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2818 Vol. 10, 2818 –2823, April 15, 2004
Clinical Cancer Research
Clinical Significance of Dysadherin Expression in Gastric
Cancer Patients
Yutaka Shimada,1 Seiji Yamasaki,1
Yosuke Hashimoto,1 Tetsuo Ito,1
Jun-ichiro Kawamura1 Toshiya Soma,1
Yoshinori Ino,2 Yukihiro Nakanishi,2
Michiie Sakamoto,3 Setsuo Hirohashi,2 and
Masayuki Imamura1
1
Department of Surgery and Surgical Basic Science, Graduate School
of Medicine, Kyoto University, Kyoto, Japan; 2Pathology Division,
National Cancer Center Research Institute, Tokyo, Japan; and
3
Department of Pathology, Keio University, Tokyo, Japan
ABSTRACT
Purpose: Dysadherin, a cancer-associated cell membrane glycoprotein, has been reported to down-regulate Ecadherin expression and promote metastasis. To evaluate
the role of dysadherin in gastric cancer, we examined dysadherin and E-cadherin expression in gastric cancer patients.
Experimental Design: Dysadherin and E-cadherin expression were evaluated in 276 gastric cancer patients by
immunohistochemistry, and the results were compared with
the clinicopathological findings of the subjects.
Results: Dysadherin was not expressed in normal gastric epithelium. Both dysadherin and E-cadherin were localized to the cell membrane. Dysadherin expression was sometimes largely localized to infiltrating tumor cells or cells
dissociating. Ninety gastric cancer patients (32.6%) were
positive for dysadherin, and 151 patients (54.7%) showed
preservation of E-cadherin expression. Expression of dysadherin was associated with moderately differentiated carcinoma and hematogenous metastasis, whereas reduced expression of E-cadherin showed an association with poorly
differentiated carcinoma and peritoneal dissemination. As a
result, dysadherin positivity and reduced E-cadherin expression were associated with a poor prognosis. In addition,
patients with both dysadherin positivity and reduced Ecadherin had the worst prognosis. Multivariate analysis re-
Received 4/25/03; revised 1/23/04; accepted 1/27/04.
Grant support: This work was supported in part by a grant-in-aid from
the Japanese Ministry of Education, Culture, Sports, Science, and Technology (Grant 14370385).
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.
Requests for reprints: Yutaka Shimada, Department of Surgery and
Surgical Basic Science, Graduate School of Medicine, Kyoto University, Kawaracho 54, Shogoin Sakyo-ku, Kyoto, 606-8507 Japan. Phone:
81-75-751-3626; Fax: 81-75-751-4390; E-mail: [email protected].
vealed that reduced E-cadherin expression was an independent prognostic factor, but dysadherin expression was not.
Conclusion: Combined analysis of dysadherin and Ecadherin expression may help to predict the prognosis and
the mode of metastasis in gastric cancer patients. Patients
with dysadherin positivity have a higher risk of hematogenous metastasis, whereas patients with reduced E-cadherin
expression have an increased risk of peritoneal dissemination.
INTRODUCTION
The cadherins are a family of intercellular adhesion molecules that are essential for the formation of tight junctions
between cells (1), and E-cadherin is the most important among
them. It has been suggested that inactivation of cadherin-mediated intercellular adhesion plays a role in the initial steps of
tumor invasion and metastasis (2, 3). Several mechanisms that
lead to irreversible and reversible inactivation of the E-cadherin/
catenin complex in human tumors have been reported (4), and
the most recent studies have indicated that a cell membrane
glycoprotein known as “dysadherin” down-regulates E-cadherin
expression and promotes metastasis (5). Transfection of the
dysadherin gene was shown to decrease E-cadherin protein
expression and function without affecting its mRNA expression
in an experimental model. In addition, a prognostic influence of
dysadherin has already been suggested in patients with breast,
pancreatic, and colorectal cancer (5–7).
Gastric cancer is one of the most aggressive tumors and
tends to be associated with hematogenous metastasis, peritoneal
dissemination, and lymph node metastasis. Several studies have
shown that down-regulation of the E-cadherin/catenin complex
is associated with a poor prognosis of gastric cancer (8 –12).
Reduced E-cadherin expression had been reported to show a
positive association with peritoneal dissemination of gastric
cancer (8, 11) but not with hematogenous metastasis (13). In
fact, Shino et al. (8) indicated that preserved E-cadherin expression was associated with hematogenous metastasis, whereas
multiple liver metastases of gastric cancer uniformly show
strong E-cadherin expression (10). Therefore, the role of Ecadherin in hematogenous metastasis still remains controversial.
In the present study, we examined the expression of dysadherin and E-cadherin in patients with gastric carcinoma and
evaluated the prognostic influence of these parameters as well as
the relationship with various clinicopathological factors.
MATERIALS AND METHODS
Patients
Two hundred and seventy-six patients with gastric carcinoma who underwent gastrectomy at the Department of Surgery
and Surgical Basic Science of Kyoto University from 1990
through 1997 were studied. All patients had a pathological
diagnosis of adenocarcinoma (tumor-node-metastasis grade 1 to
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Clinical Cancer Research 2819
Table 1 Clinicopathological characteristics of the subjects
The mean age and standard deviation was 63.1 ⫾ 10.9 yrs.
Variable
pTNM stage
1a
1b
2
3a
3b
4
Gender
Male
Female
Postoperative chemotherapy
a
No.
53
41
37
42
18
85
183
93
124
pTNM, pathological tumor-node-metastasis.
grade 3). Each patient was classified according to the pathological tumor-node-metastasis system (International Union Against
Cancer 1997, 5th edition; Table 1), and patients with Tis tumors
were excluded from this study. There were no operative deaths.
Standard D2 lymph node dissection was performed, with
reconstruction of the stomach being done as follows: Roux-en-Y
reconstruction was used for total gastrectomy, jejunal interposition was done for proximal gastrectomy, and gastroduodenostomy or gastrojejunostomy was performed for distal gastrectomy. Patients who received preoperative chemotherapy were
excluded from this study, and postoperative chemotherapy was
not performed routinely. However, 77 of 145 patients in stages
3a, 3b, and 4 received postoperative i.v. chemotherapy (cisplatin- and 5-fluorouracil-based), whereas 45 patients received oral
uracil-tegafur. For the investigation of hematogenous metastasis
and peritoneal dissemination, data on the preoperative and postoperative occurrence of metastasis were combined.
Written informed consent was obtained from the patients
regarding the performance of surgery and the use of resected
samples for research. (The approval numbers of Kyoto University Institutional Review Board were 232 and G48, respectively.)
Immunohistochemical Staining
Immunohistochemical analysis was done retrospectively.
Resected gastric specimens, which included both tumor and
normal mucosa, were fixed in 10% formaldehyde solution and
embedded in paraffin. Sections (4 ␮m) were cut and mounted on
aminopropyltriethoxysilane-coated glass slides, and immunohistochemical staining was performed using the avidin-biotin
method, as described previously (14). NCC-M53 (diluted 1:5)
was used for the detection of dysadherin expression (6) and
HECD1 (diluted 1:20) was used for the detection of E-cadherin
(a kind gift from Professor Takeichi, Kyoto University).
Unmasking of antigens was performed by incubation in
citrate buffer (pH 6.0) at 121°C for 20 min in autoclave. Then
the sections were incubated overnight at 4°C with each antibody
in PBS containing 5% horse serum and counterstained with
Mayer’s hematoxylin. As a negative control, the primary antibody was replaced by normal mouse IgG.
Evaluation of Immunohistochemical Staining
The intensity of immunostaining was evaluated in five
areas of each section for correlation and confirmation of the
tissue analysis.
E-Cadherin. After cell membranes were stained by
HECD1, the pattern of E-cadherin immunostaining in cancer
tissue was compared with that in normal gastric epithelium. The
percent staining was scored as follows: 0 –9%, 0; 10 – 49%, 1;
50 – 89%, 2; 90 –100%, 3). When over 50% of the tumor cells
were positive, the tumor was classified as showing “preserved
E-cadherin expression,” whereas tumors were evaluated as
showing “reduced E-cadherin expression” when fewer than 50%
of the cells were positive (15).
Dysadherin. After cell membranes were stained by
NCC-M53, the pattern of dysadherin immunostaining in cancer
tissue was compared with that observed in endothelial cells and
lymphocytes. The percent staining was scored in the same
manner as for E-cadherin. Tumors were classified as positive for
dysadherin when ⬎50% of the cells were stained (6, 7).
E-cadherin and dysadherin expression were evaluated by
two authors (Y. S. and Y. H.), and the mean of the two scores
assigned was calculated. If different scores were assigned, final
agreement was obtained after discussion between the two researchers.
Scoring of the Results
Positive staining was assigned a score of “1,” and negative
staining was scored as “0.” In addition, pT, pN, pM, histological
grade, age, and gender were scored as follows: pT1, pT2 versus
pT3, pT4: 1; pN0 versus pN1, pN2, pN3: 1; pM0 versus pM1; G1,
G2 versus G3; R0 versus R1, ⬍64 years old versus ⱖ64 years
old; Female versus Male. With regard to postoperative treatment, the two categories used were not done (0) or done (1).
Statistical Analysis
The ages of the patients were compared by the t test.
Survival curves were calculated by the Kaplan-Meier method,
and differences were analyzed by the log-rank test and Wilcoxon test. Multivariate analysis was performed using Cox’s
proportional hazard model (16). The correlation between dysadherin and E-cadherin expression was statistically evaluated
using Spearman’s correlation coefficients. Correlations between
the expression of these adhesion molecules and each clinicopathological factor were evaluated using Fisher’s exact test and
the ␹2 test. All tests of statistical significance were two-sided
and JMP version 5 software for Macintosh (SAS Institute Inc.,
Cary, NC) was used.
RESULTS
Dysadherin staining was observed on the membranes of
cancer cells, lymphocytes, and endothelial cells, as reported
previously (5). E-cadherin was expressed in normal gastric
epithelium, whereas dysadherin was not. Dysadherin expression
by tumor cells was heterogenous, and it was concentrated in
infiltrating tumor cells or cells dissociating in 24.7% of the
patients (66 of 267; Fig. 1). Contrary to our expectation, dysadherin expression was not associated with E-cadherin expression (Fig. 2).
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2820 E-Cadherin/Dysadherin Expression in Gastric Cancer
Fig. 1 Dysadherin and E-cadherin expression. Dysadherin and Ecadherin expression were both localized to the cell membrane. Dysadherin expression was observed in cancer cells (Fig. 1A), infiltrating
lymphocytes, and endothelial cells but not in the normal gastric epithelium (Fig. 1B). On the other hand, E-cadherin was expressed by the
normal gastric epithelium and also by cancer cells (Fig. 1C). Dysadherin expression was heterogenous in tumor cell nests (Fig. 1D), and its
expression was predominantly observed in infiltrating tumor cells or
cells dissociating in some cases (Fig. 1E). The arrows indicated the
cancer cells (original magnification: 1, A-C at ⫻400; 1, D and E at
⫻200).
The background characteristics of the patients and their
immunostaining profiles for dysadherin and E-cadherin are
summarized in Tables 2 and 3. Dysadherin staining was positive
in 32.6% (90 of 276) and E-cadherin staining was preserved in
54.7% (151 of 276). Expression of dysadherin was associated
with the patient’s age, moderately differentiated carcinoma
(grade 2), M factor (tumor-node-metastasis classification), hematogenous metastasis, and residual tumor. On the other hand,
reduced of E-cadherin expression showed an association with
the poorly differentiated carcinoma (grade 3) and peritoneal
dissemination. When the N factor (tumor-node-metastasis classification) was divided into N negative and N positive, dysadherin expression was also associated with N factor status (P ⫽
0.023), but E-cadhedrin expression was not.
Calculation of survival by the Kaplan-Meier method revealed that dysadherin positivity and reduced E-cadherin expression were both significant prognostic factors (Figs. 3 and 4).
Combined analysis of E-cadherin and dysadherin staining re-
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Clinical Cancer Research 2821
ported to show an association with distant metastasis of pancreatic cancer or colorectal cancer (6, 7). Therefore, our findings
regarding dysadherin expression in gastric cancer were consistent with such previous reports. There are several steps and
factors that are already known to contribute to the establishment
of hematogenous metastasis (17–22), and dysadherin may also
have a role in the establishment of such metastasis arising from
gastric cancer.
In patients with breast, pancreatic, and colorectal cancer,
dysadherin positivity is associated with a worse prognosis than
dysadherin negativity (5, 6, 7). The present study also suggested
that dysadherin expression may predict the survival of gastric
cancer patients. Dysadherin expression was also associated with
age, moderately differentiated carcinoma (grade 2), and the M
factor. The reason for the association between dysadherin ex-
Fig. 2 Relationship between dysadherin and E-cadherin expression.
The Y axis represents expression of dysadherin (%) and the X axis
represents expression of E-cadherin (%). There was no association
between the expression of these two molecules (r ⫽ 0.098; P ⫽ 0.105).
Table 2
Clinicopathological characteristics of the patients stratified
by dysadherin expression
Variables
vealed that patients with preservation of E-cadherin and no
dysadherin expression had the best survival, whereas patients
with reduced E-cadherin expression plus dysadherin positivity
had the worst survival (Fig. 5). Those with abnormal expression
of either dysadherin or E-cadherin showed intermediate survival
(Fig. 5). Cox’s multivariate analysis revealed that pT, pN, pM,
histological grade, residual tumor, and reduced E-cadherin expression were independent prognostic factors, but dysadherin
expression was not (Table 4).
DISCUSSION
The cadherins are a family of transmembrane glycoproteins
involved in homotypic calcium-dependent intercellular adhesion
and are crucial facilitators of mutual association between vertebrate cells (1). More than 10 subclasses of cadherins have been
identified, including E-cadherin. Reduced expression of Ecadherin is frequently observed in tumors with aggressive
histopathological characteristics (8 –12). In several studies, Ecadherin has been found to be a significant prognostic factor for
gastric cancer, because of an association with lymph node
metastasis, poorly differentiated carcinoma, and peritoneal dissemination (8, 11, 12). In this study, we also found a significant
association of E-cadherin expression with survival and with the
above-mentioned tumor characteristics, although there was no
association with lymph node metastasis.
With regard to hematogenous metastasis, several reports
suggested that reduced E-cadherin expression is not associated
with this mode of tumor spread (8, 13). Interestingly, one study
even suggested that preservation of E-cadherin expression was
associated with hematogenous metastasis (8). Like these reports,
our study also showed that E-cadherin expression was not
associated with hematogenous metastasis. However, we also
found that dysadherin was a significant prognostic factor for
hematogenous metastasis of gastric cancer. Overexpression of
dysaherin was originally reported to promote liver metastasis in
an animal model (5), and dysadherin expression was also re-
Dysadherin(⫺)a Dysadherin (⫹)b
(n ⫽ 186)
(n ⫽ 90)
Age
Mean
SD
Gender
Male
Female
T
pT1
pT2
pT3
pT4
N
pN0
pN1
pN2
pN3
M
pM0
pM1
Grade
1
2
3
R
R0
R1
Operation
DGc
PG
TG
Postoperative chemotherapy
No
Yes
Hematogenous metastasisd
No
Yes
Peritoneal disseminationd
No
Yes
P
0.019
62.1
11.3
65.3
9.9
0.148
118
68
65
25
45
98
34
9
13
53
17
7
77
55
31
23
24
32
18
16
150
36
58
32
15
52
119
11
45
34
151
35
60
30
103
1
82
46
2
42
102
84
50
40
171
15
68
22
134
52
64
26
0.252
0.115
0.003
2E-04
0.008
0.391
0.911
2E-04
0.872
a
Negative.
Positive.
DG, distal gastrectomy; PG, proximal gastrectomy; pT, pathological tumor; pN, pathological node; pM, pathological metastasis; TG,
total gastrectomy; R, residual tumor.
d
Including postoperative metastasis
b
c
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2822 E-Cadherin/Dysadherin Expression in Gastric Cancer
Table 3 Clinicopathological characteristics of the patients stratified
by E-cadherin expression
Variables
E-Cadherin (⫺)a E-Cadherin (⫹)b
(n ⫽ 125)
(n ⫽ 151)
Age
Mean
SD
Gender
Male
Female
T
pT1
pT2
pT3
pT4
N
pN0
pN1
pN2
pN3
M
pM0
pM1
Grade
1
2
3
R
R0
R1
Operation
DGc
PG
TG
Postoperative chemotherapy
No
Yes
Hematogenous metastasisd
No
Yes
Peritoneal disseminationd
No
Yes
P
0.382
63.8
11.6
62.6
10.3
0.461
80
45
103
48
18
74
24
9
40
77
27
7
39
42
22
22
62
45
27
17
89
36
119
32
7
39
79
19
58
74
91
34
120
31
62
1
62
87
2
62
63
62
89
62
106
19
113
18
78
47
120
31
0.092
0.253
pression and age is unclear, but more differentiated carcinoma
of the stomach was reported to be associated with hematogenous
metastasis (23), and our results may help to explain this association.
Contrary to our expectation, dysadherin expression showed
no relationship with E-cadherin expression by the tumor cells. In
pancreatic cancer and colon cancer, there was also no significant
association between dysadherin expression and E-cadherin expression (6, 7), so our data are consistent with these previous
reports.
In conclusion, our findings suggested that combined analysis of dysadherin and E-cadherin expression may help to predict the prognosis and mode of metastasis in gastric cancer
patients, thus providing useful information for the follow-up of
patients to detect recurrence.
0.144
0.03
0.194
0.35
0.156
0.426
0.002
a
Reduced.
Preserved.
c
DG, distal gastrectomy; PG, proximal gastrectomy; pT, pathological tumor; pN, pathological node; pM, pathological metastasis; TG,
total gastrectomy; R, residual tumor.
d
Including postoperative metastasis.
Fig. 3 Survival of patients with and without dysadherin positivity. The
survival of patients with dysadherin expression was worse than that of
patients without dysadherin expression. Dysadherin (⫹), dysadherin
positivity; dysadherin (⫺), dysadherin negativity.
b
Table 4
Results of Cox multivariate analysis
Variables
Risk ratio
95% CIa
P
Age (⬎64)
Gender (male)
pT (⬎T2)
pN
pM
Grade (⬎G2)
R
Postoperative chemotherapy
E-Cadherin preserved
Dysadherin positive
1.5
1.29
2.67
5.16
3.35
1.6
1.98
0.86
0.59
1.16
0.79–1.7
0.85–2.00
1.80–3.95
2.81–10.26
1.83–6.09
1.06–2.43
1.07–3.70
0.56–1.37
0.41–0.85
0.78–1.72
0.454
0.232
⬍0.0001
⬍0.0001
0.0001
0.025
0.03
0.49
0.004
0.458
a
CI, confidence interval; pT, pathological tumor; pN, pathological
node; pM, pathological metastasis; R, residual tumor.
Fig. 4 Survival in relation to E-cadherin expression. The survival of
patients with reduced E-cadherin expression was worse than that of
patients with preserved E-cadherin expression. E-cadherin (⫹), preserved E-cadherin expression; E-cadherin (⫺), reduced E-cadherin expression.
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Clinical Cancer Research 2823
Fig. 5 Survival in relation to the combined E-cadherin/dysadherin
status. Patients with preserved E-cadherin expression and negative dysadherin expression had the best survival, whereas patients with reduced
E-cadherin expression plus dysadherin positivity had the worst survival.
E-Cad (⫹), preserved E-cadherin expression; E-Cad (⫺), reduced Ecadherin expression; dysad (⫹), dysadherin positivity; dysad (⫺), dysadherin negativity.
ACKNOWLEDGMENTS
We thank Sakiko Shimada for technical assistance with immunohistochemistry; Toby Cavanaugh for support in proofreading the manuscript; and Shunzou Maetani, MD, PhD (Vice President of Tenri Hospital Research Center) for excellent advice on statistical analysis.
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Clinical Significance of Dysadherin Expression in Gastric
Cancer Patients
Yutaka Shimada, Seiji Yamasaki, Yosuke Hashimoto, et al.
Clin Cancer Res 2004;10:2818-2823.
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