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Clinical Cancer Research Vol. 8, 2570-2575, August 2002
© 2002 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Clinicopathological Significance of Galectin-3 Expression in Ductal Adenocarcinoma of the Pancreas1

Takeshi Shimamura, Michiie Sakamoto2, Yoshinori Ino, Kazuaki Shimada, Tomoo Kosuge, Yasuto Sato, Katsuaki Tanaka, Hisahiko Sekihara and Setsuo Hirohashi

Pathology Division [T. S., M. S., Y. I., S. H.] and Cancer Information and Epidemiology Division [Y. S.], National Cancer Center Research Institute, Tokyo 104-0045; Department of Surgery, National Cancer Center Hospital, Tokyo 104-0045 [K. S., T. K.]; and Third Department of Internal Medicine, Yokohama City University, Yokohama 236-0004 [K. T., H. S.], Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Galectin-3, a member of the ß-galactoside-binding lectin family, has multiple biological functions including cell-cell interactions and cell-extracellular matrix adhesion, cellular proliferation, cellular differentiation, and apoptosis. The aim of this study was to determine the relationship of galectin-3 expression to clinicopathological findings and patient prognosis in ductal adenocarcinoma of the pancreas.

Experimental Design: We examined galectin-3 expression in 104 surgically resected pancreatic ductal adenocarcinoma cases with stages I through IV using immunohistochemistry and investigated the relationship of it to overall survival.

Results: Patients were divided into two groups: a low expression group, where <60% of tumor cells were positive; and a high expression group, where >=60% of tumor cells were positive. Cases in the low expression group had a significant tendency to be at later stages, to have distant metastasis, and to have less differentiated tumors, compared with cases in the high expression group (P = 0.001 for stage, P = 0.001 for metastasis, and P = 0.006 for differentiation). Postoperative overall survival was worse in the low galectin-3 expression group than in the high galectin-3 expression group (P = 0.004). Multivariate analysis showed that the risk ratio of prognosis was 2.06 among patients in the low galectin-3 expression group compared with the high galectin-3 expression group (P = 0.006).

Conclusions: Decreased expression of galectin-3 was associated with advanced stage, tumor de-differentiation, and metastasis in ductal adenocarcinoma of the pancreas. Galectin-3 expression might be a useful prognostic marker for survival in ductal adenocarcinoma of the pancreas.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pancreatic cancer is the fourth and fifth leading cause of cancer-related deaths in the United States and Japan, with an estimated 28,900 and 17,000 patients dying of this disease in a year, respectively (1 , 2) . Because of its aggressive growth and early metastatic dissemination, the overall 5-year survival rate for pancreatic cancer is <5%, and only 20% of patients can be treated by surgery with curative intent at the time of diagnosis (3) . To determine the molecules that cause the biological aggressiveness of pancreatic cancer, we raised mAbs3 against a pancreatic cancer cell line, ASPC-1, and selected them by immunohistochemical reactivity with pancreatic ductal adenocarcinoma. One of these antibodies was an anti-galectin-3 mAb.

Galectin-3 is a member of a family of ß-galactoside-binding animal lectins (4 , 5) . Although the precise function of galectin-3 remains unknown, there is some evidence that galectin-3 plays a role in cell-cell adhesion, cell-ECM interactions, cellular proliferation, cellular differentiation, and apoptosis (6, 7, 8, 9, 10, 11, 12, 13, 14) . The significance of galectin-3 expression has already been evaluated in many neoplasms (15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30) . Galectin-3 is up-regulated in cancers of the thyroid, liver, stomach, and tongue (15, 16, 17, 18) . In contrast, galectin-3 is down-regulated in cancers of the ovary, uterus, and breast (19, 20, 21, 22) . In some other cancers, the role of galectin-3 is unclear. For example, in colon cancer, some studies have shown an increase in galectin-3, and other studies have shown a decrease (23, 24, 25) . In intrahepatic cholangiocarcinoma, galectin-3 expression is up-regulated in the early stages of carcinoma and down-regulated in later stages (26) . Thus, it seems that differences in galectin-3 expression depend on tumor type.

In this study, we have investigated the relationship between galectin-3 expression and clinicopathological findings of pancreatic ductal adenocarcinoma. Galectin-3 expression of the normal pancreas, chronic pancreatitis, and pancreas cancer cases with stages I, II, and III has already been studied (27 , 28 , 31) . High levels of galectin-3 expression were detected in cancer cells, but there was no correlation between the level of galectin-3 expression and clinicopathological features. In this study, we analyzed a large number of patients with pancreatic ductal adenocarcinoma stages I through IV. We found changes of galectin-3 expression in different stages and histological grades, with a significant relationship between the level of galectin-3 expression and prognosis.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Tissue Specimens.
The specimens used for immunohistochemical analysis were obtained from 104 patients with pancreatic ductal adenocarcinoma who had undergone initial surgical resection, without any prior therapy, at the National Cancer Center Hospital (Tokyo, Japan) between 1990 and 1998 (62 males and 42 females; median age, 62 years; age range, 45–82 years). All of the patients received standard therapy, based on their clinical stages. According to individual cancer extension, lymphadenectomy at the hepatoduodenal ligament and around the abdominal aorta was performed. Tumors were histologically classified according to the WHO classification and staged according to the International Union against Cancer tumor-node-metastasis (TNM) classification (32 , 33) . Histologically, 44, 47, and 13 cases were well-, moderately, and poorly differentiated ductal adenocarcinomas, respectively. By pathological T classification, 5, 18, 32, and 49 cases were pT1, pT2, pT3, and pT4, respectively. In 49 stage pT4 patients with invasion to the portal vein or superior mesenteric vein, tumor resection including the superior mesenterico-portal vein confluence had been performed to undergo a margin-negative resection. By pathological lymph node status, 14, 39, and 51 cases were pN0, pN1a, and pN1b, respectively. In addition, 23 cases with distant lymph node metastasis were classified as pM1(LYM), 4 cases with liver metastasis were classified as pM1(HEP), and 2 cases with peritoneal dissemination were classified as pM1(PER). Accordingly, 7, 3, 33, 32, and 29 cases were at stages I, II, III, IVA, and IVB, respectively.

Immunohistochemistry.
A mouse mAb specific for galectin-3, mAb 19-1, was established in our laboratory and used for immunohistochemical investigation. Hybridomas were produced from spleen cells of A/J mice immunized with the human pancreatic carcinoma cell line ASPC-1, which was obtained from the American Type Culture Collection (Manassas, VA). A hybridoma clone producing mAb 19-1 was selected by immunohistochemical reactivity with pancreatic ductal adenocarcinoma tissue. The partial amino acid sequence of the affinity-purified protein obtained from lysates of ASPC-1 cells after 19-1 mAb immunoprecipitation was IQVLVEP and LGISGDIDLTSA (Takara, Otsu, Japan). These amino acid sequence data correspond to the galectin-3 amino acid sequence at residues 200–206 and 234–245. ASPC-1 cell lysates were immunoprecipitated with an anti-galectin-3 antibody (9C4; Ylem S.R.L., Roma, Italy), and the resulting immunoprecipitates were reacted with mAb 19-1 on Western blots, and vice versa as described previously (34) , indicating that mAb 19-1 and mAb 9C4 immunologically recognized an identical protein (Fig. 1)Citation . Using immunohistochemistry, mAb 19-1 had the same immunoreactivity in the specimens of this study as did mAb 9C4. These analyses clearly showed that mAb 19-1 reacted specifically with galectin-3.



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  		Fig. 1. Reactivity of the purified mouse mAb 19-1 with galectin-3. ASPC-1 cell lysates were immunoprecipitated with mAb 9C4 (anti-galectin-3), and the resulting immunoprecipitates were reacted with mAb 19-1 on Western blots and vice versa, indicating that mAb 19-1 and mAb 9C4 immunologically recognized an identical protein.

 
Two or three formalin-fixed, paraffin-embedded sections (5-µm thick) containing the maximum diameter of the tumor were subjected to immunohistochemistry by the avidin-biotin complex method. Sections were deparaffinized with graded ethanol and xylene, treated with 0.3% hydrogen peroxide in methanol, and immersed in 10 mM citrate buffer (pH 6.0). After autoclaving, the sections were incubated for 10 min with normal swine serum to block nonspecific antibody binding. The sections were exposed to mAb 19-1 at 4°C overnight and then incubated for 30 min with biotinylated horse antimouse immunoglobulin as the secondary antibody (Vector Laboratories, Burlingame, CA). Next, they were incubated for 30 min with avidin-biotinyl-peroxidase complex from the Vectastain avidin-biotin complex kit (Vector Laboratories) and then subjected to the peroxidase reaction. This was followed by nuclear counterstaining with hematoxylin. Between each step, the slides were washed three times with PBS. The positive control, which was included in every assay, was a section of a formalin-fixed, paraffin-embedded cell pellet of ASPC-1, which produces large amounts of galectin-3, detected by immunoblot analysis, as described above. Negative control staining, which was performed using an irrelevant isotype-matched mouse immunoglobulin instead of mAb 19-1, yielded negative results in every case.

Immunohistochemical Evaluation.
Galectin-3, consistently expressed at pancreatic nerves, was used as an internal control. Cancer cells with equal or more intense expression of galectin-3 compared with that at pancreatic nerves were judged to be positive. The percentage of pancreatic cancer cells positive for galectin-3 was evaluated on a x100 field (x10 objective and x10 ocular) using a grid, and the average percentage of 5 fields/section in 104 specimens was 58.6%. Based on this, patients were divided into two groups: (a) low galectin-3 expression, where <60% of tumor cells were positive; and (b) high galectin-3 expression, where >=60% of tumor cells were positive. All slides were evaluated independently by two observers, who were blind to the clinical outcome and features of patients (interobserver reliability, r = 0.96). To confirm the quality of all sections, we examined all samples by immunohistochemistry using an antibody for cytokeratin (KL-1; Immunotech, Marseilles, France) and found that this antibody diffusely and homogeneously stained all of the epithelial cells in tumor and nontumor tissues, as described previously (Fig. 2, E and FCitation ; Ref. 35 ).



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  		Fig. 2. Immunohistochemical staining of galectin-3. Galectin-3 was slightly present in the cytoplasm of normal pancreatic duct cells. However, its expression was less than that of pancreatic nerves (A). Galectin-3 was diffusely expressed at the site of lymph node metastasis, in the same case as D(B). Well-differentiated adenocarcinoma revealed more intense galectin-3 immunoreactivity than pancreatic nerves (C). Galectin-3 immunoreactivity was absent in the case of poorly differentiated adenocarcinoma (D). Cytokeratin (KL-1) diffusely and homogeneously stained cancer cells in the well (E) and poorly (F) differentiated adenocarcinoma, in the same cases as C and D, respectively.

 
Statistical Analysis.
The Cochran-Mantel-Haenszel test was used to assess the correlation between the clinicopathological findings and galectin-3 staining. Survival curves were generated using the Kaplan-Meier method and compared using the log-rank test (36 , 37) . To determine significant prognostic factors related to survival, multivariate analysis was performed using the Cox proportional hazards regression model, using SAS statistical analysis software (SAS Institute Inc., Cary, NC; Ref. 38 ). The hazard ratio of galectin-3 status has been adjusted for age, gender, T status, perineural invasion, and differentiation. Differences at P <0.05 were considered significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Galectin-3 Expression and Clinicopathological Features.
Galectin-3 expression was examined in 104 sections, of both tumorous and nontumorous tissue. Faint galectin-3 expression was present in the cytoplasm of some ductal and acinar cells of normal tissue, and moderate galectin-3 expression was present in pancreatic nerves, as described previously (Fig. 2ACitation ; Refs. 27 and 28 ). In contrast, moderate to strong galectin-3 expression was present in the cytoplasm and also in the nuclei of pancreatic cancer cells (Fig. 2C)Citation . Galectin-3 expression was both significantly decreased and less intense in moderately to poorly differentiated carcinomas, compared with well-differentiated carcinomas (Fig. 2, C and DCitation ; Table 1Citation ). One case in stage IVA and 2 cases in stage IVB of 104 pancreatic ductal adenocarcinoma cases were negative for galectin-3 expression in cancer cells. Cases were divided into low (n = 52) and high (n = 52) galectin-3 expression groups, based on the criteria described in "Materials and Methods." The correlation between clinicopathological findings and galectin-3 expression is shown in Table 1Citation . Galectin-3 expression was found to be significantly correlated with pathological T status (P = 0.01), N status (P = 0.04), M status (P = 0.001), stage (P = 0.001), and tumor differentiation (P = 0.006). All five cases with pT1 tumors were in the high galectin-3 expression group, and > 80% of their cells were galectin-3 positive (data not shown). In contrast, 46 of 52 cases (88.5%) in the low galectin-3 expression group were pT3 and pT4 tumors. Galectin-3 expression was significantly correlated with the absence of distant metastasis, especially distant lymph node metastasis. Whereas 22 of 52 cases (42.3%) in the low galectin-3 expression group had distant metastasis, including 19 cases (36.5%) with distant lymph node metastasis, 4 of 52 cases (7.7%) in the high galectin-3 expression group had distant metastasis, which was only in the lymph nodes. In an apparent contrast to this correlation between galectin-3 expression and distant metastasis, galectin-3 tended to be diffusely expressed at the site of lymph node metastasis. This discrepancy was most prominent in all seven cases that had distant metastasis at lymph nodes where galectin-3 was diffusely positive; these cases had <30% galectin-3-positive cancer cells in their primary cancerous tissue (Fig. 2, B and D)Citation . All seven cases at stage I were in the high galectin-3 expression group, in contrast with 22 of 29 cases (76%) at stage IVB, which were in the low galectin-3 expression group. No significant difference was seen with age, gender, perineural invasion, vascular invasion, or lymphatic permeation.


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  		Table 1 Correlations between galectin-3 expression and clinicopathological findings

 
Prognostic Significance of Galectin-3 Expression.
Fig. 3Citation depicts the Kaplan-Meier plot of overall survival curves of the low and high galectin-3 expression groups. The prognosis became significantly worse in the low galectin-3 expression group (P = 0.004; Fig. 3Citation ). Mean survival was 12.6 months for the low galectin-3 expression group and 27.3 months for the high galectin-3 expression group. The crude hazard ratio of prognosis was 1.94 in cases with low galectin-3 expression (Table 2)Citation . We then analyzed the multivariate Cox proportional hazard ratio for overall survival. The risk ratio of prognosis was 2.06 for patients in the low galectin-3 expression group compared with those in the high galectin-3 expression group (P = 0.006).



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  		Fig. 3. Kaplan-Meier survival curves of 104 patients. The prognosis became significantly worse in the low galectin-3 expression group (thick line; mean, 12.6 months) compared with the high galectin-3 expression group (thin line; mean, 27.3 months; log-rank test, P = 0.004).

 

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  		Table 2 The hazard ratio of galectin-3 for overall survival

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, we raised an anti-galectin-3 mAb (19-1) and investigated the significance of the relationship between galectin-3 expression and clinicopathological features of pancreatic ductal adenocarcinoma cases of stages I through IV. Galectin-3 was frequently and strongly expressed in the cytoplasm and nucleus of stage I and well-differentiated cases, and its expression was significantly decreased and less intense or even absent in stage IVB with distant metastasis and moderately to poorly differentiated cases. Patients in the low galectin-3 expression group had poor prognosis for overall survival.

Galectin-3 expression by cancer cells has been implicated as a key factor of malignant transformation and metastatic regulation in various neoplasms (8 , 23) . On the other hand, significantly higher levels of galectin-3 expression have been demonstrated in ductal cells of chronic pancreatitis compared with normal ductal cells and indicated that this played an important role in the process of tissue remodeling (31) . In pancreatic cancer, Berberat et al. (27) have reported overexpression of galectin-3 in stages I, II, and III. In this study, we included stage IV cases and investigated galectin-3 expression in a large number of cases. Although galectin-3 was strongly expressed in stage I cases without lymph node metastasis, its expression was significantly decreased in stage IVA and stage IVB cases with distant metastasis at lymph nodes. It has been reported that galectin-3 is essential for cell-cell and cell-ECM interactions such as adhesion to laminin and the homotypic adhesion of tumor cells (12 , 39 , 40) . In addition, exclusion of galectin-3 has been detected at the tips of protruding and expanding tubules in Madin-Darby canine kidney cells cultured in three-dimensional matrices: this would be indispensable for the cells to expand into the surrounding matrix (41) . These studies suggest that decreased expression of galectin-3 may loose cell-cell and cell-ECM interactions and facilitate cancer cell invasion. This could explain the decreased number of galectin-3-expressing cells in late cancer stages compared with early stages in breast cancer, cholangiocarcinoma, and also as found in our present study (19, 20, 21) . Interestingly, in the metastatic portion of the lymph nodes, galectin-3 expression was detected in almost all cancer cells in the cases that had <30% galectin-3-positive cancer cells in the primary cancer tissue. This suggests that galectin-3 expression is not fixed but rather is modulated depending on the environment of the cancer cells.

The survival analysis showed that the prognosis for survival was significantly poorer in the low galectin-3 expression group compared with the high galectin-3 expression group, in both univariate and multivariate analysis. It is interesting to note that there have been some contrasting data on survival analysis in colon and prostate cancer that showed worse survival rates in cases overexpressing galectin-3 (25 , 29) . In these studies, galectin-3 was detected in the cytoplasm and nuclei of normal cells and mainly in the cytoplasm of cancerous cells in the colon and prostate. However, we found that the galectin-3 expression pattern and localization in the normal and cancerous portions of pancreas were different from those of the colon and prostate gland. Therefore, the expression pattern and localization of galectin-3 expression might depend on tumor type and thus might have a different function in different tumors.

Galectin-3 overexpression has been detected in the serum of patients with various types of cancer, including pancreatic cancer (42) . We detected galectin-3 expression levels in the tissue culture supernatant of pancreatic cancer cell lines (data not shown). Considering the high level of galectin-3 expression in stage I and II cases, it might be useful to examine the concentration of galectin-3 in serum to detect early pancreatic cancer.

In conclusion, we have found a significant association between galectin-3 expression and clinicopathological data, and we suggest that galectin-3 expression might be a useful prognostic marker in ductal adenocarcinoma of the pancreas. A further preoperative, prospective, serological study is needed to establish the clinical importance of galectin-3 expression in ductal adenocarcinoma of the pancreas.


   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.

1 Supported by a Grant-Aid for the Second Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan and by Research Resident Fellowships from the Foundation for Promotion of Cancer Research (to T. S.) in Japan. Back

2 To whom requests for reprints should be addressed, at Pathology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Phone: 81-3-3542-2511; Fax: 81-3-3248-2463; E-mail: msakamot{at}gan2.res.ncc.go.jp Back

3 The abbreviations used are: mAb, monoclonal antibody; ECM, extracellular matrix. Back

Received 1/ 4/02; revised 5/14/02; accepted 5/21/02.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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