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Clinical Cancer Research 14, 2351, April 15, 2008. doi: 10.1158/1078-0432.CCR-07-4499
© 2008 American Association for Cancer Research
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Imaging, Diagnosis, Prognosis

Amphiregulin Is a Promising Prognostic Marker for Liver Metastases of Colorectal Cancer

Michiyo Yamada1, Yasushi Ichikawa1, Shigeru Yamagishi1, Nobuyoshi Momiyama1, Mitsuyoshi Ota2, Syoichi Fujii2, Kuniya Tanaka1, Shinji Togo1, Shigeo Ohki2 and Hiroshi Shimada1

Authors' Affiliations: 1 Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine and 2 Department of Surgery, Yokohama City University Hospital, Yokohama, Kanagawa, Japan

Requests for reprints: Yasushi Ichikawa, Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan. E-mail: yasu0514{at}med.yokohama-cu.ac.jp.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: Aberrant activation of epidermal growth factor receptors (EGFR/HER1) by ligand stimulation or heterodimerization with human epidermal growth factor 2 (HER2) is considered to play an important role in the development of colorectal carcinoma. Amphiregulin (AR) is a ligand of EGFR that might be related to the development and progression of gastrointestinal tumors. The aim of this study was to determine the AR, EGFR, and HER2 protein expression levels and to evaluate their prognostic relevance to the clinical course of colorectal cancer.

Experimental Design: The AR, EGFR, and HER2 protein levels in primary tumors of colorectal cancer (n = 106) were examined using immunohistochemistry. Metastatic sites in liver specimens (n = 16) were also analyzed in the same manner.

Results: Thirteen (81.6%) metastatic lesions of the liver stained positive for AR. Among the primary lesions of colorectal cancer, 58 (54.7%) stained positive for AR, 13 (12.3%) stained positive for EGFR, and 5 (4.7%) stained positive for HER2. When the relationships between each protein expression level and the clinicopathologic factors were examined, only the AR expression level was significantly related to liver metastasis (P = 0.0296). A multivariate analysis of liver metastasis proved that AR expression was an independent prognostic factor of liver metastasis from colorectal cancer (P = 0.0217).

Conclusions: AR expression in primary lesions of colorectal cancer is an important predictive marker of liver metastasis.

Epidermal growth factor (EGF) receptors (EGFR) and their various ligands seem to be involved in the progression of gastrointestinal tumors (1). The EGF signal pathway is reportedly activated by several kinds of stimulation. First, ligands like amphiregulin (AR), transforming growth factor-{alpha} (TGF-{alpha}), and EGF may bind to EGFR. EGFR, a 170-kDa transmembrane glycoprotein (2), is composed of an extracellular ligand-binding domain, a transmembrane region, and an intracellular protein tyrosine kinase domain (3–5). The above-mentioned ligands bind to the extracellular ligand-binding domain of EGFR and stimulate the pathway. Second, the heterodimerization of EGFR and HER2 can reportedly stimulate signaling in the absence of ligands (2). These steps are followed by the stimulation of intrinsic tyrosine kinase activity and tyrosine autophosphorylation (3, 6–8). Receptor activity is modulated by intracellular kinases that mediate negative feedback control via receptor phosphorylation at specific regulatory domains, and receptor inactivation is mediated by receptor internalization and ligand-receptor dissociation. AR has been implicated in the growth and regeneration of intestinal mucosa and might be related to the development and progression of gastrointestinal tumors (9–12). Our microarray analysis in colorectal tumors and liver metastases revealed that AR was down-regulated in adenomatous tumors but was up-regulated in metastatic tumors of the liver (data not shown). These findings suggested that AR might contribute to liver metastasis from colorectal cancer. The aim of this study was to clarify the relationship between AR expression and liver metastasis and to uncover any correlations between the protein levels of AR, EGFR, and HER2 and the proliferation of colorectal cancer.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Human tissues. The study population comprised 106 consecutive patients who underwent the resection of colorectal cancer at the Department of Gastroenterologic Surgery, Yokohama City University Hospital. The patient characteristics are described in Table 1 . There is another figure, related to patient profile, which shows whether each case has liver metastasis. There were 106 cases. Eighteen cases had synchronous liver metastasis at the surgical treatment of a primary tumor. In 88 cases, there were no liver metastases, but in the remaining 18, liver metastases occurred later. This analysis of the investigation has three parts: The first is concerned with the correlation between the pathologic factors and protein expression and liver metastases; the second about overall survival, or disease-free survival; and the third, about metachronous liver metastases (Fig. 1 ).


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  		Table 1. Patient profile (n = 106)

 

Figure 1
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  		Fig. 1. Diagram of 106 colon cancer patients according to liver metastasis (L-mets) and AR staining. Eighteen synchronous L-mets, 88 nonsynchronous L-mets, 11 metachronous L-mets, and 77 no L-mets are the results of AR staining of the primary lesions. Sixteen L-mets obtained by hepatectomy is a result of AR staining of liver metastases.

 
For the immunohistochemical study, formalin-fixed, paraffin-embedded tissue samples from 106 primary colorectal cancers and 16 metastatic tumors of the liver were obtained. The median age of the patients at the time of initial surgery was 67 y (range, 35-84 y). The follow-up period after the initial operation for primary lesions was between 3.5 and 5 y (median, 41.2 mo).

Immunohistochemistry. For AR and HER2 immunostaining with rabbit polyclonal antibodies, tissue sections (3 µm) were deparaffinized in xylene and rehydrated in an ethanol series. The sections were then treated for 30 min with 0.3% hydrogen peroxide to block endogenous peroxidase activity. The sections were subsequently washed with PBS and unmasked in citrate antigen unmasking solution (Mitsubishi Kagaku Iatron, Inc.) in an autoclave for 20 min at 120°C. The sections were incubated with goat serum for 15 min at 37°C and then were incubated with the primary antibody [polyclonal antibody to AR (1/100): Quartett, Inc.; polyclonal rabbit anti–c-erbB-2: Zymed Laboratories, Inc.] for 1 h at 37°C. The bound primary antibodies were detected by adding anti-rabbit secondary antibodies and avidin/biotin/horseradish peroxidase complex (DAKO) for 30 min at room temperature. The sections were visualized using solid diaminobenzine diluted in PBS, counterstained with Mayer's hematoxylin, and finally mounted.

Immunohistochemical staining for EGFR was done using the EGFR pharmDx kit (DakoCytomation), according to the manufacturer's instructions.

Evaluation of immunostaining. Two pathologists with no knowledge of the clinical outcome independently examined the stained sections. For AR, the slides were graded according to the staining intensity and the percentage of immunopositive cells, as previously described (13). Specific staining with postimmune serum was semiquantitated by assigning a score of 0 to 3 based on the color intensity of the brown diaminobenzidine precipitate, with 1 representing light brown staining; 2, a moderately brown color; and 3, an intense brown color. The number of positive cells per slide was stratified into three groups based on the percentage of positive cells: group 1, <33%; group 2, 33% to 67%; and group 3, >67%. Semiquantitative scores ranging from 1 to 9 for the specific staining of each specimen were obtained by multiplying the staining intensity by the number of the group that represented the percentage of positive cells within each specimen. A score of zero represents no specific staining. For EGFR and HER2, immunoreactivity was defined in the same manner as the Hercep Test evaluation (ref. 14; Fig. 2 ).


Figure 2
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  		Fig. 2. Immunohistochemical analysis for primary tumor of colorectal cancer. A. AR-positive staining, x100. B, EGFR (+2) expression, x100. C, HER2 (+3) expression, x100.

 
Statistics. Nonparametric tests were used throughout this study. Two-sided P values <0.05 were considered significant. Correlations were examined using the Fisher's exact, two-tailed Student's t test. Kaplan-Meier survival curves were used to estimate the survival of the patients. All calculations were done using Dr. SPSS II for Windows 11.0.1J software (SPSS, Inc.).


   Results
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 Results
Discussion
 References
 
Immunohistochemical analysis. Among the 106 primary lesions, 58 (54.7%) were AR(+), 13 (12.3%) were EGFR(+), and only 5 (4.7%) were HER2(+) (Table 2 ). The expression of EGFR or HER2 was not significantly related with any of the clinicopathologic factors, whereas AR(+) was significantly correlated with liver metastasis (P = 0.0296). Among the 16 liver metastases obtained by hepatectomy, 13 (81.6%) were AR(+).


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  		Table 2. Relationship between AR, EGFR or HER2 expression, and clinicopathologic factor

 
A univariate analysis done to explore factors determining the metastasis of colon cancer to the liver using clinicopathologic factors, including AR expression, revealed that vascular invasion (P = 0.0068), AR expression (P = 0.0296), the depth of the tumor (P = 0.068), and lymph node metastasis (P = 0.0804) of the primary lesions were important factors (Table 3 ). The results of a multivariate logistic regression analysis using these selected factors are summarized in Table 4 . AR expression was associated with an increase in the risk of liver metastasis (P = 0.0217; hazard ratio, 3.204; 95% confidence interval, 1.185-8.659). Vascular invasion was the next most strongly associated factor for liver metastasis. Among the 88 patients who had no liver metastasis at the time of the resection of the primary lesions, the disease-free survival period of the 26 patients whose primary lesions were positive for both of these two factors was significantly shorter than that of the other 62 patients (Fig. 3 ), and hepatic metastasis-free survival of the 26 patients was also shorter than that of the other 62 patients (Fig. 3).


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  		Table 3. Univariate analyses for liver metastases

 

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  		Table 4. Multivariate analyses for liver metastases (logistic regression analysis)

 

Figure 3
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  		Fig. 3. Disease-free survival (A) and hepatic metastasis-free survival (B) after curative colectomy for colorectal cancer without synchronous metastases (n = 88).

 
In the coexpression analysis, 10 (10.6%) patients were AR(+) and EGFR(+), 2 (1.8%) were AR(+) and HER2(+), and only 1 (0.9%) was EGFR(+) and HER2(+). The number indicates the number of cases. These coexpressions were not significantly related with any of the clinicopathologic factors.


   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
This study shows that AR expression in primary lesions of colorectal cancer is a promising predictive marker of liver metastasis. AR is categorized as belonging to the EGF family; thus, AR might work in collaboration with EGFR. In this study, however, the immunohistopathologic coexpression of AR with EGFR or HER2 was not correlated with metastasis.

EGFR seems to be involved in regulating the growth of the intestinal mucosa and might be related to the development and progression of gastrointestinal tumors. EGFR, which can be detected in ~60% to 80% of colorectal carcinomas (15, 16), has emerged as a rational target for anticancer therapy for colorectal cancer. Cetuximab, a monoclonal antibody that specifically blocks EGFR, has good clinical activity in ~10% of patients with chemotherapy-refractory advanced colorectal cancer (17–20). Thus, EGFR clearly plays an important role in the development and progression of colorectal cancer, although the ligand for EGFR remains uncertain.

AR, a ligand of EGFR, is synthesized as a transmembrane precursor that is proteolytically processed to its mature secreted form (10) and is localized in the cytoplasm and nuclei of terminally differentiated, nonproliferative surface columnar and secretory epithelial cells of the mucosa, such as the human ovary, placenta, and colon (21), and has been implicated in the growth and regeneration of intestinal mucosa (9–12). In our study, AR was also detected in the cytoplasm and/or nuclei of cancer cells, and the percentage of AR(+) nuclei in the AR(+) cases was 51.7%.

AR also reportedly contributes to the mitogenic and antiapoptotic growth of human colon malignant cells as well as breast, prostate, cervix, and liver cancer cells (22, 23). Interference with AR production by specific antisense small interfering RNAs or neutralizing antibodies reduced cell proliferation (24) and reversed many of the neoplastic phenotypic traits of cancer cells in vitro, although the expressions of other ligands of the EGFR were preserved in these cells (21, 25, 26). In ~50% of human primary colon carcinomas, AR was overexpressed (27). These reports suggest that AR is an important ligand for EGFR in colon cancer cell transformation.

Zvibel et al. (28) showed that site-specific metastasis was determined by the extracellular matrix of the colonized organ, whereas AR at the secondary colonization site was induced by typical liver-matrix components and stimulated cancer cell proliferation. Under certain conditions, hepatocyte-derived extracellular matrix stimulated the proliferation of colon cancer cells via the induction of AR. Thus, we supposed that AR-positive cells had a strong affinity with the liver, explaining why AR expression was related to liver metastasis and why AR-positive cancer cells were more frequently observed in metastatic lesion of the liver than in the primary lesion. We also indicated that disease-free survival and hepatic metastasis-free survival were related to both venous invasion and AR expression in the primary lesion (Fig. 3). These results might depend on the malignant behavior of AR, as mentioned above.

Previous reports showed that the coexpression of EGFR and c-erbB-2 protein may be related to the distant metastasis of colon cancer (29–32). In the present study, a relationship between malignant behavior and the coexpression of EGFR, HER2, and/or AR in colorectal cancer could not be shown. The low immunoreactivity for EGFR (12.3%) and HER2 (4.7%) in this study might explain the above result. Generally, immunoreactivity depends on the fixation time or the storage time of the archived tissue sections, especially when testing colorectal adenocarcinomas for EGFR expression using the DakoCytomation EGFRpharmDX or breast cancer using the Herceptest. The evaluation of EGFR expression is also dependent on the storage time of archived tissue sections, especially with colorectal adenocarcinomas. The tissue sections should be tested within 9 months to avoid false-negative results (1, 33, 34).

This study is the first report revealing that AR expression in primary lesions of colorectal cancer is significantly correlated with liver metastasis. We conclude that AR expression in colorectal cancer is an important predictive marker for liver metastases.


   Footnotes
 
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.

Received 9/30/07; revised 1/ 1/08; accepted 1/ 3/08.


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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