ARTICLE |
Correspondence to: Helmut Friess, Dept. of Visceral and Transplantation Surgery, University of Bern, Inselspital, CH-3010 Bern, Switzerland. E-mail: helmut.friess@insel.ch
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Summary |
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Galectins are galactoside-binding proteins that exhibit an important function in tumor progression by promoting cancer cell invasion and metastasis formation. Using Northern blotting and Western blotting analysis, in situ hybridization (ISH), and immunohistochemistry (IHC), we studied galectin-1 and galectin-3 in tissue samples of 33 primary pancreatic cancers and in tumor metastases in comparison to 28 normal pancreases. Furthermore, the molecular findings were correlated with the clinical and histopathological parameters of the patients. Northern blotting and Western blotting analysis showed significantly higher galectin-1 and galectin-3 mRNA and protein levels in pancreatic cancer samples than in normal controls. For galectin-1, no ISH signals and immunoreactivity were observed in acinar or ductal cells in the normal pancreas and in pancreatic cancer cells, whereas fibroblasts and extracellular matrix cells around the cancer mass exhibited strong mRNA signals and immunoreactivity. Galectin-3 mRNA signals and immunoreactivity were strongly present in most pancreatic cancer cells, whereas in the normal controls only faint ISH and IHC signals were seen in some ductal cells. Metastatic pancreatic cancer cells exhibited moderate to strong galectin-3 immunoreactivity but were negative for galectin-1. No relationship between the galectin-1 and galectin-3 mRNA levels and the tumor stage or between the IHC staining score and the tumor stage was found. However, galectin-1 mRNA levels and the IHC staining score were significantly higher in poorly differentiated tumors compared with well/moderately differentiated tumors, whereas for galectin 3 no differences were found. The expression pattern of galectin-1 and galectin-3 in pancreatic cancer tissues indicates that galectin-1 plays a role in the desmoplastic reaction that occurrs around pancreatic cancer cells, whereas galectin-3 appears to be involved in cancer cell proliferation. High levels of galectin-3 in metastatic cancer cells suggest an impact on metastasis formation. (J Histochem Cytochem 49:539549, 2001)
Key Words: galectins, pancreas, pancreatic carcinoma, metastasis
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Introduction |
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IN THE SEARCH for genes that promote or suppress tumor spread, it has been reported that pancreatic cancer cells overexpress several growth factors and growth factor receptors which are associated with tumor aggressiveness and shorter patient survival (
A potentially new pro-metastatic functioning gene family named the galectins was recently discovered (
Galectins are a family of ß-galactoside-binding proteins, also known as S-type lectins. They have been proposed to regulate cell growth, to mediate cell adhesion, and to influence apoptosis. At least 10 different animal galectins have been isolated, and all of them recognize galactose-containing oligosaccharides. There appears to be a difference in the carbohydrate specificity of the various galectins, with the implication of different functional roles among the members of the family (
Galectin-3 (also named Mac-2, -BP, L-34, L-29, CBP-35, CBP-30, hL-31, or LBL) is a monomer with two functional domains (
Galectin-1 and galectin-3 overexpression has been detected in several tumors (
The aim of this study was to continue the work of Schaffert and co-workers (1998) by analyzing galectin-1 and galectin-3 expression in a large representative number of pancreatic cancers and to correlate the molecular findings with clinicopathological patient data to further evaluate galectin's influence on tumor growth behavior and metastasis formation.
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Materials and Methods |
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Patients
Normal human pancreatic tissue samples were obtained from 28 individuals (11 women, 17 men; median age 43 years; range 1857 years) through a multiorgan donor program in which no recipients were available for pancreatic transplantation. Tissue samples of 33 patients with carcinoma of the pancreas (17 women and 16 men; median age 67 years; range 4983 years) were obtained after a Whipple resection. The patients were operated on in the Department of Visceral and Transplantation Surgery, Inselspital. From the patients resected since November of 1993, the tissue samples taken for this study were randomly selected. The diagnosis of pancreatic adenocarcinoma was confirmed by histopathological analysis. According to the TNM classification (
Tissue Sampling
For RNA and protein extraction, normal and tumor specimens were frozen in liquid nitrogen immediately after surgical removal and stored at -80C until use. In addition, freshly removed normal and cancerous tissue samples were immediately fixed in formaldehyde solution for 1224 hr and paraffin-embedded for ISH and IHC. The studies were approved by the ethical committee of the University of Bern, Switzerland.
Northern Blotting Analysis
Total RNA was extracted by the single-step guanidinium isothiocyanate method, size-fractionated on 1.2% agarose/1.8 mol/liter formaldehyde gels, and stained with ethidium bromide for verification of RNA integrity and loading equivalency (
For the cRNA probes, the blots were prehybridized overnight at 65C and hybridized for 18 hr at 65C in the presence of the 32P-labeled antisense galectin-1 and galectin-3 riboprobes, washed twice at 65C in a solution containing 2 x SSC (0.3 M NaCl, 0.03 M Na3 citrate, pH 7) and 0.5% SDS, then washed twice for 15 min at 65C in a solution containing 0.1 x SSC and 0.5% SDS (
To assess equivalent RNA loading, the membranes were rehybridized with the 32P-labeled mouse 7S cDNA probe that cross-hybridizes with human 7S RNA, as reported previously (
In Situ Hybridization
ISH was performed as reported in detail previously using DIG-labeled cRNA probes (
Pretreatment of the slides with RNAse abolished the hybridization signals and hybridization with the appropriate sense probes failed to produce an ISH signal.
The ISH signals were semiquantitatively evaluated by two independent observers unaware of patient status. This was followed by resolution of any differences by joint review and consultation with a third observer. The ISH results were scored as previously described (
Preparation of the Galectin cRNA Probes
A 245-bp fragment of the human galectin-1 cDNA (corresponding to nucleotides 165410) and a 352-bp fragment of the human galectin-3 cDNA (corresponding to nucleotides 382734) were generated by RT-PCR and subcloned into the pGEM-T Easy vector (Promega Biotechnology; Madison, WI), which contains promoters for DNA-dependent SP6 and T7 RNA polymerases. The identity of the cDNA fragments was confirmed by sequence analysis using the dye terminator method (ABI 373A; Perkin Elmer, Rotkreuz, Switzerland). After linearization of the plasmid, the antisense galectin-1 and -3 probes were transcribed using SP6 polymerase and the Ribomax System (Promega Biotechnology). 32P-labeled galectin-1 and -3 cRNA probes were used for Northern blotting analysis, whereas ISH was performed with DIG-labeled cRNA probes, generated by using the Ribomax System (Promega Biotechnology) (
Preparation of 7S cDNA Probe
To verify equivalent RNA loading and transfer on Northern blotting membranes, all filters were rehybridized with a 212-bp fragment of 7S cDNA. The 7S cDNA probe was radiolabeled with [-32P]-dCTP using a random primer labeling system (Pharmacia Biotech; Dubendorf, Switzerland) (
Immunohistochemistry
After deparaffinizing and rehydrating, 3-µm tissue sections were submerged for 15 min in Tris-buffered saline (10 mmol/liter Tris-HCl, 0.85% NaCl, pH 7.4) containing 0.1% Triton X-100 and briefly rinsed three times for 12 min in TBS solution. After incubation in methanol containing 0.6% hydrogen peroxide for 30 min to block endogenous peroxidase activity, the slides were covered with 10% normal goat serum at 23C for 30 min before overnight incubation at 4C with a polyclonal rabbit anti-galectin-1 antibody (kindly supplied by Dr. Douglas N.W. Cooper (Langley Porter Psychiatric Institute; University of California, San Francisco) or anti-galectin-3 antibody. The specificity of the galectin-1 and galectin-3 antibodies has already been shown in previous studies (
After washing with TBS buffer, biotinylated goat anti-mouse immunoglobulin and streptavidinperoxidase complex (Kirkegaard & Perry Laboratories; Gaithersburg, MD) were added at 23C for 45 min, followed by incubation with a 3,3'-diaminobenzidine tetrahydrochloride and hydrogen peroxide mixture (
The IHC results from all pancreatic cancer tissues were analyzed semiquantitatively by two independent observers, followed by resolution of any differences by joint review and consultation with a third observer. The intensity of immunostaining and the percentage of immunoreactive cancer cells were evaluated. The staining intensity was recorded as 0, no immunostaining; 1, weak immunostaining; 2, moderate immunostaining; and 3, intense immunostaining. An IHC staining score was calculated for each sample as intensity times percentage of immunopositive cancer cells, as reported previously (
Western Blotting Analysis
Approximately 200 mg of tissue samples was powdered in liquid nitrogen and then homogenized in lysis buffer (150 mmol/liter NaCl, 10 mmol/liter Tris-HCl, pH 7.5) supplemented with protease inhibitor cocktail (Roche Diagnostics). The lysate was collected and centrifuged at 4C for 30 min at 14,000 rpm to remove the insoluble material. The protein concentration of the supernatant was measured by spectrophotometry using the BCA protein assay (Pierce; Rockford, IL). Protein extracts were subjected to 12% (galectin-1) and 7% (galectin-3) SDS-PAGE. After electrophoresis, proteins were transferred to nitrocellulose filters. For immunoblotting, unspecific binding was blocked with 510% non-fat milk and the membranes were incubated with the primary antibodies (0.01 µg/ml for anti-galectin-1 and 0.5 µg/ml for anti-galectin-3) at room temperature (RT) for 1 hr. Then the filters were washed in TBST buffer (5% non-fat milk in 20 mM Tris-HCl, 150 mM NaCl, 0.1% Tween-20) and incubated with a horseradish peroxidase-conjugated donkey anti rabbit IgG at RT for 30 min. After washing in TBST buffer, the signal was detected using the enhanced chemiluminescence (ECL) method. The intensity of the radiographic bands for each normal and pancreatic cancer sample was quantified by video densitometry.
Statistical Analysis
Results are expressed as median and range or as mean ± SD. For statistical analysis, the Student's t-test, the Pearson correlation analysis, and a multivariate Cox analysis were used. Significance was defined as p<0.05.
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Results |
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Northern Blotting Analysis
Northern blotting analysis revealed high expression levels of galectin-1 and galectin-3 mRNA in pancreatic cancer samples compared with normal controls. As shown in Fig 1, galectin-1 and galectin-3 mRNA signals in pancreatic organ donor tissues were weak or too low to be detected by Northern blotting analysis (Fig 1, Lanes 110). In contrast, galectin-1 and galectin-3 mRNA levels were markedly increased in most of the pancreatic cancer tissues (Fig 1, Lanes 1122). For galectin-1, 88% (30/34) of the pancreatic cancer tissues exhibited elevated mRNA levels in comparison with normal controls. By densitometry, galectin-1 mRNA levels were 11.9-fold higher in the cancer samples than in normal controls (p<0.001). Galectin-3 mRNA expression was increased in 77% (26/34) of the cancer samples. Densitometric analysis revealed that galectin-3 mRNA expression levels were 4.7-fold higher in the cancer samples compared with the normal controls (p<0.005). In the remaining pancreatic cancers, galectin-1 and galectin-3 mRNA expression was similar to that of the normal controls.
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When galectin-1 and galectin-3 mRNA expression was analyzed simultaneously in pancreatic cancer samples, 74% (25/34) of the pancreatic cancers exhibited concomitant overexpression of galectin-1 and -3. In 9% (3/34) of the pancreatic cancers, galectin-1 and -3 were simultaneously not increased; in 14% (5/34) galectin-1 was increased but not galectin-3, and in 3% (1/34) of the cancers galectin-3 was increased but not galectin-1.
In Situ Hybridization
ISH was performed to determine the exact site of galectin-1 and galectin-3 mRNA expression in the normal and cancerous tissue. Consecutive slides were hybridized with the galectin-1 and galectin-3 antisense and sense probes. In the normal pancreatic tissue samples, only faint or no mRNA signals of galectin-1 (Fig 2A) were present in some fibroblasts but not in acinar or ductal cells. Weak galectin-3 mRNA signals (Fig 2B) were found in some ductal cells in the normal pancreas. In contrast, there were moderate to strong galectin-1 mRNA signals in most of the fibroblasts of the extracellular matrix in and around the pancreatic cancer mass (Fig 2C and Fig 2E), but no signals were seen in the pancreatic cancer cells. In contrast, strong galectin-3 mRNA staining was present in most pancreatic cancer cells (Fig 2D) and was absent in the extracellular matrix.
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In addition, moderate to strong galectin-1 (Fig 2C, inset) and galectin-3 (Fig 2D, inset) mRNA signals were present in pancreatic nerves in normal and in cancerous tissue samples.
Immunohistochemistry
The IHC staining pattern in the normal and cancerous pancreatic tissues was similar to that of ISH. In the normal controls, no galectin-1 (Fig 3A) immunostaining was found in the acinar, ductal, and islet cells. Faint galectin-1 immunostaining was present in some fibroblasts of the intra- and interlobular stroma (Fig 3A) of the normal pancreas. Faint galectin-3 immunoreactivity was present in some ductal cells, whereas no signals were found in acinar cells (Fig 3C). Pancreatic cancer cells showed moderate to strong immunoreactivity for galectin-3 (Fig 3D) but not for galectin-1 (Fig 3B). In contrast, strong galectin-1 immunoreactivity was present in the fibroblasts of fibrotic tissue strains in and around the tumor mass (Fig 3B). Furthermore, strong galectin-3 immunoreactivity was present in the cancer cells of metastatic lesions in lymph nodes (Fig 3E, arrows) and in the liver (Fig 3F), whereas no immunostaining was found for galectin-1 in metastatic pancreatic cells (data not shown).
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Pancreatic nerves in the normal and in the cancerous tissues exhibited strong galectin-1 (Fig 3B, inset) and galectin-3 (Fig 3D, inset) immunoreactivity.
Western Blotting Analysis
To semiquantitatively compare the presence of galectin-1 and galectin-3 proteins in the normal and cancerous tissue samples and to confirm the stronger immunoreactivity in pancreatic cancer than in the normal pancreas, Western blotting analysis was performed. Fig 4 shows markedly higher galectin-1 and galectin-3 protein levels in pancreatic cancer tissue samples (Fig 4, Lanes 38) in comparison with normal controls. Densitometry analysis revealed that galectin-1 protein levels were 8.6-fold higher and those of galectin-3 were 2.5-fold higher in pancreatic cancer than in the normal pancreatic tissue samples.
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Correlation Between the Molecular Findings and the Histopathological Parameters
The fold increase of galectin-1 and galectin-3 mRNA levels above the normal controls obtained by Northern blotting analysis was compared in tumor samples without metastases (Stages I + II) and tumors with lymph node metastases (Stage III) and for well/moderately differentiated (G1 + 2) and poorly differentiated (G3) tumors. Statistical analysis revealed no difference in galectin-1 and galectin-3 mRNA levels between tumors with and without metastases. Galectin-3 mRNA levels were also not different between G1 + 2 and G3 tumors; however, galectin-1 mRNA levels were significantly higher (p=0.01) in G3 tumors compared with G1 + 2 tumors. In awareness of the limitation of such whole tissue examinations, we performed similar analysis using the IHC staining score in the 33 pancreatic cancer samples (Table 1). There was no difference in the mean immunohistochemical staining score of galectin-1 and galectin-3 between metastatic (Stage III) and non-metastatic (Stage I/II) tumors. The mean galectin-3 immunohistochemical staining score was also not different in G1 + 2 tumors vs G3 tumors. However, in G3 tumors the galectin-1 IHC staining score was significantly higher than in G1 + 2 tumors (p=0.02).
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Pearson correlation analysis revealed no relationship between the galectin-1/galectin-3 IHC staining score and the tumor stage or between the galectin-3 IHC staining score and the tumor grading. However, a significant relationship (r=0.38, p=0.03) was present between the galectin-1 IHC staining score and the tumor grading. Furthermore, multivariate Cox analysis, including age, presence of metastasis, tumor stage, tumor grading, the galectin-1 or galectin-3 IHC staining score, and the galectin-1 or galectin-3 mRNA expression levels, showed no significant relationship. No relationship was found either between the galectin-1 and galectin-3 mRNA levels and postoperative survival or between the IHC staining score of galectin-1 and galectin-3 and postoperative survival.
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Discussion |
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Pancreatic cancer is characterized by extremely aggressive growth, with early development of metastases in lymph nodes and distant organs (
In the processes of local invasion and metastasis, tumor cells leave their primary tumor, protrude through the surrounding extracellular matrix and the endothelium, invade blood and lymph vessels, and finally attach and proliferate at a distant site (
Through malignant cell transformation, the pattern of surface molecules can be dynamically changed. Thus, the cancer cells develop the ability to disrupt and invade normal tissue structures and finally form metastases in distant organs (
Galectins have been implicated as key factors in the processes of malignant transformation and metastasis in a variety of gastrointestinal tumors, including stomach, hepatocellular, and colon cancer (
In a first immunohistochemical analysis in a small number of pancreatic cancer samples and cell lines, increased immunoreactivity of galectin-3 was reported (
It was the goal of this study to further analyze galectin-3 in a larger series of human pancreatic cancer samples and corresponding metastatic lesions. Furthermore, we also investigated galectin-1, which had not been previously studied in pancreatic cancer. Our present data show that galectin-3 and galectin-1 are strongly overexpressed at the mRNA and protein level in human pancreatic cancer in comparison to normal human pancreas. ISH and IHC confirmed the results of the Northern and Western blotting analyses. Galectin-3 mRNA and protein signals were present in most cancer cells in more than two thirds of the pancreatic cancer samples. In comparing the immunohistochemical staining pattern of metastatic and non-metastatic primary pancreatic cancer samples, we found no difference. The presence of galectin-3 in pancreatic cancer cells was not associated with advanced disease, as has been proposed in other malignancies (
Thus far, no information has been available on galectin-1 in pancreatic cancer. mRNA and protein analysis of galectin-1 revealed its low abundance in the normal pancreas. However, strong immunostaining was observed in most fibroblasts in the stromal strains of desmoplastic tissue in and around the pancreatic cancer mass. These galectin-1 signals in the extracellular matrix were more intense and were uniformly present in the fibroblasts in and around the cancer lesions in comparison to the normal pancreatic stroma. However, no galectin-1 expression was detectable in pancreatic cancer cells, which is similar to the findings in colon cancer, in which galectin-1 overexpression in the stromal component has already been observed (
Overexpression of galectin-1 and -3 in pancreatic cancer did not show a relationship with patient or histopathological tumor parameters, nor was a relationship found with the tumor stage or postoperative survival. However, there was a tendency toward higher galectin-1 and galectin-3 expression in more dedifferentiated cancer samples (G3).
In conclusion, the expression pattern of galectin-1 and galectin-3 in pancreatic cancer tissues implies a role of galectin-1 in the desmoplastic reaction occurring around the cancer cells, whereas galectin-3 appears to be involved in cancer cell development and growth.
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Acknowledgments |
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Supported by the Swiss National Foundation (SNF Grant 32-049494) and by a Research Grant of the Department of Clinical Research of the University of Bern.
We would like to thank Dr Cooper Douglas for giving us his anti-galectin-1 antibody and Dr Hans Graber for his technical support in preparing the galectin-1 and galectin-3 cDNA probes.
Received for publication June 1, 2000; accepted November 22, 2000.
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