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Second Department of Surgery, School of Medicine [Y. Y., S. F., E. B., K. T., Ka. K., I. N.], and Department of Experimental Therapeutics, Cancer Research Institute [Y. E., Ke. K., T. S.], Kanazawa University, Kanazawa 920, Japan; Virology Division, National Cancer Center Research Institute, Tokyo 104, Japan [K. S.]; and Department of Pediatrics, Division of Clinical Chemistry, University of Zurich, Zurich, Switzerland [C. W. H., B. W. S.]
ABSTRACT
S100A4 is known to be involved in cancer cell motility by virtue of its ability to activate nonmuscle myosin. E-cadherin has an important role in the homophilic cell-cell adhesion and is called an invasion suppressor gene. In the current study, we investigate the histological type and metastatic potential of gastric cancer from the aspect of the interrelationship of E-cadherin and S100A4 expression.
Expression of E-cadherin and S100A4 in gastric cancer cell lines, primary gastric cancers, and their normal counterparts were analyzed by reverse transcription-PCR, Western blot, and immunohistochemical methods.
S100A4 protein and E-cadherin were expressed in five of eight gastric cancer cell lines, and inverse expression of the two proteins are found in four cell lines. In the clinical specimens, E-cadherin mRNA expression in differentiated adenocarcinomas (88%, 14 of 16) was significantly more frequent than that in poorly differentiated adenocarcinomas (50%, 22 of 44; P = 0.015). Western blot analysis demonstrates that S100A4 protein expression in poorly differentiated adenocarcinomas was 1.6-fold higher than in well differentiated adenocarcinoma. Immunohistochemically, S100A4 expression was detected in 51 (55%) of 92 primary gastric cancers. Reduced expression of E-cadherin in primary tumors was found in 66 (72%) of 92 tumors. S100A4 expression in the poorly differentiated adenocarcinomas had a strong relation to positive lymph node involvement or peritoneal dissemination. Reduced E-cadherin expression showed a strong relationship with positive serosal involvement and infiltrating type. Tumors classified as a group with reduced E-cadherin and high expression of S100A4 reveal positive peritoneal dissemination, serosal involvement, and infiltrating type in the growth pattern. Furthermore, these tumors showed a strong correlation with the poorly differentiated adenocarcinoma. In contrast, tumors with preserved E-cadherin and low expression of S100A4 have a close relation to the well differentiated adenocarcinoma and a favorable prognosis. By the Cox proportional hazard model, S100A4 and E-cadherin tissue status was judged as an independent prognostic factor. S100A4 and E-cadherin tissue status may be a powerful aid in evaluating metastatic potential or the prognosis of patients with gastric cancer.
INTRODUCTION
The S100 protein family was first isolated from bovine brain
by Moore (1)
. Subsequent studies identified 16 members of
this family, based on amino acid sequence homology and similar
structural properties (2)
. Each member of the family has a
feature of calcium-binding properties and exhibits a unique pattern of
expression,2
with some cells
expressing multiple members of the family. The calcium-binding capacity
is thought to be mediated through a highly conserved calcium-binding
loop consisted of 12 amino acids, which is flanked by two 
helices.
This helix-loop-helix motif is called as an EF-hand, and calcium ion
binding via EF-hands mediates a conformation change in these proteins,
resulting in an alteration of target protein activity and production of
intracellular response (3)
.
Among the 16 S100 proteins, S100A4 has functions in cell cycle progression (4) and cell motility (5) . The mechanisms by which S100A4 might be exerting control over cell cycle progression are yet unclear. In contrast, it is well known that S100A4 protein alters cell motility by virtue of its ability to alter cytoskeletal dynamics (6) . The ability of S100A4 to interact with nonmuscle myosin supports the view that it takes part in cellular motility (7) . Filamentous actin, nonmuscle myosin, and nonmuscle tropomyosin have been suggested as target molecules for S100A4 (7, 8, 9) . Furthermore, several investigators reported that S100A4 expression is intimately related to tumor progression and metastasis (4 , 10) .
E-cadherin is the strongest molecule for homophilic adhesion of epithelial cells and has an important role in the formation of epithelial architecture. The adhesive function of E-cadherin is dependent on the intracellular molecules, like catenin and actin. In the progression of carcinogenesis, irreversible inactivation of E-cadherin at the genomic level gene or through methylation of its promoter is frequently found (11 , 12) . As a result, the mutual adhesive ability of cancer cells is weakened and cell dispersion occurs. Accordingly, E-cadherin is called a metastasis-suppressor gene.
Especially in gastric cancer, E-cadherin is known to be one of the causative genes because germ-line mutations of E-cadherin gene cause familial gastric cancer (13) . We already reported that reduced expression of E-cadherin in gastric cancer is closely associated with invasive phenotype, poorly differentiated tumor, and poor prognosis (14) .
Here, we demonstrate the intimate relationship between highly invasive potential of gastric cancer and the phenotype showing simultaneous overexpression of S100A4 and reduced expression of E-cadherin.
MATERIALS AND METHODS
Cell Lines.
Eight gastric cancer cell lines (KATO-III, TMK-1, NKPS, KKLS, NUGC-3,
MKN-28, MKN-45, and AZ 521) were cultured in RPMI 1640 with 10% FCS
(Life Technologies, Inc., Gaithersburg, MD).
Patients and Tumor Samples.
Ninety-two patients with primary gastric cancer diagnosed and treated
in the Department of Surgery II, Kanazawa University Hospital, between
1990 and 1997, were entered into the study. All patients underwent
gastrectomy with lymph node dissection.
Immediately after resection of the primary tumor, samples of about 5 mm in diameter were taken from 60 primary tumors and normal mucosa, and these samples were stored at -80°C for the RT-PCR3 and Western blot analyses. In addition, small pieces of tissue about 5–8 mm in diameter were sampled from 92 primary tumors, fixed in acetone at -20°C overnight, and prepared to make paraffin-embedded blocks by the AMeX method (15) . All of the resected primary tumors and regional lymph nodes were histologically examined by H&E staining according to the general rules of the Japanese Classification of Gastric Carcinoma (16) .
Antibody and Immunohistochemistry.
Immunohistochemistry was done as described previously
(14)
. Two deparaffinized sections were incubated overnight
at 4°C with anti-E-cadherin monoclonal antibody (Takara Biochemicals,
Tokyo, Japan) and S100A4 polyclonal antibody (17)
, diluted
1:100 in PBS. Next, the slides were incubated with biotinylated goat
antimouse IgG for 20 min (LSAB kit; DAKO, Copenhagen, Denmark) and
biotinylated antigoat rabbit IgG. Immunostaining was done with
diaminobenzidine (DAKO) solution with hydrogen peroxide for 1 min. Only
cases in which at least 20% of the tumor cells were immunoreactive
were scored as positive for S100A4 (Fig. 1
A). When >60% of all cancer
cell were stained for E-cadherin on the cell membrane, the tumors were
evaluated as preserved E-cadherin expression (Fig. 2
B). In contrast, when the
E-cadherin immunoreactivity on the cell membrane was found in <60% of
all cancer cells or was expressed in the cytoplasm and not on the
membrane, they were classified as reduced E-cadherin expression (Fig. 3)
.
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Specific primers for the S100A4 gene were S100A4-sense (5'-GAGGGTGACAAATTCAAGCTCAACAAG-3') and S100A4-antisense (5'-GGT CTCTTGGATAAGGAAGTCT-3' and the target fragment of which is 644 bp), and the probe oligonucleotide was 5'-TGGCAGTGTCTGACCCATTCAT-3'. Primer sequences for E-cadherin were ECAD-7 (sense, 5'-ACCTCTGTGATGGAGGTC-3') and ECAD-10 (antisense, 5'-CCACATTCGTCACTGCTACG-3' and the target fragment of which is 554 bp), and the probe oligonucleotide was 5'-AACGTCGTAATCACCACACT-3'.
As internal standard, primer pairs specific to the ß-actin gene (ß-act-sense, 5'-TTGAAGGTAGTTTCGTGGAT-3'; ß-act-antisense, 5'-GAAAATCTGGCACCACACCTT-3'; PCR products, 591 bp) were used. ß-act-probe 5'-ACTGACTACCTCATGAAGAT-3' was used as the probe.
Western Blot Analysis.
Twelve microliters of protein sample (total protein, 12 µg)
were mixed with a 6-µl sample buffer [50 mM Tris-HCl (pH
6.5), 10% glycerol, 2% SDS, and 0.1% bromphenol blue] and 0.6 µl
of DTT before separation by a NuPAGE Electrophoresis System (NOVEX, San
Diego, CA). After completion of electrophoresis, samples were
transferred to polyvinylidene difluoride membrane filters (Immobilon;
Millipore, Bedford, MA). The transferred samples were incubated with
anti-S100A4 antibody (17)
and anti-E-cadherin antibody
(1:2000; Takara Biochemicals, Tokyo, Japan) for 2 h. The second
antibodies [peroxidase-conjugated affipure F(ab')2 F(ab')2 fragment
(1:5000, Santa Cruz Biotechnology, Santa Cruz, CA) for S100A4 and
antimouse IgG and horseradish peroxidase-linked F(ab')2 fragment
(1:5000; Amersham Life Science Co., Ltd.) for E-cadherin and ß-actin
] were incubated for 40 min, rinsed, and then incubated with enhanced
chemiluminescence Western blotting detection reagent (Amersham Life
Science Co., Ltd.) for 10 min. Then, the membrane was exposed to X-ray
film for 1–10 min.
Data Presentation and Statistical Analysis.
All statistical calculations were done with SPSS statistical software.
The 
2
test and Student’s t test
for unpaired samples were used to analyze data. The outcomes of the
different groups of patients were compared by the generalized Wilcoxon
test. To clarify the E-cadherin and S100A4 tissue status as the
independent prognostic factor, we did Cox stepwise regression analysis.
RESULTS
S100A4 and E-cadherin mRNA and Protein Expression in Gastric Cancer
Cell Lines.
S100A4 mRNA was expressed in KATOIII, TMK-1, KKLS, MKN-28, and MKN-45;
but NKPS, NUGC-3, and AZ-521 did not express S100A4 mRNA (Fig. 4)
. The expression pattern of S100A4
protein was similar to those of S100A4 mRNA, but KATOIII did not
express S100A4 protein. E-cadherin mRNA expression was detected in
KATOIII, TMK-1, NKPS, NUGC-3, and MKN-45, but was not found in KKLS,
MKN-28 and AZ521. Western blot analysis showed that E-cadherin was
detected in TMK-1, NKPS, NUGC-3, MKN-28, and MKN-45.
|
S100A4 and E-cadherin mRNA and Protein Expression in Primary
Gastric Cancer.
E-cadherin mRNA expression was detected in 22 (50%) of 44 poorly
differentiated adenocarcinomas (Fig. 5)
.
In contrast, 14 (88%) of 16 differentiated adenocarcinomas expressed
E-cadherin mRNA. There was a statistical significance in the incidence
of E-cadherin mRNA expression between differentiated (88%) and poorly
differentiated adenocarcinomas (50%; P = 0.015).
S100A4 mRNA expression was detected in differentiated adenocarcinomas
(12 of 16, 75%) and poorly differentiated adenocarcinomas (26 of 44,
59%; Fig. 5
). Western blot analysis demonstrated that S100A4 protein
was expressed not only from normal gastric mucosa but also primary
tumors. Poorly differentiated adenocarcinomas expressed higher S100A4
protein than did the normal gastric mucosa (Fig. 6)
. By the densitomertic analysis, the
relative mean S100A4 density against that of ß-actin in poorly
differentiated adenocarcinomas was 1.6-fold higher than that in well
differentiated adenocarcinoma (Fig. 6)
. E-cadherin of 124 kDa was
detected in all of the normal mucosa and differentiated
adenocarcinomas. In contrast, three of six poorly differentiated
adenocarcinomas did not express the 124-kDa E-cadherin molecule.
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A). In contrast, E-cadherin expression was mainly found on
the cell membrane of cancer cells, and well differentiated
adenocarcinoma tended to show the uniform expression of E-cadherin on
the cell membrane (Fig. 2
B). In contrast, the intensity of
E-cadherin expression in the poorly differentiated tumors was
heterogeneous or completely lost (Fig. 1
B). Some tumors show
cytoplasmic staining of E-cadherin without stain on the cell membrane
(Fig. 3)
, and this staining pattern was exclusively found in the
moderately differentiated adenocarcinomas or poorly differentiated
tumors. S100A4 expression in primary gastric cancer was detected in 51 (55%) of 92 primary gastric cancers. Reduced expression of E-cadherin in the primary tumors was found in 66 (72%) of 92 tumors.
Table 1
shows the correlation
between immunohistochemical expression of S100A4 and
clinicopathological parameters. There was a strong relationship between
S100A4 expression and poorly differentiated adenocarcinomas, and
positive lymph node involvement or peritoneal dissemination.
|
. Gastric
cancers showing reduced E-cadherin expression had a strong relationship
to positive serosal involvement and infiltrating type.
|
depicts a
typical tumor of E-cad+/S100A4-, and Fig. 1
shows a tumor classified
as a group of E-cad-/S100A4+, as listed in Table 3
.
|
The most interesting finding was the strong correlation between the histological type and the expression pattern of S100A4 and E-cadherin. E-cad-/S100A4+ tumors showed a strong correlation with the poorly differentiated type. In contrast, 12 (75%) of 16 E-cad+/S100A4- tumors were classified as the well differentiated adenocarcinomas.
Survival of Patients in Terms of S100A4 and E-Cadherin
Tissue Status after Surgery.
The analysis of E-cadherin tissue status and survival is depicted
in Fig. 7
. Patients with tumors of
preserved E-cadherin expression had a significantly better prognosis
than did those with tumors of reduced E-cadherin expression. With
regard to the expression of S100A4, patients with S100A4-positive
tumors survived significantly poorer than did those with
S100A4-negative tumors (Fig. 8)
.
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shows the survival curves of four
groups subdivided according to the expression of E-cadherin and S100A4.
Patients with E-cad+/S100A4- tumors and with E-cad+/S100A4+ tumors had
a significantly better prognosis than those with E-cad-/S100A4- or
E-cad-/S100A4+ tumors. Furthermore, patients with E-cad-/S100A4+
tumor had the poorest survival than did the other three groups.
|
. Patients with E-cad-/S100A4+ tumor
had a 5-fold higher relative risk for death than did those with
E-cad+/S100A4- tumor.
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Several cancers, like breast cancer, colon cancer, and osteosarcoma, are known to produce S100A4, and the S100A4 expression is now known to be involved in the malignant potential of these tumors (4) . To our knowledge, there was no report about the correlation of S100A4 and gastric cancer. Our present study clearly demonstrated that S100A4 tissue status closely relates to the lymph node metastasis, peritoneal dissemination, and histological type. Albertazzi et al. (19) reported that in human breast cancer S100A4 gene expression correlates strongly with the potential to metastasis to axillary lymph nodes.
In human smooth muscle cells, S100 A4 interacts with the sarcoplasmic reticulum and with actin stress fibers in a Ca2+-dependent manner, resulting in the regulation of cell deformability and morphology (20) . In cancer cells, S100A4 activates the nonmuscle myosin that participates in cellular motility. This concept is supported by the fact that S100A4 is highly expressed during embryonic development in the highly invasive mesenchymal elements (21) . Similarly, Merzak et al. (22) reported that the expression of S100A4 correlates with the in vitro invasive potential of glioma cells. Additionally, the transfection of the S100A4 gene into a benign rat mammary epithelial cell line has been shown to lead to the metastatic phenotype when the transfected cells are injected into the mammary fat pads of syngeneic rats (23 , 24) . Ambartsumian et al. (25) also reported that overexpression of the mts1 gene in the mouse mammary carcinoma cells give rise to more aggressive tumors that are able to metastasize. More recently, Kriajevska et al. (26) reported that the S100A4 protein modulates protein kinase C phosphorylation of the heavy chain of nonmuscle myosin in a calcium-dependent manner. These results strongly suggest S100A4 overexpression may increase the motility of cancer cells by activation of cytoskeletal nonmuscle myosin, resulting in conferring enhanced metastatic ability.
Metastasis is considered to be formed through multistep mechanisms and is not regarded merely by an increased motility via S100A4. Simultaneous accumulation of matrix-degrading enzymes and reduced expression of metastasis-suppressor genes is considered to be involved in tumor invasion and metastasis. Furthermore, an intimate relationship of the expression between S100A4 and the matrix-degrading enzymes were reported. Bjørnland et al. (27) reported that up-regulation of TIMP-2 and down-regulation of MT1-MMP and MMP-2 were introduced by the down-regulation of S100A4 by an anti-S100A4 ribozyme. Accordingly, S100A4 may exert its effects on metastasis formation not only by stimulating the motility of tumor cells but also by affecting their invasive properties through influencing the expression of MMPs and their inhibitors. Like E-cadherin, nm23 is known as a tumor suppressor gene, and reduced expression of nm23 is associated with lymph node metastasis in the breast cancer (28) . Albertazzi et al. (19) also reported that in breast cancer simultaneous overexpression of S100A4 and reduced expression of nm23 is strongly associated with a highly metastatic phenotype. The present study clearly demonstrates that gastric cancers with high expression of S100A4 and reduced expression of E-cadherin have a highly invasive and metastatic potential, as compared with the tumors with low expression of S100A4 or preserved E-cadherin expression. Furthermore, these tumors are associated with a diffuse infiltrating type, positive serosal invasion, and peritoneal dissemination. The Cox proportional hazard model demonstrated that gastric cancers with high expression of S100A4 and reduced expression of E-cadherin have a 5-fold relative risk for death than those with preserved E-cadherin and low expression of S100A4. E-cadherin is an important cell-cell adhesion molecules and controls cell polarity and tissue morphology (29) . E-cadherin gene alterations and the silence of E-cadherin expression by the methylation of the E-cadherin promoter are the frequent findings in gastric cancer (30, 31, 32) . We already reported that the reduced expression of E-cadherin was found in 66% of 125 primary gastric cancers (33) . The loss or reduction of E-cadherin expression may induce the dissociation of cells from primary tumors, due to loosened intercellular adhesion. When gastric cancer cells simultaneously obtain both the reduced E-cadherin expression and overexpression of S100A4, these cancer cells acquire high motility and invasive ability, resulting in the diffuse infiltrating type and the formation of peritoneal dissemination.
An interesting finding in the study is that simultaneous up-regulation of S100A4 and down-regulation of E-cadherin was found more frequently in the poorly differentiated adenocarcinomas than in the well differentiated ones. This finding was confirmed by the immunohistochemistry. The results from RT-PCR or Western blot analysis should be always judged by considering the intratumoral contamination of lymphocytes and vascular smooth muscle, which express considering amounts of S100A4 mRNA and protein.
Gene abnormalities in the functioning domain of E- cadherin are more frequently found in poorly differentiated adenocarcinomas than in the well differentiated ones (31 , 34) . Furthermore, in gastric cancer, the poorly differentiated adenocarcinomas are known to have a higher invasive ability and poorer prognosis than the differentiated adenocarcinomas. Keirsebilck et al. (35) reported that E-cadherin and S100A4 expression levels are inversely regulated in tumor cell lines derived from the mouse mammary gland. Accordingly, in the poorly differentiated adenocarcinoma of stomach, down-regulation of E-cadherin may induce up-regulation of S100A4, and the inverse expression of these two gene products may provide the biological features of its histological type.
In conclusion, the present study indicates that the combined analysis of E-cadherin and S100A4 may be a good prognostic indicator of patients with gastric cancer and that tumors with overexpression of S100A4 and reduced E-cadherin can be classified as highly malignant phenotype. Inverse expression of S100A4 and E-cadherin seems to be associated with the diffuse histological type and with invasive ability of gastric cancer.
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 To whom requests for reprints should be
addressed, at Second Department of Surgery, School of Medicine,
Kanazawa University, Takara-Machi 13-1, Kanazawa 920, Japan. Phone:
81-762-65-2000; Fax: 81-762-34-4260; E-mail: yonemu{at}med.kanazawa-u.ac.jp 
2 The abbreviations used are: RT-PCR, reverse
transcription-PCR; MMP, matrix metalloproteinase.
3 The new nomenclature of S100 protein was adopted
from Schafer et al. (Genomics, 25:
638–643, 1995).
Received 4/20/00; revised 8/ 7/00; accepted 8/16/00.
REFERENCES
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|
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 |
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|
|
|
|
 |
|
 S.-S. Park, S.-H. Kang, J.-M. Park, J.-H. Kim, S.-C. Oh, J.-H. Lee, Y.-S. Chae, S.-J. Kim, C.-S. Kim, and Y.-J. Mok Expression of Liver-Intestine Cadherin and Its Correlation with Lymph Node Metastasis in Gastric Cancer: Can It Predict N Stage Preoperatively? Ann. Surg. Oncol., January 1, 2007; 14(1): 94 - 99. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
Y. Shimada, S. Yamasaki, Y. Hashimoto, T. Ito, J.-i. Kawamura, T. Soma, Y. Ino, Y. Nakanishi, M. Sakamoto, S. Hirohashi, et al. Clinical Significance of Dysadherin Expression in Gastric Cancer Patients Clin. Cancer Res., April 15, 2004; 10(8): 2818 - 2823. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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