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Clinical Cancer Research Vol. 10, 2790-2796, April 15, 2004
© 2004 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

MUC1 and Nuclear ß-Catenin Are Coexpressed at the Invasion Front of Colorectal Carcinomas and Are Both Correlated with Tumor Prognosis

Stephan E. Baldus1, Stefan P. Mönig2, Sandra Huxel1, Stephanie Landsberg1, Franz-Georg Hanisch3, Katja Engelmann1,3, Paul M. Schneider2, Jürgen Thiele1, Arnulf H. Hölscher2 and Hans P. Dienes1

1 Institute of Pathology, 2 Department of Visceral and Vascular Surgery, and 3 Center of Biochemistry, University of Cologne, Cologne, Germany


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Overexpression of MUC1 and cytosolic interaction of the mucin with ß-catenin are claimed to be involved in colorectal carcinogenesis. In vitro data published recently suggest that MUC1 overexpression results in an increase of steady state levels of nuclear ß-catenin. We tried to elucidate the coexpression of both molecules in colorectal cancer to demonstrate possible correlations with clinical, pathological, and prognostic data.

Experimental Design: An immunohistochemical double staining study was performed to characterize the expression and subcellular distribution of MUC1 and ß-catenin in a series of 205 patients with colorectal carcinoma. The results were correlated with clinicopathological variables as well as overall survival.

Results: MUC1 was strongly expressed in the tumor center and at the invasion front in ~50% of the cases. Similar results were obtained with regard to nuclear accumulation of ß-catenin at the invasive tumor parts. MUC1 protein expression in the tumor center correlated significantly with a low grade of differentiation, and nuclear ß-catenin in the tumor periphery was more frequent in carcinomas of the left colon and rectum. Overexpression of MUC1 and ß-catenin, as well as their nuclear coexpression at the invasion front correlated with a worse overall survival in an univariate analysis. However, only pathological tumor-node-metastasis staging and MUC1 at the invasion front revealed as independent prognostic factors.

Conclusions: These results suggest that MUC1 and ß-catenin are coexpressed at the invasion front of colorectal carcinomas and that this feature is associated with an accelerated course of disease and worse prognosis.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The impact of an increased or strong expression of MUC1 peptide epitopes in human gastric (1, 2, 3) and colorectal cancer (4 , 5) as a predictor for tumor progression and worsening of prognosis was demonstrated repeatedly. A comparable finding was reported regarding the presence of MUC1 at the invasion front (6 , 7) . However, ethnic factors may influence such correlations, because MUC1 could be established as a prognostic factor for Caucasian but not for African-American colorectal cancer patients (8) . The functional role of MUC1 during the process of carcinogenesis and tumor progression as reflected by invasive growth and metastasis is only partially elucidated up to now. Antiadhesive effects can be exerted by an inhibition of integrin-mediated carcinoma cell adhesion and binding of kalinin, laminin (9 , 10) , and ICAM-1 (11) . An important feature of overexpressed MUC1 in carcinoma cells is its interaction with ß-catenin via a peptide motif in the cytosolic domain (12 , 13) , which competes in this way with binding of ß-catenin by E-cadherin. This MUC1 binding to ß-catenin is regulated by various proteins including glycogen synthase kinase-3ß, c-src tyrosine kinase, protein kinase C{delta}, and epidermal growth factor receptor (13, 14, 15) .

It has been demonstrated that ß-catenin and its intracellular distribution play an important role for the morphogenesis and progression of colorectal adenocarcinoma (CRC; Ref. 16 ) and binding to E-cadherin (17) . On the other hand, an increasing nuclear expression of ß-catenin in colorectal adenomas exhibiting low-grade and high-grade dysplasia was described (18) . However, a strong nuclear expression is only observed in dedifferentiated tumor cells at the invasion front of well- and moderately differentiated CRCs (19 , 20) . Nuclear ß-catenin acts as a transcriptional activator and represents an important downstream effector molecule in the so-called canonical Wnt/wingless pathway influencing tumor morphogenesis (16) . Its nuclear accumulation is regulated by a variety of molecules. In a study published recently it was revealed that MUC1 is also involved in this process. Using epitope-tagged constructs, an association of fragments of the MUC1 cytosolic tail with ß-catenin in both cytoplasm and nuclei could be demonstrated. MUC1 overexpression resulted in an increase of steady state levels of nuclear ß-catenin (21) . Due to this observation, it is tempting to speculate that interactions of MUC1 and ß-catenin may represent decisive aspects in the tumor biology of the colon and rectum. According to our knowledge, the correlation between both molecules and their impact on the clinical course of CRC was not characterized up to now, investigating their expression within the same series of patients. Therefore, we investigated the expression of MUC1 and nuclear ß-catenin at the invasion front of CRCs applying immunohistochemical colocalization to determine their importance as a predictor of disease progression and prognosis.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients.
A series of primary CRCs from 205 patients was derived from the files of the Institute of Pathology and the Department of Visceral and Vascular Surgery of the University of Cologne. In all of the cases, a potentially curative (R0) resection was performed between 1985 and 1991. Patients suffering from familial cancer syndromes or chronic inflammatory bowel diseases were not included. Patients who died within 4 weeks after the surgical intervention (postoperative mortality) were also excluded. Within an observation time of up to 11 years, follow-up of surviving patients was at least 5 years. Ninety patients (43.9%) were alive at the closure of the study. The clinical and pathological characteristics of the patients are summarized in Table 1Citation . The areas containing mucinous differentiation were determined as follows: (a) mucinous area <10% of the tumor tissue; (b) mucinous area 10–50% of the tumor; and (c) mucinous differentiation in >50% of the tumor (i.e., mucinous carcinomas according to the WHO classification).


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  		Table 1 Clinical and pathological characteristics of the patients

 
Immunohistochemistry.
MUC1 was detected by the monoclonal antibody HMFG-2 (Immunotech, Hamburg, Germany) recognizing the peptide motif DTR within the tandem repeat domain. The ß-catenin-specific monoclonal antibody was purchased from Becton-Dickinson Transduction Laboratories (Heidelberg, Germany).

Four µm-thick sections of the paraffin-embedded tissues were cut and deparaffinized according to standard histological techniques. Subsequently, a high-sensitivity immunohistochemical double staining was performed applying the DAKO EnVision Doublestain System (DAKO, Hamburg, Germany) according to the manufacturer’s instructions. In brief, endogenous peroxidase activity was blocked by 0.03% hydrogen peroxide containing sodium azide (5 min). Pretreatment was performed in a microwave using citrate buffer (pH 6.0) for 2 x 4 min at 700 W. Subsequently, monoclonal antibody HMFG-2 (1:100) was incubated for 30 min, followed by the labeled polymer AP (30 min), Fast Red substrate-chromogen (10 min), and the Doublestain Block (3 min). The second primary monoclonal antibody detecting ß-catenin was also incubated for 30 min, followed by labeled polymer horseradish peroxidase (30 min) and the liquid 3,3'-diaminobenzidine + chromogen (10 min). After rinsing in aqua dest., the nuclei were counterstained with hematoxylin, and the tissues were embedded in glycerol jelly.

Evaluation and Statistical Analysis.
The microscopic evaluation was performed at a magnification of x400 independently and in a blind fashion by two pathologists. In <10% of the specimens, differences of opinion were observed. A consensus was achieved in these cases. MUC1 staining at the invasion front and in central tumor areas was separately scored according to the percentage of cells exhibiting a positive staining in < or > 35% of the cells, as published previously (5) . The nuclear ß-catenin immunoreactivity at the invasion front was regarded as positive, if >50% of the nuclei were stained. This cutoff value was chosen after a preliminary quantification, because it was near to the mean value.

Correlations between the degree of staining, and the subgroups according to the clinical and pathological classifications were calculated by the {chi}2 test at a significance level of 5%. The overall univariate survival analysis was performed according to the Kaplan-Meier product limit method, the multivariate survival analysis according to the Cox proportional hazards model, as described earlier (3) .


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The immunohistochemical staining resulted in a visualization of MUC1 as a red, and of ß-catenin as a brown staining product. MUC1 was mostly present in a cytoplasmic or membrane-associated staining pattern, whereas ß-catenin additionally showed a nuclear reactivity, especially at the invasion front (Fig. 1)Citation . MUC1 binding was separately evaluated at the tumor center and at the invasion front. On the other hand, membrane-associated and cytoplasmic ß-catenin was disregarded, and only nuclear ß-catenin was included into the scoring of reactivity.



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  		Fig. 1. Immunohistochemical localization of MUC1 and ß-catenin. MUC1 (red) color and ß-catenin (brown) color could be colocalized in the tissue specimens. In the tumor center, both were mostly detected in a membranous or cytoplasmic pattern (A), whereas ß-catenin showed a nuclear accumulation at the invasion front (B–D).

 
MUC1 was regarded as strongly expressed, if >35% of the tumor cells at the tumor center or at the invasion front, respectively, expressed the antigen. On the other hand, an overexpression of nuclear ß-catenin was defined as a reactivity of >50% of the nuclei. MUC1 was strongly reactive in 102 cases (49.8%) in the tumor center and in 103 cases (50.2%) at the invasion front. On the other hand, an accumulation of nuclear ß-catenin at the invasion front could be observed in 105 cases (51.2%). If these staining results were correlated with the various clinical and pathological variables, MUC1 in the tumor center was associated significantly with the histological grading (more strongly in carcinomas with low differentiation; P < 0.05), whereas MUC1 expression at the invasion front did not correlate with any of these characteristics (localization, grading, pTNM stage, pT stage, pN stage, WHO classification, and amount of the mucinous component). On the other hand, nuclear ß-catenin was significantly stronger in carcinomas of the left colon and rectum (P < 0.05), but was not associated with the other variables (Table 2)Citation .


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  		Table 2 Correlation of MUC1 and ß-catenin antigen expression with clinical and pathological variables

 
The expression of MUC1 and nuclear ß-catenin at the invasion front correlated significantly (P < 0.05), as shown in Table 3Citation . In an additional evaluation, carcinomas exhibiting a strong coexpression of MUC1 (in >35% of the tumor cells) as well as ß-catenin (in >50% of the tumor cell nuclei) at the invasion front were separately compared with carcinomas not showing this pattern. Sixty patients (29.3%) belonged to the group strongly coexpressing both molecules. However, the statistical evaluation did not result in any significant differences with regard to the clinical and pathological classifications and subgroups under study.


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  		Table 3 Correlation between MUC1 and nuclear ß-catenin at the invasion front

 
Univariate survival analyses were performed to investigate a possible prognostic impact of MUC1 and nuclear ß-catenin in colorectal cancers. As demonstrated in Table 4Citation and Fig. 2Citation , expression of MUC1 at the tumor center and at the invasion front, as well as the presence of nuclear ß-catenin at the invasion front correlated with a worse survival probability, which was statistically significant. The same result was obtained if the coexpression of MUC1 and ß-catenin at the invasion front was evaluated. In a multivariate survival analysis, which included all of these variables, as well as pTNM staging and histological grading, representing well-established prognostic factors of colorectal cancer; only pTNM staging and MUC1 expression at the invasion front revealed as independent predictors of prognosis (Table 5)Citation .


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  		Table 4 Univariate survival analysis (according to Kaplan and Meier)

 


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  		Fig. 2. Kaplan-Meier analyses showing overall survival of colorectal cancer patients. Patients are categorized according to the status of MUC1 in the tumor center (A), MUC1 at the invasion front (B), nuclear ß-catenin at the invasion front (C), and strong coexpression of MUC1 and nuclear ß-catenin at the invasion front (D). P values were calculated by the log-rank test.

 

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  		Table 5 Multivariate survival analysis (according to the Cox proportional hazards model)

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the current study, clinical and pathological implications of the coexpression of MUC1, and nuclear ß-catenin at the invasion front of CRCs were investigated by applying a highly sensitive immunohistochemical double-staining protocol. MUC1 immunoreactivity in the tumor center was evaluated separately. A significant correlation between MUC1 and pTNM stage was not observed, as described previously (8) , whereas MUC1 expression in central parts of the carcinomas correlated significantly with a low grade of differentiation. Other investigators reported contradictory results, because they observed a correlation of MUC1 expression with lymph node or distant metastasis (4 , 6 , 7 , 22) and increasing Dukes’ or pTNM stages (4, 5, 6, 7) . Some of these authors evaluated MUC1 immunoreactivity without respect to its localization within the tumor (4 , 5 , 8 , 22) , whereas others included a staining at the invasion front only (6 , 7) . Our data confirm that a strong MUC1 expression represents an indicator of a worse prognosis in CRC. In this context, the presence of MUC1 in the tumor center and at the invasion front have the same prognostic impact. Similar data were reported by some studies cited above in univariate (5, 6, 7) as well as multivariate (5 , 6) survival analyses. In a study including individuals from different ethnic groups, the same observations were made for Caucasian but not for African-American patients (8) .

Some aspects of the role of MUC1 in tumor biology could be elucidated during the last years. Besides interactions with extracellular matrix components (9 , 10) and ICAM-1 (11) , MUC1 exerts antiadhesive effects and is involved in signaling cascades. In this context, it seems to be important that its YTNP sequence represents a binding motif for Grb2-SH2, an adapter protein of the ras signal cascade (23 , 24) . Additionally, seven distinct phosphorylation sites and a binding motif (SAGNGGSSLS) for ß-catenin are constituents of MUC1 (12) . MUC1 overexpression has two effects on ß-catenin. On the one hand, it reduces the binding of ß-catenin to E-cadherin, thereby inducing an antiadhesive effect on tumor cells. This effect can be abrogated by glycogen synthase kinase-3ß, which phosphorylates serine within the motif DRSPYAKV in the cytoplasmic domain (13) . In contrast, the c-src tyrosine kinase enhances ß-catenin binding to MUC1 by phosphorylation of the cytoplasmic domain of MUC1 at the YEKV motif, which is localized between the binding site of glycogen synthase kinase-ß3 and ß-catenin (14) . MUC1-ß-catenin binding is also up-regulated by the protein kinase C{delta}. Its binding and phosphorylation site is represented by a thymidine sequence in the neighborhood of the ß-catenin binding site (15) . Within the YEKV sequence of the cytoplasmic part, the activated epidermal growth factor receptor also phosphorylates MUC1. Thereby, MUC1 binding to c-src and ß-catenin is induced (14) . Whereas these data support an involvement of MUC1 in the control of tumor cell adhesion and invasion, observations published recently revealed a second effect of MUC1, because its overexpression increased the steady state levels of nuclear ß-catenin (21) .

All of these results suggest that colocalization, and interactions between MUC1 and ß-catenin may represent important factors for disease progression and prognosis of CRC. Whereas membranous ß-catenin determines an epithelial phenotype, nuclear ß-catenin represents a transcriptional regulator and main effector of the Wnt signaling pathway (16) . It accumulates in dedifferentiated tumor cells at the invasion front (19 , 20) . In the so-called canonical Wnt/wingless pathway, ß-catenin forms a complex with DNA-binding proteins of the T-cell factor/lymphoid enhancer factor family (25 , 26) . Numerous target genes in carcinomas are regulated by ß-catenin/T-cell factor, including c-myc, cyclin D1, and many others (16 , 27) .

Correlations between nuclear ß-catenin and important clinicopathological variables were not observed in the present study. The only exception represented a significantly stronger expression in CRCs of the left colon and rectum, as reported earlier (28 , 29) . In general, we observed a higher rate of nuclear ß-catenin at the invasion front compared with previous investigations (29, 30, 31) . This fact may be due to the application of a very sensitive double-staining kit in the present study. Previous data regarding an association with tumor stage or presence of metastasis were contradictory. Whereas one group reported a correlation of nuclear ß-catenin accumulation with tumor stage and/or metastasis (29) , others did not (30, 31, 32) . With regard to prognosis, patients with nuclear ß-catenin staining at the invasion front showed a significantly longer survival in our univariate survival analysis. Another study reported an analogous result (32) , whereas contradictory observations were also published (30 , 31) . However, this pattern did not represent an independent prognostic factor according to our data, as opposed to other authors (32) . In addition, we observed a strong correlation between MUC1 and nuclear ß-catenin expression at the invasion front. About 30% of the patients strongly coexpressed both molecules and had a significantly worse prognosis compared with patients not exhibiting this pattern. In addition to MUC1, the nuclear accumulation of ß-catenin itself is regulated by a variety of other molecules. Numerous cytokines lead to tyrosine phosphorylation of the molecule and to nuclear accumulation of ß-catenin (33, 34, 35, 36) . All of these aspects indicate that complex mechanisms control the nuclear accumulation of ß-catenin.

Our data demonstrate that MUC1 is indeed coexpressed with nuclear ß-catenin at the invasion front of CRCs. They also confirm previous findings indicating a significant role of both interaction partners in colorectal carcinogenesis, because the expression of MUC1 and ß-catenin (as well as their coexpression) is correlated with a worse prognosis of CRC patients. Up to now, the molecular basis of these phenomena is not completely understood, and additional studies will have to reveal the details of MUC1 overexpression-mediated dysregulation in cell adhesion and the onset of invasion.


   FOOTNOTES
 
Grant support: Deutsche Krebshilfe (project 70–2396-Ba II) and the Cologne Fortune Program.

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: Stephan E. Baldus, Institute of Pathology, University of Cologne, Joseph-Stelzmann-Str. 9, 50931 Cologne, Germany. Phone: 49-221-478-6372; Fax: 49-221-478-6360; E-mail: s-e.baldus{at}uni-koeln.de

Received 9/15/03; revised 12/11/03; accepted 12/23/03.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Cancer Research Clinical Cancer Research
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