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10.1245/s10434-006-9072-2
Annals of Surgical Oncology 13:1604-1609 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Nuclear Translocation of ß-Catenin Protein but Absence of ß-Catenin and APC Mutation in Gastrointestinal Carcinoid Tumor

Min-Cheng Su, MD1, Chia-Chi Wang, MD2, Chun-Chin Chen, MD3, Rey-Heng Hu, MD, PhD4, Ting-Huang Wang, MS5, Hsin-Lien Kao, MS5, Yung-Ming Jeng, MD5 and Ray-Hwang Yuan, MD, PhD4

1 Department of Pathology, Min-Sheng General Hospital, 168 Ching-Kuo Road, Taoyuan City, Taiwan, ROC
2 Department of Gastroenterology, Buddhist Tzu Chi General Hospital Taipei Branch, 289 Jianguo Road, Xindian city, Taipei, Taiwan, ROC
3 Departments of Gastroenterology, Min-Sheng General Hospital, 168 Ching-Kuo Road, Taoyuan City, Taiwan, ROC
4 Department of Surgery, National Taiwan University Hospital and College of Medicine, National Taiwan University, 7, Chung-Shan South Road, Taipei, Taiwan, ROC
5 Department of Pathology, National Taiwan University Hospital and College of Medicine, National Taiwan University, 7, Chung-Shan South Road, Taipei, Taiwan, ROC

Correspondence: Address correspondence and reprint requests to: Ray-Hwang Yuan, MD, PhD; E-mail: yuan{at}ha.mc.ntu.edu.tw


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Carcinoid tumors are a group of heterogeneous tumors with neuroendocrine differentiation and are mainly located in the gastrointestinal tract. A high frequency of cytoplasmic accumulation and/or nuclear translocation of ß-catenin with frequent mutations of exon 3 of ß-catenin gene in gastrointestinal carcinoid tumor has been previously described, but the role of Wnt/ß-catenin/APC pathway in the genesis of carcinoid tumor remains largely unknown.

Methods: To further characterize the role of Wnt/ß-catenin/APC pathway, we investigated 91 gastrointestinal carcinoid tumors and, for comparison, 26 extragastrointestinal carcinoid tumors by immunohistochemical detection of ß-catenin protein and direct sequencing of exon 3 of the ß-catenin gene and exon 15 of the APC gene.

Results: Cytoplasmic accumulation and/or nuclear translocation of ß-catenin were found in 27 gastrointestinal carcinoid tumors (29.7%) but not in any extragastrointestinal carcinoid tumors. Interestingly, neither ß-catenin nor APC gene mutation was detected in all of the cases with nuclear expression of ß-catenin.

Conclusions: Our results indicate that the role ß-catenin plays in the genesis of gastrointestinal and extragastrointestinal carcinoid tumors is different. Nuclear expression of ß-catenin does not occur in extragastrointestinal carcinoid tumors, and mutation of exon 3 of ß-catenin gene and exon 15 of APC gene does not contribute to the activation of Wnt/ß-catenin/APC pathway in gastrointestinal carcinoid tumors.

Key Words: Carcinoid tumors • ß-catenin mutation • APC mutation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Carcinoid tumor belongs to a group of heterogeneous neuroendocrine tumors that originate in tissues that contain cells derived from the embryonic neural crest, neuroectoderm, and endoderm. Carcinoid tumors occur 1.2 to 2.0 cases per 100,000 persons per year, and most carcinoid tumors arise within the gastrointestinal tract.1,2 The appendix, small bowel, and rectum are the most common sites in the gastrointestinal tract, and the bronchopulmonary system is the most frequent site for extragastrointestinal carcinoid tumors.2–5 But the esophagus, Merkel’s diverticulum, liver, pancreas, and biliary tract, as well as the pelvis, the otolaryngic organs, and the breast are among the rare locations for carcinoid tumors.6 Carcinoid tumors can be classified according to their embryologic sites of origin as foregut carcinoids (respiratory tract, stomach, duodenum, biliary system, and pancreas), midgut carcinoids (small intestine, appendix, cecum, and proximal colon), and hindgut carcinoids (distal colon and rectum).7 But this classification is not used in routine diagnosis because neuroendocrine tumors in the gastrointestinal tract display a broad morphological and biological spectrum. Instead, it is recommended, in the latest World Health Organization (WHO) classification, published in 2000, that the neuroendocrine tumors be divided into three groups: (1) well-differentiated endocrine tumors (carcinoids); (2) well-differentiated endocrine carcinomas (malignant carcinoids); and (3) poorly differentiated endocrine carcinomas (small cell carcinomas).8 Even though the latter two categories clearly represent malignant neoplasms, carcinoid tumors of small size (≤1 cm), with less mitotic figures (≤2 mitoses per 10 high-power fields), and no evidence of angioinvasion are considered to be benign, whereas others are thought to have a risk of clinical malignancy.8 Gastrointestinal carcinoid tumor often has no signs in its early stages. But carcinoid syndrome, which occurred in approximately 8% of patients with carcinoid tumors at any site,8 including flushing of the face, flat angiomas of the skin, diarrhea, bronchial spasm, rapid pulse, and sudden drops in blood pressure, may occur if the tumor spreads to the liver or other parts of the body.

ß-Catenin is a dual functional protein that plays an important role in the cadherin-mediated cell adhesion system9 and Wnt signaling pathway.10 As a component of adherent junctions, ß-catenin promotes cell adhesion by linking cadherin to the actin cytoskeleton through the adaptor protein {alpha}-catenin. In contrast, the soluble cytoplasmic pool of ß-catenin served as a signal transducer of Wnt pathway. In the absence of Wnt signaling, ß-catenin forms complexes with the tumor suppressor protein APC,11,12 leading to its own N-terminal phosphorylation by glycogen synthase kinase-3 beta (GSK-3ß), and this phosphorylation regulates the cytoplasmic level of ß-catenin13 by targeting ß-catenin for degradation by the proteasome system.14 Wnt signaling, by inhibition of GSK-3ß, induces accumulation and nuclear translocation of ß-catenin. In the nucleus, ß-catenin functions as a transcriptional activator by interacting with the Tcf/Lef family of DNA binding proteins.15,16 Thus, ß-catenin is involved in signaling pathways that regulate cell differentiation and proliferation.17,18

Aberrant activation of ß-catenin plays an important role in carcinogenesis.19 Mutations of the APC gene lead to constitutive activation of ß-catenin–mediated transcription. The APC gene is mutated in most colorectal tumors, and the decreased APC-associated degradation of ß-catenin is critical to APC’s tumor suppressive effect.20 Another pathway for constitutive activation of ß-catenin is mutation in exon 3 of ß-catenin, which is a phosphorylation site of ß-catenin by GSK-3ß.20 Mutations of ß-catenin are frequently identified in endometrioid cancers,21,22 hepatocellular carcinoma,23 hepatoblastoma,24 desmoid tumor,25 and many other types of benign and malignant tumors. Fujimori et al.26 described a high frequency of cytoplasmic accumulation and/or nuclear translocation of ß-catenin with frequent mutations in exon 3 of ß-catenin gene in gastrointestinal carcinoid tumor.

To further clarify the role of Wnt/ß-catenin/APC pathway in the genesis of carcinoid tumor, we analyzed the expression of ß-catenin protein and mutation of ß-catenin and APC genes in 91 gastrointestinal carcinoid tumors and 26 extragastrointestinal carcinoid tumors. We found that cytoplasmic accumulation and/or nuclear translocation of ß-catenin did not occur in extragastrointestinal carcinoid tumors and was not a frequent event in gastrointestinal carcinoid tumors. In addition, mutation of exon 3 of ß-catenin gene and exon 15 of APC gene did not play a crucial role in cytoplasmic accumulation and/or nuclear translocation of ß-catenin in gastrointestinal carcinoid tumors.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Tumor Samples
From January 1993 to December 2004, a total of 91 surgically resected gastrointestinal carcinoid tumors, which received detailed pathological assessment at National Taiwan University Hospital and Min-Sheng General Hospital, were selected for this study, and the study was executed according to the regulations of the Ethical Committee of National Taiwan University Hospital and Min-Sheng General Hospital. There were 10 gastric, 6 small intestinal, 11 appendiceal, 11 colonic, 50 rectal, and 3 pancreatic carcinoid tumors. In the same period, 26 extragastrointestinal carcinoid tumors including 18 pulmonary, 6 thymic, 1 hypopharyngeal, and 1 ovarian carcinoid tumors were included in this study for comparison (Table 1Go). The appendiceal tumors were mucinous carcinoids, and the ovarian tumor was a struma ovarii. Three of the pulmonary carcinoid tumors and the hypopharyngeal tumor were atypical carcinoids.


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  		TABLE 1. Immunohistochemical staining of ß-catenin protein in carcinoid tumor
 
Immunohistochemical Detection of ß-Catenin Protein
The ß-catenin protein was detected on formalin-fixed, paraffin-embedded sections by the labeled streptavidin-biotin method after antigen retrieval, as previously described.23 Briefly, sections with paraffin removed were heated in a pressure cooker. After blocking with 3% H2O2 and nonimmune horse serum, the slides were allowed to react with a monoclonal antibody against human ß-catenin (Transduction Laboratories, Lexington, KY) at a dilution of 1:80, or with control nonimmune serum at 4°C overnight. The slides were then incubated with link antibodies, then followed by a peroxidase-conjugated streptavidin complex (labeled streptavidin-biotin kit, Dako, Carpentaria, CA). The peroxidase activity was visualized with diaminobenzidine tetrahydroxychloride solution (Dako). The sections were lightly counterstained with hematoxylin. The adjacent epithelial cells in the same section served as internal positive controls.

Scoring of ß-Catenin Protein Expression
Because of the different biological role of membranous and nuclear proteins, ß-catenin immunostaining was scored according to the cellular localization (along the membrane or in the nucleus) and the fraction of positively stained cells. Membranous staining was scored as diffuse (>60% positive tumor cells), heterogeneous (mixed positive and negative areas, with positive cells between 30% and 60%), focal (<30%), or trace (<5%). Nuclear staining that was constantly associated with cytoplasmic staining was scored as diffuse (>60% positive tumor cells), focal to scattered cells (<60%), or negative.

Analysis of the ß-Catenin and APC Mutations
To further analyze the role of ß-catenin and APC mutations, tumor cells from the 27 gastrointestinal carcinoid tumors with cytoplasmic accumulation and/or nuclear translocation of ß-catenin protein were taken by microdissection from paraffin-embedded sections, and the genomic DNAs were extracted by a DNA/RNA extraction kit (Viogene, Sunnyvale, CA) for polymerase chain reaction and direct sequencing of exon 3 of the ß-catenin gene and exon 15 of the APC gene, which were the hot spots of mutations in tumors. Polymerase chain reaction was performed in an automatic DNA Thermal cycler 480 (Perkin-Elmer, Wellesley, MA), with initial heating at 94°C for 2 minutes followed by 35 cycles of 94°C for 30 seconds, 58°C for 1 minute, 72°C for 30 seconds, and a final step at 72°C for 10 minutes. The primers used for sequencing of exon 3 of the ß-catenin gene and exon 15 of the APC gene are listed in Table 2Go. DNA sequencing was performed by an ABI 373 Automated Sequencer with the ABI Prism Dye Terminator Cycle Sequencing Ready Reaction Kit (Perkin-Elmer). Each mutation was verified in both sense and antisense directions. Paraffin-embedded blocks of samples of two cases of hepatocellular carcinoma with ß-catenin mutations served as positive controls for sequencing exon 3 of ß-catenin. Samples from five cases of colorectal cancer served as positive controls for sequencing exon 15 of APC.


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  		TABLE 2. Primers used in sequencing of ß-catenin and APC genes
 

   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subcellular Expression of ß-Catenin
In immunohistochemical stain, ß-catenin protein was detected in a membranous pattern in normal epithelium of gastrointestinal tract, lung, and other organs. Among the 91 gastrointestinal carcinoid tumors, 64 cases expressed membranous ß-catenin alone, similar to normal epithelium (Fig. 1Go). Of these, 54 cases had a diffuse or normal pattern, and 10 had decreased membranous expression, ranging from heterogeneous to very low levels. ß-Catenin was detected in the tumor cell nuclei in addition to membrane expression in 27 cases (29.7%), diffusely in 13, and in focal distribution to scattered cells in 14 (Figure 1Go). In addition, the nuclear ß-catenin expression occurred in almost all sites of gastrointestinal tract. Nuclear ß-catenin expression was often accompanied by cytoplasmic ß-catenin and reduced membrane expression. None of the tumors was completely negative for ß-catenin. However, all 26 extragastrointestinal carcinoid tumors expressed membranous ß-catenin alone without nuclear translocation (Table 1Go).


Figure 1
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  		FIG. 1. Immunostaining of ß-catenin in carcinoid tumors. Pulmonary (A) and gastric (B) carcinoid tumor shows membranous staining. Two rectal carcinoid tumors (C, D) show nuclear translocation and cytoplasmic accumulation of ß-catenin.

 
Correlation of Protein Expression With Mutation of ß-Catenin and APC Genes
ß-Catenin and APC gene mutations are two major mechanisms that lead to cytoplasmic accumulation and/or nuclear translocation of ß-catenin protein in tumor cells. Among all the tumors examined, including 27 gastrointestinal carcinoid tumors with nuclear translocation of ß-catenin, no mutation of the ß-catenin gene was found. Furthermore, in all 27 gastrointestinal carcinoid tumors expressing nuclear ß-catenin without ß-catenin mutation, we also did not find APC mutation.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, we detected nuclear translocation of ß-catenin in 27 of 91 gastrointestinal carcinoid tumors, and the nuclear translocation was not caused by APC or ß-catenin mutation. Wnts interacts with serpentine receptors of the Frizzled (Fz) family and members of the low-density lipoprotein protein (LRP) family, generates signal transduction that compromises the APC, GSK3ß, and axin complex, and promotes stabilization of nuclear localization of ß-catenin.27 Therefore, expression of nuclear ß-catenin can result from mutations in the APC or ß-catenin gene,20 inactivation of GSK-3ß,18 mutation of axin,28 stimulation by Wnts, or inhibition of the proteasome degradation of ß-catenin.14 In many tumor types, the frequency of nuclear translocation was reported to be much higher than the mutation rate,29–31 indicating mechanisms other than mutations play an important role in the nuclear translocation of ß-catenin.

Interestingly, we did not detect genetic alterations of ß-catenin in all the gastrointestinal carcinoid tumors with nuclear translocation of ß-catenin by direct sequencing of exon 3. Although the sample size was larger in our series, the frequency of somatic mutation of exon 3 of ß-catenin was significantly lower than that was reported previously by Fujimori et al.26 (27 [37.5%] of 72; P < .00001). Consistent with our finding, Semba et al.32 detected nuclear expression of ß-catenin in 8 of 22 of gastrointestinal and hepatic carcinoid tumors but did not detect genetic alteration in exon 3 of the ß-catenin gene-encoding serine/threonine-rich domain. Therefore, our study did not support the past study that has suggested ß-catenin mutation as one of the important factors in gastrointestinal carcinoid tumors. The discrepancy may be related to the different genetic background of the patients examined.

However, the results of Fujimori et al.26 seem unusual in several aspects. First, nearly all the tumors with ß-catenin mutation should also have nuclear expression of ß-catenin.24,33,34 Fujimori et al. reported that only 5 of 27 gastrointestinal carcinoid tumors with ß-catenin mutation expressed both cytoplasmic and nuclear accumulation of ß-catenin, with a low concordance rate of 22.2% (P = .0044, Fisher exact test, 2-tailed).26 Second, most ß-catenin mutations detected in human neoplasms occurred at any of four serine/threonine residues (codons 33, 37, 41, and 45) of exon 3 or at the contiguous residues of serine 33.21–24 However, in the study of Fujimori et al., nearly all the mutations are replacements of Ser37 by alanine (26 [96.3%] of 27). In the summary of published results of ß-catenin mutations from Sanger Center (http://www.sanger.ac.uk/genetics/CGP/cosmic/), of the 1488 mutations registered, only 43 were S37A (2.9%), and 26 of them were contributed by the study of Fujimori et al. In our analysis of hepatocellular carcinoma,23 none of the 57 mutations identified was S37A. Hence, S37A is not a very frequent mutation event in human tumor. Third, the other mutation site in the report of Fujimori et al. is G48D. Gly48 is not a mutation hot spot in human tumor. In the Sanger Center’s registry of 1488 ß-catenin mutations, the only two G48D mutations were derived from this study. Fourth, because mutation of ß-catenin is a dominant activating mutation, only one allele is mutated in human cancers. Fujimori et al.26 reported a case with double mutations of S37A and G48D, which is also a very unlikely event.

Approximately two-third of the carcinoid tumors were found in the gastrointestinal system, and the bronchopulmonary system, as in our series, is the most frequent site in the extragastrointestinal system.4 However, no nuclear expression of ß-catenin was found in extragastrointestinal carcinoid tumors. Pelosi et al.35 found that in pulmonary neuroendocrine tumors, the subcellular localization of the E-cadherin/ ß-catenin complex is altered and affects the tumor growth pattern and cell motility of atypical carcinoid tumors, and is correlated with lymph node metastases. But they also failed to demonstrate nuclear translocation of ß-catenin in both typical carcinoids and atypical carcinoids. Hence, the molecular pathogenesis of carcinoid tumor in gastrointestinal tract and extragastrointestinal sites should be different.

In summary, our studies suggest that alteration of Wnt/ß-catenin/APC pathway is different in relation to genesis of gastrointestinal and extragastrointestinal carcinoid tumors. Nuclear translocation of ß-catenin occurred in gastrointestinal carcinoid tumors but is not a frequent event. Although mutations or other abnormalities elsewhere in the ß-catenin or the APC gene that we did not check could possibly contribute to the nuclear translocation of ß-catenin, mutation of exon 3 of ß-catenin gene and exon 15 of APC gene did not play a crucial role in nuclear translocation of ß-catenin in gastrointestinal carcinoid tumors. More studies are warranted to clarify the role of the genetic alterations, including other genes that function in this pathway, in the genesis and progression of gastrointestinal carcinoid tumors.

Received for publication June 27, 2006. Accepted for publication June 28, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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