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1649
Pancreatic Carcinoma
Correlation between E-Cadherin and a-Catenin Expression Status
and Liver Metastasis
Naoto Gunji, M.D.1
Tatsuya Oda, M.D.1
Takeshi Todoroki, M.D.1
Nobuo Kanazawa, M.D.1
Tohru Kawamoto, M.D.1
Kenji Yuzawa, M.D.1
Aldo Scarpa, M.D.2
Katashi Fukao, M.D.1
BACKGROUND. Dysfunction of the E-cadherin/catenin-mediated cell-cell adhesion
system has been associated with invasiveness and poor differentiation of human
carcinomas. However, its importance in the genesis of liver metastasis has not
been examined sufficiently.
METHODS. A series of 26 primary pancreatic carcinomas and the concomitant liver
metastases from 15 of them, obtained at autopsy, were analyzed for E-cadherin
and a-catenin protein expression by immunohistochemistry.
RESULTS. Both E-cadherin and a-catenin expression were preserved in 15 (58%)
1
Department of Surgery, Institute of Clinical
Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
2
Institute of Pathology, Verona University, Verona, Italy.
and reduced in 11 (32%) of the 26 primary pancreatic carcinomas. In the former
15 primaries, carcinoma cells were attached to each other tightly, whereas the
latter 11 primaries showed isolated or loosely connected attachments. The metastatic ratio was higher in tumors exhibiting tight adhesion than in those with
loose adhesion: 73% and 36%, respectively (P Å 0.059). E-cadherin and a-catenin
expression patterns in liver metastases basically followed those in the corresponding primaries (P õ 0.01).
CONCLUSIONS. Reduced E-cadherin and a-catenin expression in primary pancreatic carcinoma has no significant predictive value regarding the presence of liver
metastasis. Rather, there is a greater tendency for liver metastasis in cases in which
the integrity of the E-cadherin/catenin-mediated cell-cell adhesion system is intact.
Cancer 1998;82:1649–56. q 1998 American Cancer Society.
KEYWORDS: pancreatic carcinoma, E-cadherin, a-catenin, liver metastasis, immunohistochemistry.
Presented at the 55th annual meeting of the
Japanese Cancer Association Yokohama, Japan,
October 1996.
Supported in part by grants from the Ministry
of Education, Japan, Consorzio Studi Universitari and Banca Popolare, Verona, Italy, and
A.I.R.C., Milan, Italy.
The authors thank Professor Noguchi, Pathology Division, University of Tsukuba, Tsukuba,
Ibaraki, Japan, for scientific discussions on the
topic covered in this article.
Address for reprints: Tatsuya Oda, M.D., Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba-shi, 3058575, Japan.
Received May 29, 1997; revision received October 8, 1997; accepted December 10, 1997.
P
ancreatic carcinoma is a lethal disease; the 5-year survival rate
is less than 10% even after radical surgical resection.1 This poor
outcome may be due to the biologic malignancy of the carcinoma,
which easily invades surrounding tissues or metastasizes to distant
organs. The most frequent site of metastasis is the liver (67%), followed by the lung (57%), the adrenal gland (28%), and the kidneys
(12%).2 Liver metastasis is known to be the major cause of postoperative mortality (28%).3 Therefore, elucidation of the molecular mechanisms involved in liver metastasis is important for devising appropriate treatment for patients with pancreatic carcinoma.
Metastasis is a multistep process that begins with detachment
of tumor cells from the primary lesion and ends with their attachment to a different organ and formation of new tumor nodules
there.4 Dysfunction of the cell – cell adhesion system, normally mediated through adherent junctions, may play an important role in
initiating the process.5 E-cadherin (E-cad) is the main molecule
in the adherent junction, and its function is completed when the
cytoplasmic domain is anchored to the actin filament network,
q 1998 American Cancer Society
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CANCER May 1, 1998 / Volume 82 / Number 9
with the cooperation of cytoplasmic proteins termed
a-, b-, and g-catenin (cat).6
Dysfunction of E-cad, including loss of expression7
or expression of mutated molecules,8 is often observed
in patients with poorly differentiated carcinomas, in
which cell – cell adhesion is lost and there is a tendency
for cells to scatter into the surrounding stroma. However, the actual effect of dysfunction in the E-cad/cat –
mediated cell – cell adhesion system on the subsequent steps of the metastatic cascade, including pancreatic carcinoma, has not been examined sufficiently.
There is only one limited study reporting that loss of
membranous E-cad expression might be associated
with distant metastasis, based on the findings in 2 of
36 cases of pancreatic carcinoma.9 This limitation may
be due to the difficulty in obtaining sample sets of
primary and metastatic lesions (liver metastases, when
detected in patients with pancreatic carcinoma, are
considered to be inoperable). Even in cases without
liver metastasis, in which only the primary lesion is
available, the possibility of small metastases or micrometastases in the liver cannot be ruled out, because
it is difficult to detect liver metastasis less than 1 cm
in greatest dimension with current diagnostic imaging
modalities.10,11 Autopsy cases enabled us to analyze
both primary and metastatic tumors.
In this study, we examined E-cad and a-cat protein expression in 26 primary pancreatic carcinomas
and the concomitant liver metastasis in 15 of them,
obtained from autopsy cases. Our results were at variance with the assumption that dysfunction of the Ecad/cat – mediated cell – cell adhesion system is related
to a phenotype of scattered growths that are favorable
for metastasis formation. Rather, our results suggest
that there is a greater tendency for pancreatic carcinoma to metastasize to the liver when the E-cad/cat –
mediated cell – cell adhesion system is intact.
MATERIALS AND METHODS
Patients and Tissue Specimens
Forty-five patients with carcinoma of the pancreas
were autopsied between 1978 and 1996 at Tsukuba
University Hospital (Table 1). Of these 45 cases, 19
were excluded because morphology and/or antigenicity were somewhat damaged (probably because of
postmortem degeneration commonly observed in autopsy materials), and remaining 26 cases were included in the study. All 26 tumors were pancreatic
ductal carcinomas, including 24 adenocarcinomas, 1
mucinous carcinomas, and 1 adenosquamous carcinoma. Fifteen were positive for liver metastasis and
11 were negative. Formalin fixed, paraffin embedded
tissue blocks of these 26 autopsy cases were subjected
to analysis of E-cad and a-cat expression.
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TABLE 1
Characteristics of 26 Autopsied Patients with Pancreatic Carcinoma
Characteristics
Age, yrs (mean { SD)
Female:male
Histopathologic type
Adenocarcinoma
Mucinous carcinoma
Adenosquamous carcinoma
Stage
III
IV
Liver metastasis
Present
Absent
No. of
patients
61 { 11.2
(range, 30–79)
9:17
24
1
1
2
24
15
11
Antigen Retrieval by Incubation in an Autoclave
To retrieve the antigenicity of the paraffin sections for
immunohistochemical analysis, we applied the autoclave technique.12,13 Two-mm-thick paraffin sections
were mounted on poly-L-lysine-coated glass slides
and stored at 45 7C overnight. The sections were deparaffinized in xylene, rehydrated in a graded ethanol
series, and washed in deionized water. They were then
immersed in sodium citrate buffer (0.01 M sodium
citrate monohydrate, pH 6.0) and heated in an autoclave (121 7C, 2 atm [standard atmosphere]) for 10
minutes. Subsequently, the sections were cooled to
room temperature and rinsed in 0.01 M CaCl2 in phosphate-buffered saline (PBS).
Immunostaining
To determine the presence and distribution of E-cad
and a-cat protein, we performed immunohistochemical analysis using the anti-human E-cad monoclonal
antibody HECD-114 (Takara Co. Ltd., Tokyo, Japan)
and anti-human a-cat15 (Transduction Laboratories,
Lexington, Kentucky). The avidin-biotin-peroxidase
complex (ABC) method was used for immunostaining.16 To block endogenous peroxidase activity, the
sections were incubated in methanol with 3% hydrogen peroxide for 20 minutes and then washed 0.01 M
CaCl2 in PBS. HECD-1 was applied at a dilution of
1:1000 in 0.01 M CaCl2 PBS, and anti-a-cat at a dilution
of 1:200. The sections were incubated for 24 hours at
4 7C in a moist chamber and then with biotinylated
goat antimouse immunoglobulin (Dako Co. Ltd.,
Glostrup, Denmark) at 1:500 dilution in 0.01M CaCl2
PBS for 45 minutes, followed by incubation with streptavidin-biotin-peroxidase complex (Dako Co. Ltd.,
Glostrup Denmark) at 1:500 dilution for 45 minutes.
W: Cancer
E-cad/a-cat in Pancreatic Carcinoma/Gunji et al.
1651
FIGURE 1. Normal epithelial controls show immunohistochemical detection of E-cadherin (A, C) and a-catenin (B, D). (A, B) Normal pancreatic ductal
cells are shown. (C, D) Normal bile ductal cells are shown. More than 90% of the epithelial cells express E-cadherin and a-catenin strongly at the cell–
cell boundaries, exhibiting a membranous staining pattern.
The reaction product was visualized by immersing the
sections in diaminobenzidine (DAB) solution (0.2 mg/
mL in 0.01 M CaCl2 PBS) containing 0.003% hydrogen
peroxidase for 10 minutes. Finally, the sections were
counterstained with Mayer’s hematoxylin.
Evaluation of E-cad and a-cat Staining
E-cad and a-cat expression in each section was evaluated semiquantitatively by comparison with internal
positive controls in the same section. Normal ductal
cells in pancreatic and bile ductal cells in Glisson’s
capsule were used as internal positive controls for primary tumor and for liver metastasis, respectively. Almost all cells (more than 90%) in the internal controls
strongly expressed E-cad and a-cat at the cell – cell
boundaries, exhibiting a membranous staining (Fig. 1).
Those cases with obscure staining in internal controls
were excluded. Negative controls were serial, similarly
stained sections in which the primary antibody was
omitted.
E-cad and a-cat staining in tumor cells was evalu-
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ated as positive when strongly membranous staining,
as in normal epithelial cells, was observed. If the tumor cells showed less intense membranous staining
than in normal epithelial cells, the tumor cells were
evaluated as borderline. If the staining was completely absent, or positive but diffusely distributed
within the cytoplasm, the tumor cells were evaluated
as negative. The staining evaluations were done independently and blindly by three observers on two separate occasions (N.G., T.O., N.K.). There was no significant disagreement between observers and occasions.
Because there was somewhat heterogeneous expression in E-cad and a-cat even within a single section, primary tumors and metastatic liver tumors were
categorized into two types, according to a previous
report.17 When more than 90% of tumor cells were
positive, the tumor was categorized as having preserved expression (Ps-type); and when the proportion
of positive cells was less than 90%, it was designated
as having reduced expression (Rd-type).
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TABLE 2
E-cadherin and a-catenin Expression in Primary Pancreatic Tumors
TABLE 3
Correlation of E-cadherin/a-catenin Expression Types and
Intercellular Adhesion in Primary Pancreatic Tumors
Expression type
Psa
E-cadherin
a-catenin
Rdb
15
15
11
11
a
Ps: Preserved expression. More than 90% of tumor cells were positive, exhibiting strongly membranous
staining.
b
Rd: Reduced expression. Less than 90% of tumor cells were positive, exhibiting weaker or diffuse
membranous staining or absence of staining.
Combined
expression of Ecadherin/a-catenin
Cell–cell adhesion
Tighta
Looseb
Psc / Ps
Ps / Rdd
Rd / Ps
Rd / Rd
Total
15
0
0
0
15
0
0
0
11
11
a
Morphologic Assessment of Adherence in Carcinoma
Cells
The cases were categorized into two groups according
to their cell – cell adhesion. When tumor cells maintained well-organized glandular formation and/or
formed aggregate with a dense cell – cell adhesion,
these tumors were categorized as having ‘‘tight cell –
cell adhesion.’’ Tumors that lacked any glandular formation, and/or single tumor cells diffusely infiltrated
into the surrounding tissue, were regarded as having
‘‘loose cell – cell adhesion.’’ Morphologic assessment
of adherence was performed by one pathologist without knowledge of the staining results.
Those samples with damaged cell – cell adhesion
in normal duct were excluded from the series, because
autopsy samples have postmortem degeneration of
morphology and cell – cell adhesion.
Tight: Tumor cells maintained well organized glandular formation and/or form aggregates with dense
cell–cell adhesion.
b
Loose: Tumor cells lacked any glandular formation and/or single tumor cells diffusely infiltrate into
the surrounding tissue.
c
Ps: Preserved expression. More than 90% of tumor cells were positive, exhibiting strongly membranous
staining.
d
Rd: Reduced expression. Less than 90% of tumor cells were positive, exhibiting weaker or diffuse
membranous staining or absence of staining.
Statistical Analysis
The chi-square test was used to test for correlation
between the expression categories of E-cad and a-cat
and the existence of liver metastasis.
RESULTS
Of 26 primary pancreatic carcinomas, E-cad expression was Ps-type in 15 (73%) and Rd-type in the remainder. a-cat expression was equivalent to E-cad expression (Table 2).
Correlation of E-cad/a-cat Expression Type and
Intercellular Adherence in the Primary Tumor
E-cad/a-cat expression and morphologic cell – cell adhesiveness in the primary tumors were compared (Table 3). In all 15 primary tumors with Ps-type of both
E-cad and a-cat, carcinoma cells were tightly bound
(Fig. 2). All 11 primary tumors with Rd-type of E-cad
and a-cat expression showed isolated or loosely connected tumor cells (Fig. 3). As a whole, the cell – cell
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FIGURE 2. E-cadherin (Ps) and a-catenin (Ps) primary pancreatic carcinoma shows immunohistochemical detection of E-cadherin (A) and acatenin (B). More than 90% of the cells are positive both for E-cadherin
and a-catenin. Morphologically, the tumor cells are attached tightly to one
another.
W: Cancer
E-cad/a-cat in Pancreatic Carcinoma/Gunji et al.
1653
FIGURE 3. E-cadherin (Rd) and a-catenin (Rd) primary pancreatic carci-
FIGURE 4. Expression of (A) E-cadherin (Ps) and (B) a-catenin (Ps) is
noma shows immunohistochemical detection of E-cadherin (A) and acatenin (B). Less than 90% of tumor cells are positive for E-cadherin and
a-catenin. Morphologically, tumor cells lack any glandular formation and
single tumor cells diffusely infiltrate the surrounding tissue.
shown in metastatic liver tumor. Note that both molecules are distributed
to the intercellular border, mediating tight cell–cell adhesion. Ps: preserved
expression, with more than 90% of tumor cells positive.
The metastatic ratio was higher in tumors exhibiting
tightly attached cells than in tumors with loose adhesion (73% and 36%, respectively) (P Å 0.059).
TABLE 4
Intercellular Adhesion in the Primary Tumor in Relation to the Liver
Metastatis Ratio
Intercellular
adhesion
Metastatis ratio (%)
Tight
Loose
11/15 (73%)
4/11 (36%)
P value
(chi-square test)
0.059
adhesion system was intact in 15 primary tumors but
damaged in the remaining 11 tumors.
Cell–Cell Adhesion Type in the Primary Tumor and the
Frequency of Liver Metastasis
In the 15 cases in which the primary tumors showed
tight cell – cell adhesion, 11 (73%) had liver metastasis.
Of the 11 cases with loose cell – cell adhesion in their
primaries, only 4 (36%) had liver metastasis (Table 4).
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E-cad/a-cat Expression in Liver Metastases
E-cad and a-cat expression types in metastases were
compared with those of primary tumors in the 15 cases
with liver metastases (Fig. 4). The pattern of E-cad
expression of the liver metastases in 14 cases (93%)
was identical to that of the primary tumors, including
10 with Ps-type and 4 with Rd-type (Fig. 5). The remaining case had Ps-type in the primary tumor and
Rd-type in the liver metastasis. a-Cat expression was
also identical in 15 cases, including 11 with Ps-type
and 3 with Rd-type, and again was different in 1 case,
which had Rd-type in the primary and Ps-type in the
liver metastasis. These results indicate that E-cad and
a-cat expression patterns in liver metastases basically
follow those of the corresponding primary tumors (P
õ 0.01).
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CANCER May 1, 1998 / Volume 82 / Number 9
FIGURE 5.
Identical expression type of Ecadherin/a-catenin in the primary tumors and
corresponding liver metastases is shown. Ps:
preserved expression, with more than 90% of
tumor cells positive; Rd: reduced expression,
less than 90%.
DISCUSSION
The current analysis of E-cad/a-cat expression in 26
primary pancreatic carcinomas, including 15 with liver
metastasis, revealed that the supposition that E-cad
dysfunction has a metastasis-promoting effect in pancreatic carcinoma is incorrect.
Normal pancreatic ductal cells showed Ps-type for
both E-cad and a-cat, reflecting maintenance of morphologic intercellular adhesiveness (Fig. 1). In 15 primary tumors that expressed Ps-type both for E-cad
and a-cat, carcinoma cells showed tight intercellular
adhesion, as in normal pancreatic ductal cells (Fig. 2);
none showed damaged cell – cell adhesion. We assume, therefore, that the ‘‘preserved’’ expression of Ecad and a-cat is a good indicator of tight cell – cell
adhesion.
a-Cat is known to work as an anchor protein not
only with E-cad but also with other cadherin molecules. Carcinoma cells are known to express various
types of cadherin on occasion.18,19 If cadherin other
than E-cad was expressed with the presence of a-cat,
their cell – cell adhesion might be mediated in those
cases with E-cad (Rd)/a-cat (Ps) expression. In this
study, however, we did not observe any such cases.
As previously reported, abnormal expression of acat, which anchors E-cad to cytoskeletal actin filaments, also damages the E-cad/cat – mediated cell –
cell adhesion system, even if E-cad expression is normal.20,21 In the current series, however, no cases were
categorized as Ps-type E-cad and Rd-type a-cat. Gen-
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erally, catenin molecules in cells in which cadherin
molecules are absent do not show membranous staining because they are unable to bind to the cytoplasmic
domain of the cadherin molecules, and vice versa.5
This is in agreement with the current series, in which
the carcinoma cells in the 11 primary tumors with
Rd-type expression of both molecules showed loose
intercellular adhesion (Fig. 3).
The current analysis, which focused on autopsy
cases, enabled us to compare the pattern of expression
in primary lesions and liver metastases. Our data indicate that almost all cases with Ps-type E-cad (10 of
11) and all 11 with Ps-type a-cat in primary lesions
maintained the same expression pattern in liver metastases (Figs. 4 and 5). The finding that pancreatic
carcinoma metastasizes to the liver while preserving
the E-cad/cat – mediated cell – cell adhesion system
may be explained by one of the two following molecular mechanisms. The first is that temporal or partial,
rather than constitutive, E-cad dysfunction occurs
during the first step of invasion, and that this function
is recovered at the site of liver metastasis.17,22 Various
molecular mechanisms can explain this reversible Ecad function, including impaired transcription of the
E-cad gene,23 protease cleavage of E-cad protein,24
CpG methylation of the E-cad promoter,25 and tyrosine
phosphorylation of b-cat.26 The second possibility is
that carcinoma cells may detach from the primary lesion and invade the stroma even though the E-cad/
cat – mediated cell – cell adhesion system is still func-
W: Cancer
E-cad/a-cat in Pancreatic Carcinoma/Gunji et al.
tioning. In fact, differentiated gastric and colorectal
carcinomas whose cell – cell adhesion system is preserved do metastasize to the liver,27,28 and an electron
microscopic study has revealed that cluster cells can
actually invade the stroma.29 In these cases, abnormalities of other factors may play critical roles in detachment and invasion.30 – 35
With regard to attachment and growth of tumor
cells at the metastatic foci, preserved cell – cell adhesion seems to have a beneficial effect. Tumor cells
that maintain their mutual adhesion tend to cluster in
vessels or sinusoids and form ‘‘micro-tumor thrombi’’
by physical entrapment. Maintenance of E-cad expression on the surface of released carcinoma cells after
extravasation may allow direct binding to hepatocytes,
which also express E-cad molecules.36 After attachment, carcinoma cells are required to grow in different
organ environments. Tumor cells are known to secrete
paracrine growth factor36; thus, they may generate microenvironments similar to those of primary sites, assisting in the production of metastatic tumor nodules.
Small cell masses released from primary pancreatic carcinomas have been found to aid the formation
of liver metastases.37 Recently, Osada et al. demonstrated a important role of E-cad preservation in the
process of liver metastasis.38 They injected two types
of hepatocellular carcinoma cells, one type positive
and the other negative for E-cad expression, into the
spleens of nude mice, and found that the E-cad positive cells preferentially produced liver metastases.
Morphologically, these E-cad positive cells were
attached tightly to one another, whereas E-cad negative cells grew separately or were only loosely connected. Our current data may support these findings,
i.e., a beneficial effect of preserved cell – cell adhesion
in generating hematogeneous liver metastasis in human patients with pancreatic carcinoma.
2.
CONCLUSIONS
14.
Our analysis of 26 autopsy cases with pancreatic carcinoma and 15 corresponding liver metastases showed
that an impaired E-cad/cat – mediated cell – cell adhesion system is not an indispensable event for the generation of liver metastasis. This may be at variance
with previous reports regarding an impaired E-cad/
cat – mediated cell – cell adhesion system as an initiator
of invasion and metastasis. Rather, there seems to be
a greater tendency for liver metastasis in cases in
which the E-cad/cat – mediated cell – cell adhesion system remains intact.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
15.
16.
17.
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