue blocks from 57 human primary pancreatic duct adenocarcinomas—1 tumor contained only carcinoma-in-situ, and 6 contained adjacent foci of carcinoma-in-situ—were cut into 4-µm-thick sections and placed onto positively charged slides. Slides were incubated overnight, deparaffinized in xylene, and rehydrated in decreasing concentrations of ethanol to water. Epitope unmasking was accomplished by boiling in 10 mM of citrate buffer, pH 6.0, for 15 minutes, followed by cooling for 30 minutes at room temperature. Immunohistochemical staining was performed by using an indirect biotin streptavidin diaminobenzidine method and the Ventana 320 ES automated immunostainer (Ventana Medical Systems, Tucson, AZ). Slides were lightly counterstained with Mayer’s hematoxylin. The ß-catenin antibody was used at a concentration of 1/25. Appropriately pretreated negative controls were run concurrently by using purified nonimmune mouse immunoglobulin G. Staining was scored in a semiquantitative manner by at least two independent observers (OJK, AG, or CF-P). In cases in which there was a disparity in scoring, a consensus was reached after re-review of the specimens. Scores were correlated with clinical and pathologic factors, including survival, stage, differentiation, and lymphovascular and perineural invasion. Statistical significance was defined as P < .05. Data were analyzed with SPSS software (SPSS Inc., Chicago, IL) for a 
- test and with Kaplan-Meier survival analysis.
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RESULTS
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Initially, two pancreatic cancer cell lines, MiaPaca-2 and Panc-1, were examined for ß-catenin expression by immunofluorescence. These cell lines are poorly differentiated, have a fibroblastoid morphology in culture, and do not form ductal structures. ß-Catenin expression was minimal to absent in both of these lines (Fig. 1A and B). Eight additional pancreatic adenocarcinoma cell lines, most moderately to well differentiated, epithelioid, and capable of forming rudimentary glands, were then similarly evaluated. Each of these lines expressed ß-catenin, primarily localized at the cell membrane. Staining in the ASPC1 and Capan-1 lines is depicted (Fig. 1C and D). No nuclear staining of ß-catenin was observed in any of these 10 cell lines after DAPI co-staining (data not shown). To verify these observations and to address whether loss of ß-catenin was associated with alterations in protein size, ß-catenin expression in these 10 cell lines was then examined by Western analysis. Western analysis confirmed the results of immunofluorescence: ß-catenin was absent in MiaPaca-2 and Panc-1 (Fig. 2A). Of note, ß-catenin levels were also markedly reduced in the Capan-2 and CFPAC lines as compared with actin-loading controls. No size differences were observed for ß-catenin in any of the cell lines examined. All results from immunofluorescence and Western analyses are listed in Table 1.
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FIG. 1. Immunofluorescent staining of pancreatic cancer cell lines demonstrates decreased expression of ß-catenin. Panels A and B indicate poorly differentiated cell lines MiaPaca-2 and Panc-1, respectively. Note the paucity of ß-catenin expression as compared with the Capan-1 and ASPC-1 lines depicted in panels C and D, respectively.
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FIG. 2. Western analysis of 10 pancreatic cancer cell lines demonstrates decreased ß-catenin and/or E-cadherin expression in four cell lines. (A) Results of Western analysis with an antibody that recognizes ß-catenin. (B) Actin control. Expected protein sizes are highlighted by the arrows on the right, as determined by protein standards (not shown). Protein lysates from all cell lines were electrophoresed in lanes 1–12 as follows: (1) HCT116, a colon cancer cell line with a point mutation in ß-catenin; (2) SW480, a colon cancer cell line with mutant adenomatous polyposis coli; (3) ASPC1; (4) BxPc3; (5) Capan-1; (6) Capan-2; (7) CFPAC; (8) HPAFII; (9) HS766T; (10) MiaPaca-2; (11) Panc-1; and (12) SU8686. Note that cell lines Capan-2, CFPAC, MiaPaca-2, and Panc-1 have reduced expression of ß-catenin.
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Northern analysis of pancreatic cancer cell lines was used to determine whether loss of ß-catenin expression was due to changes in gene expression. Abundant ß-catenin transcription was noted in all cell lines, including MiaPaca-2 and Panc-1 (Fig. 3). ß-Catenin messenger RNA was observed at the expected size of 2.3 kilobases. These data suggest that reduction of ß-catenin expression in these two cell lines is most likely posttranslational.
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FIG. 3. Northern analysis demonstrates similar levels of ß-catenin RNA in 10 pancreatic cancer cell lines. (A) Northern analysis with a complementary DNA probe for ß-catenin; (B) glyceraldehyde phosphate dehydrogenase control. Lanes are as follows: 1 and 2, colon cancer lines (HCT116 and SW480); 3, ASPC1; 4, BxPc3; 5, Capan-1; 6, Capan-2; 7, CFPAC; 8, HPAFII; 9, HS766T; 10, MiaPaca-2; 11, Panc-1; and 12, SU8686. Note that despite differences in protein expression, RNA transcription levels are equivalent for all pancreatic cancer lines.
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Tissue sections from 57 human primary pancreatic duct adenocarcinomas, 7 foci of carcinoma-in-situ, and nonneoplastic adjacent pancreas were evaluated for ß-catenin expression to test whether the observations made in cell culture were representative of in vivo alterations (Fig. 4). In 32 of 57 primary tumors, ß-catenin membranous expression was reduced compared with adjacent nonneoplastic pancreatic ducts (Fig. 4A). No increase in cytoplasmic or nuclear expression was identified in those tumors with reduced membranous ß-catenin (Fig. 4B–D). Reduced membranous expression of ß-catenin was associated with loss of tumor differentiation (Table 2); however, correlations with survival and other clinicopathologic factors did not reach statistical significance (data not shown). In four cases in which ß-catenin expression was preserved in the primary tumor, areas of adjacent ductal carcinoma-in-situ also demonstrated preserved expression of ß-catenin, although this expression was predominantly nuclear. In addition, one well-differentiated tumor and one moderately differentiated tumor also displayed nuclear ß-catenin expression (Fig. 4E and F). Nuclear ß-catenin was not identified in any poorly differentiated tumors. Thus, expression of nuclear ß-catenin was associated with carcinoma-in-situ as opposed to invasive carcinoma (Table 2).
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FIG. 4. Photomicrographs depicting ß-catenin expression in pancreatic duct carcinoma. (A) Normal pancreatic duct (PD) and adjacent moderately to poorly differentiated carcinoma (PC) stained with hematoxylin and eosin. (B) Immunostaining for ß-catenin reveals perimembranous staining in normal pancreatic ducts. (C) Immunostaining of the tissue section seen in panel A with ß-catenin antibody. Perimembranous staining is present in normal duct and reduced or lost in most tumor cells. (D) Additional fields demonstrating reduced expression of ß-catenin in areas of invasive carcinoma (arrows). (E, F) High-power views of immunostaining for ß-catenin reveal nuclear localization (arrows) in a moderately differentiated (E) and well-differentiated (F) tumor.
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DISCUSSION
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Our work reveals that ß-catenin expression is altered frequently in pancreatic duct carcinoma cell lines and primary tumors. In this study, reduced membranous ß-catenin expression was associated with tumor dedifferentiation, whereas nuclear expression was more common in carcinoma-in-situ. These observations suggest that loss of ß-catenin expression is not an initiating event in pancreatic carcinogenesis but occurs later in the course of tumor progression, whereas activation of Wnt signaling may contribute to tumor initiation. Of course, it is possible that reduced ß-catenin expression has no functional significance but rather is a consequence of other events that occur in the setting of carcinoma progression. We believe this to be less likely given that disruption of the cadherin/catenin complex is common in pancreatic cancer cell lines and tumors.12 Previous studies have correlated loss of E-cadherin expression with decreased tumor differentiation and survival in pancreatic cancer.13–15 Furthermore, in other work from our laboratory, restoration of the cadherin/ß-catenin complex induced apoptosis in pancreatic cancer cells, indicating that a functional cadherin/catenin complex is incompatible with the transformed phenotype.9
Our finding of ß-catenin nuclear localization in pancreatic carcinoma-in-situ suggests that activation of the Wnt signaling pathway may contribute to pancreatic carcinogenesis. Caca et al. have reported increased Tcf/Lef signaling in the HS766T and ASPC1 pancreatic cancer cell lines.16 An activating mutation in exon 3 of ß-catenin was noted in HS766T, although no mutations were present in either ß-catenin or APC in ASPC1. Mutations in APC have previously been reported in pancreatic duct adenocarcinoma, and mutations in axin have been reported in hepatocellular carcinomas.17,18 APC promoter hypermethylation and alterations in the Wnt ligand and frizzled receptor isoform expression have also been reported to activate Wnt signaling in various human tumors, including pancreatic cancer.19–24 Our finding of ß-catenin nuclear localization in some primary pancreatic tumors suggests that the Wnt pathway may be activated in vivo.
In this study, we observed both reduced expression of membranous ß-catenin and instances of ß-catenin nuclear localization. In that regard, our results differ from those of two smaller studies on ß-catenin expression in pancreatic duct carcinoma. Our report of reduced membranous ß-catenin expression in 56% of pancreatic cancers remarkably mirrors that of Qiao et al.,11 who examined expression in 43 tumors. In this report, 25 tumors (58%) had reduced expression of ß-catenin at the cell membrane, whereas 28 (65%) had increased cytoplasmic ß-catenin. In contrast to their findings however, we found nuclear/cytoplasmic expression in only 2 of 57 invasive carcinomas. In this regard, our findings more closely concur with those of Gerdes et al.,10 who noted no instance of ß-catenin nuclear expression in 40 pancreatic duct carcinomas. In their report, however, no reduction in membranous ß-catenin expression was observed. Differences in immunostaining techniques and interpretation may explain some of the variability between studies. However, our findings of reduced membranous expression in 4 of 10 pancreatic cancer cell lines without evidence of nuclear expression support our in vivo findings.
The presence of full-length ß-catenin RNA in cell lines with minimal or no ß-catenin protein expression suggests that protein degradation may account for decreases in ß-catenin levels. One cellular event that may lead to ß-catenin protein degradation is phosphorylation of ß-catenin by epidermal growth factor receptor (EGFR) or other tyrosine kinases. The EGFR and the related receptor, c-erb-2, are protein tyrosine kinases that are overexpressed in approximately 50% of pancreatic cancers.25 Phosphorylation of ß-catenin may detach ß-catenin from the cadherin complex, after which it would be subject to degradation via the ubiquitin-proteasome pathway. Activation of several tyrosine kinases, including EGFR, is associated with phosphorylation of catenins, downregulation of cadherin-mediated cell adhesion, and an increase in cell migration.26,27
The central role of ß-catenin in both cell adhesion and the Wnt signaling pathway leaves open questions as to whether these functions are independent. Several investigators have reported that ß-catenin adhesion and signaling functions are separable.1 Loss of endogenous E-cadherin expression is insufficient to activate Tcf/Lef transcription in breast cancer cell lines.16 However, other studies demonstrate that overexpression of E-cadherin in Drosophila and Xenopus organisms affects downstream Wnt signaling, perhaps by titration of ß-catenin/Armadillo protein levels.28 Our data argue that ß-catenin functions in signaling and adhesion are separable and that changes in ß-catenin expression contribute to pancreatic carcinogenesis or progression via distinct mechanisms. In some pancreatic tumors, Tcf/Lef transcription may become activated, resulting in changes in gene expression that promote growth or affect adhesion. In other tumors, loss of ß-catenin expression may affect cadherin/catenin adhesion function more directly. Alternatively, there may be early events in pancreatic duct adenocarcinoma that involve activation of Wnt signaling that are followed by selection of cells within the tumor that have diminished ß-catenin and E-cadherin levels. Further characterization of the temporal dysregulation of ß-catenin may provide important prognostic information.
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Acknowledgments
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The acknowledgments are available online at www.annalssurgicaloncology.org.
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Footnotes
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ß-Catenin expression was examined in pancreatic cancer cell lines and primary tumors. Reduced membranous expression and nuclear localization were observed and found to correlate with tumor differentiation.
Received for publication May 2, 2002.
Accepted for publication October 10, 2002.
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ABSTRACT
INTRODUCTION
