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Molecular Oncology, Markers, Clinical Correlates |
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-/ß-/
-catenin. Loss or
dysfunction of E-cadherin is associated with an invasive phenotype. We
analyzed the expression of E-cadherin and ß-catenin in human lung
cancer to determine the relationship to clinicopathological factors and
prognosis. E-cadherin and ß-catenin expressions were evaluated in 331
lung cancer tissues in a immunohistochemical analysis. Reduced
E-cadherin expression was evident in 138 (42%), and reduced
ß-catenin expression was noted in 122 (37%). Reduced E-cadherin
expression significantly correlated with lymph nodes metastasis
(P = 0.0199). E-cadherin expression significantly
correlated with increasing histological differentiation
(P = 0.0403). Although reduced E-cadherin did not
correlate with the prognosis (P = 0.0652), reduced
ß-catenin expression did significantly correlate with a poor
prognosis (P = 0.0001). When both were reduced,
there was a significant unfavorable prognosis compared with either the
reduced expression (P = 0.0493) and preserved
expression (P = 0.0003). Multivariate analysis
showed a significantly lower survival rate for patients with reduced
ß-catenin (P < 0.0001). We interpret these data
to mean that dysfunction of the cell-cell adhesion molecule has a role
in the progression of lung cancer and that analysis of E-cadherin and
ß-catenin expression can provide clinically important evidence on
which to base treatment. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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E-cadherin is the prime mediator of intercellular adhesion in
epithelial cells. This transmembrane glycoprotein, localized mainly in
adherens junctions, mediates by extracellular domain cell-cell adhesion
through calcium-dependent, homotypic interactions. The carboxy
cytoplasmic domain of this molecule is associated with a group of
undercoat proteins, termed catenins (-/ß-/-catenin; Ref.
7
). E-cadherin binds directly to ß-catenin, and
-catenin links the bound E-cadherin complex to the actin
cytoskeleton. This binding is essential for formation of stable
cell-cell adhesion and is partly regulated by ß-catenin. ß-Catenin
has homology to human plakoglobin, a component of desmosomal plaques
and adherens junctions (8)
, and to the product of
Drosophila segment polarity gene armadillo (9
, 10)
. ß-Catenin may differ from cadherin-mediated cell
adhesion, because ß-catenin participates in a signaling pathway that
specifies embryonic patterning (11)
. In addition, it was
reported that the APC (3)
tumor suppresser gene product
forms a complex with ß-catenin, and disruption of this complex is a
crucial step in colorectal carcinogenesis (12
, 13)
. As a
consequence, mutation in either
APC3
or ß-catenin leads to the accumulation of cytoplasmic ß-catenin,
which binds to T-cell factor and lymphoid enhancer factor transcription
factors (14
, 15)
.
E-cadherin and ß-catenin expression is reduced in tumor progression and metastasis and the prognosis is poor in cases of the esophagus (16, 17, 18, 19, 20) , stomach (21, 22, 23, 24) , colon (25) , liver (26 , 27) , pancreas (28) , and urinary bladder (29, 30, 31, 32) . There is little documentation regarding the immunohistochemical expression of these molecules in lung cancer, and reduced E-cadherin expression correlates with differentiation, lymph node metastasis, an advanced clinical stage, and a poor prognosis (33, 34, 35, 36) . ß-Catenin expression was reported by Retera et al. (37) , but the significance was not fully determined. We evaluated the expression of E-cadherin and ß-catenin in cases of human lung cancer, and the relationship between expression and clinical features was given attention.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Immunohistochemistry.
Sections were deparaffinized in xylene three times for 5 min each and
then placed in a graded series of ethanol (100, 90, 80, and 70%). To
enhance antigen retrieval, sections were pretreated in an autoclave at
121°C for 5 min in 0.01 M citrate buffer (pH 6.0) and
cooled to room temperature, and to quench the endogenous peroxidase
activity, the sections were processed to 0.5%
H2O2 in methanol for 30 min
and then rinsed in PBS three times for 5 min each. The sections were
incubated with 10% rabbit normal serum for 20 min at room temperature.
After this blocking, sections were incubated overnight at 4°C with
primary antibodies at 1:200 dilution, one was a mouse monoclonal
antibody against human E-cadherin (C20820) and the other a human
ß-catenin (C19220) antibody purchased from Transduction Laboratories
(Lexington, KY). The sections were rinsed three times with PBS for 5
min each and sequentially incubated with biotinylated secondary
antibodies for 15 min at room temperature, rinsed three times for 5 min
each with PBS and streptavidin-biotin-peroxidase for 5 min at room
temperature, and then rinsed three times with PBS for 5 min. The
peroxidase reaction was visualized by making use of a solution of
3,3'-diaminobenzidine tetrahydrochloride-supplemented 0.2% hydrogen
peroxidase in PBS. The sections were then lightly counterstained with
hematoxylin. Paraffin-embedded tissues from normal colon epithelium of
the homogeneous immunophenotype for the studied antigens were included
as positive controls. These colon epithelium tissues were obtained from
patients undergoing surgery for colon cancer.
Immunohistochemical Assessment.
The staining was localized mainly on membranes of the tumor cells. The
rate of staining of the tumor cells was estimated as a percentage of
>500 tumor cells in five fields selected at random (x400) and scored
in one of the following categories: (a) preserved
expression: 
70% of tumor cells were stained; and (b) reduced
expression: <70% of tumor cells were stained.
Distribution of the ratio of stained cells showed bipolarity, and we separated these into two groups, at the level of 70%. Necrotic areas were not taken into consideration. Heterogeneous staining was classified into reduced expression when <70% of the tumor cells were stained. All tumor slides were examined at random by two investigators who were unaware of the clinical data.
Western Blotting.
In addition to immunohistochemical analysis, tissues stored at
-110°C until analysis were evaluated by Western blotting. We rapidly
homogenized the tissue in 2x sample buffer [125 mM Tris
(pH 6.8), 4% SDS, 10% glycerol, and 4% ß-mercaptoethanol],
centrifuged the homogenate, diluted an aliquot of the sample at least
10-fold to be used for bicinchoninic acid protein, using assay kits
purchased from Pierce (Rockford, IL). We then added 2x sample buffer
to the samples to 5 mg protein/ml and applied 10 µl (50 µg of
protein) of tissue homogenates to each well of 7.5% polyacrylamide and
0.75-mm-thick gels. Proteins were electrophoretically transferred to
nitrocellulose membrane. To saturate nonspecific protein binding sites,
we incubated the membrane in TBST [20 mM Tris-HCl (pH
7.5), 150 mM NaCl, and 0.05% Tween 20] + 1%
blot-qualified BSA for 30 min. To bind the primary antibody, we
replaced the blocking solution with TBST containing a dilution of the
primary antibody (1:2500 for E-cadherin antibody and 1:500 for
ß-catenin antibody), followed by incubation for 60 min, with gentle
agitation. To remove any unbound antibody, we washed the membrane in
TBST three times for 5 min each time. Next, the membrane was
transferred to TBST containing anti-IgG alkaline phosphatase conjugated
and incubated for 30 min. The membrane was washed in TBST three times
for 5 min each to remove any unbound secondary antibody. The membrane
was then placed into color development solution and incubated until the
bands reached the desired intensity, and then the reaction was halted
by washing the membrane for two minutes in deionized water.
Statistical Analysis.
Correlations between antigen expression and clinicopathological factors
were evaluated using 
2 Fisher’s exact test.
Data preserved from the date of complete surgical resection to death of
the patient were analyzed using the Kaplan-Meier method, and the
differences were evaluated using the log-rank test. The prognostic
significance of E-cadherin and ß-catenin expression concerning other
pathological variables was assessed using multivariate Cox proportional
hazard’s analysis. P < 0.05 was considered to have
statistical significance.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A), but in some cases it was localized in the cytoplasm.
There were some cases of heterogeneous staining, all of which accounted
for <70% of the stained cells. The expression of ß-catenin was also
localized mainly on membranes of the tumor cells (Fig. 1
B),
but staining was localized in the cytoplasm in 10% of the cases.
Similar to E-cadherin, there were some cases of heterogeneous staining,
all of which also accounted for <70% of the stained cells. With
Western blot analysis, Mr
120,000 of protein was strongly expressed with use of an
E-cadherin antibody in cases of preserved expression of E-cadherin,
whereas no protein was expressed in the case of reduced expression of
E-cadherin (Fig. 2)
. Similarly, Western blot analysis showed that
Mr 92,000 of protein was expressed by
ß-catenin antibody, preserved expression of ß-catenin strongly
expressed ß-catenin, whereas the reduced expression of ß-catenin
weakly expressed ß-catenin (Fig. 2)
. Therefore, the preserved
expression of E-cadherin and ß-catenin in this immunohistochemical
analysis expressed E-cadherin and ß-catenin by Western blotting
analysis, and the reduced expression of E-cadherin and ß-catenin by
immunohistochemical analysis did not express or only weakly expressed
E-cadherin and ß-catenin by Western blotting analysis.
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). In 206 cases without lymph node metastasis, 76 (36.5%) showed the
reduced expression, and 130 (63.5%) showed the preserved expression.
In 125 with lymph node metastasis, 62 (49.6%) showed the reduced
expression, and 63 (50.4%) showed the preserved expression. There was
a significant inverse correlation between E-cadherin expression and
lymph node metastasis (P = 0.0199; Table 1
) and a
significant inverse correlation between E-cadherin expression and
vascular invasion (P = 0.0202; Table 1
).
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).
In all of the same 331 tumors immunostained with ß-catenin antibody,
209 (63%) showed the preserved expression, and 122 (37%) tumors
showed the reduced expression. There were no significant
correlations between ß-catenin expression and histology,
differentiation, pT, pN, vascular invasion, or lymphatic invasion
(Table 2)
.
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. One hundred and ninety-three with the preserved expression of
E-cadherin showed 141 (73%) of the preserved expression of
ß-catenin, and 52 (27%) showed the reduced expression of
ß-catenin, whereas 138 of the reduced expression of E-cadherin showed
68 (49%) of the preserved expression of ß-catenin, and 70
(51%) showed the reduced expression of ß-catenin. The correlation
between E-cadherin and ß-catenin expression was statistically
significant (P < 0.0001; Table 3
).
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). With regard to the expression of ß-catenin, the lung cancer-related
5-year survival rate was 69.1% in case of the preserved expression and
46.0% for the reduced expression, and patients with the reduced
expression of ß-catenin had a significantly poorer prognosis than did
those with the preserved expression of ß-catenin (P =
0.0001; Fig. 4
). Next, survival rate was analyzed, based on the histology. With regard
to E-cadherin for both adenocarcinoma and squamous cell carcinoma,
correlations were nil. In relation to ß-catenin in cases of
adenocarcinoma, the 5-year survival rate was 46% for the reduced
expression and 82% for the preserved expression. The reduced
expression of ß-catenin in adenocarcinoma significantly correlated
with a poorer prognosis than did the preserved expression
(P < 0.0001; data not shown). In cases of squamous
cell carcinoma, there was no significant correlation regarding survival
time between preserved and reduced expression of ß-catenin. The
5-year survival rate was 72.4% in cases of the preserved expression
for both E-cadherin and ß-catenin and 58.2% in cases of the reduced
expression for either E-cadherin or ß-catenin, and 45.8% in cases of
the reduced expression for both E-cadherin and ß-catenin. Cases of
the reduced expression of both E-cadherin and ß-catenin showed a
significant unfavorable prognosis compared with cases of the reduced
expression of either E-cadherin or ß-catenin (P =
0.0493; Fig. 5
) and compared with cases of the preserved expression of both E-cadherin
and ß-catenin (P = 0.0003; Fig. 5
).
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).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Previous studies showed that the rate of reduced expression of E-cadherin of lung carcinomas was 44–81% (33 , 34 , 36 , 38) . Sulzer et al. (33) stated that when clear staining was present in <50% of the tumor cell population, the result was defined as negative or weakly positive. They did not mention the rate of negative or weakly positive cases. According to Bohm et al. (34) , the E-cadherin expression level was classified as reduced when fluorescence intensity was markedly less than that of adjacent normal epithelium and/or 90–5% of the tumor cells were stained and as absent when staining was not distinguishable from background or <5% of the tumor cells were stained, the result being that 35% were the reduced type and 18% were the absent type (39) , findings similar to ours. Bongiorno et al. (17) discussed the preserved type, disorganized type, and reduced type as a classification. Twelve (23%) showed the preserved type, 11 (21%) showed the reduced type, and 29 (56%) showed the disorganized type of E-cadherin expression, with the total reduced and disorganized types being 40 (77%). This result was much higher than ours, one reason being that the disorganized type was defined as an altered pattern of staining with cytoplasmic expression or variable staining with some areas preserved and other areas reduced, and many cases were included in the disorganized type. We considered E-cadherin and ß-catenin expression levels to be reduced when <70% of the tumor cells were stained, because the distribution of ratio of staining cells showed bipolarity.
Our data show that in 138 cases of the reduced expression of E-cadherin, 70 (51%) were the reduced expression of ß-catenin, with a statistically significant correlation (P < 0.0001), and these data were consistent with reports on colon cancers by Takayama et al. (39) and esophageal cancer by Krishnadath et al. (19) . Therefore, various carcinomas showed a significant correlation with expression of E-cadherin and ß-catenin.
We found a significant correlation between E-cadherin expression and lymph node metastasis, especially in cases of squamous cell carcinoma. Consistent with reported data (33 , 34 , 36) , our data show that reduced E-cadherin correlates with lymph node metastasis. When Bongiorno et al. (17) examined E-cadherin expression in 52 lung carcinomas, all metastatic cells in lymph nodes exhibited intense E-cadherin expression levels equal to and often greater than in the primary tumor (17) . Therefore, reduced E-cadherin expression weakens cell-to-cell attachment, and tumor cells detach from the primary tumor, invade vessels, and migrate to lymph nodes. Once tumor cells reattach to lymph nodes, E-cadherin is strongly expressed, and lymph nodes are subject to metastases. In our study, although the E-cadherin expression did not correlate lymphatic invasion, the rate of vascular invasion was statistically high in cases with the reduced expression of E-cadherin. However, only 20 of 118 cases with reduced expression of E-cadherin showed vascular invasion, and only 11 of 118 cases showed lymphatic invasion. Because the number of cases with vascular invasion or lymphatic invasion was small, it is difficult to discuss the relationship between lymph node metastasis and vascular/lymphatic invasion.
Our findings revealed that reduction of E-cadherin is associated with the degree of differentiation. Bohm et al. (34) found a correlation between differentiation and E-cadherin expression in lung squamous cell carcinoma, and Bongiorno et al. (17) found that well-differentiated lung cancers express E-cadherin, in a preserved fashion, and that poorly differentiated tumors exhibited a reduced or disorganized staining pattern (17) . Sulzer et al. (33) also found that E-cadherin expression significantly correlated with increasing tumor differentiation. In general, undifferentiated or poorly differentiated cancer cells tend to have a strong potential to invade tissues. These results suggest that reduction of E-cadherin correlates with tumor invasion.
We found that the expression of reduced ß-catenin significantly correlated with a poor prognosis. Retera et al. (37) studied 101 patients with NSCLC and found that the level of ß-catenin expression was a statistically significant prognostic factor. They classified the results into three categories according to the proportion of tumor cells with immunoreactivity for ß-catenin on the one hand and the mean staining intensity of positively stained tumor cells on the other. Total immunostaining score was divided into low, moderate, and high scores. The mean survival time was 24.9 months for patients with a low score, 42.8 months in case of a moderate score, and 44.1 months for a high score. This is apparently the only report on the correlation between reduction of ß-catenin expression with the prognosis of patients with lung cancer. In comparison with their study, we studied 331 cases of NSCLC and found a correlation between prognosis and ß-catenin expression, histologically, and also that the reduced expression of ß-catenin in adenocarcinoma meant a significantly unfavorable prognosis compared with cases of preserved expression. Concerning adenocarcinoma of the lung, this seems to be the first report that reduced ß-catenin correlates with an unfavorable prognosis.
Shibanuma et al. (36)
, who examined the
relationship between the expression of E-cadherin,
-/ß-/-catenin, and clinicopathological factors in 81 cases of
NSCLC, found statistically significant relationships between the
expression of E-cadherin and lymph node metastasis and between the
expression of E-cadherin and pathological stage. Dividing the 81 cases
into an E-cadherin functional group and other groups, there was a
statistically significant relationship between E-cadherin function and
all of the clinicopathological factors (local tumor invasion,
P = 0.033; lymph node metastasis, P <
0.001; pathological stage, P < 0.001; Ref.
36
). In our study, although the correlation was not
statistically significant between the E-cadherin expression and
prognosis, there was weak relationship (P = 0.0652).
When we analyzed the prognosis for patients with a combination of the
expression of E-cadherin and ß-catenin, cases of the reduced
expression of both E-cadherin and ß-catenin showed a significant
unfavorable prognosis compared with either reduced expression of
E-cadherin and ß-catenin and that with preserved expression of both
of E-cadherin and ß-catenin. Because of the direct binding of
E-cadherin to the ß-catenin molecule, the reduced expression of both
E-cadherin and ß-catenin resulted in a weaker cell-cell adhesion
after detachment of cancer cells from the primary lesion. Therefore,
combined analysis of the expression of E-cadherin and ß-catenin may
be more pertinent to estimate the prognosis in NSCLC.
Hypermethylation around the promoter may be a mechanism of E-cadherin inactivation in human carcinomas, and treatment of E-cadherin-inactivated cells with a demethylating agent may lead to gene expression reversion and epithelial morphogenesis with acquisition of the homophilic cell-cell adhesive property (40) . Kanai et al. (41) showed that CpG methylation around the promoter region of the E-cadherin gene correlated significantly with reduced E-cadherin expression in hepatocellular carcinoma. Sato et al. (42) reported that hypermethylation was observed in the H-cadherin gene in 9 of 20 primary lung cancers. E-cadherin expression level was not uniform, and hypermethylation around the promoter region of the E-cadherin gene may lead to the loss of E-cadherin expression.
ß-Catenin is involved not only in the cadherin cell adhesion
system but also in the growth signal pathway. Signals generated by
Wingless/Wnt, an essential embryonal organization, induce protein
expression of ß-catenin. The role of ß-catenin downstream of Wnt
seems to differ from that in cadherin-mediated cell adhesion, because
this ß-catenin, induced by Wnt, exists in the cytoplasm without
binding to cadherin (11)
. Moreover, the overexpression of
truncated ß-catenin, which cannot bind with -catenin, has an
effect in embryogenesis similar to that of the wild-type of ß-catenin
or growth signal of Wnt (43)
. Wnt also
functions as an oncogene in human mammary carcinogenesis
(44)
. We found ß-catenin protein expressed in the
cytoplasm. However, this type of expression of ß-catenin was minimal,
and little influence was noted regarding clinical features and outcome
in NSCLC.
It has been demonstrated that ß-catenin binds with the APC tumor-suppresser gene product in the cytoplasm and this complex does not include cadherin (45) . The wild-type APC has little effect on ß-catenin binding with cadherin, but it does decrease protein content of the cytoplasmic free ß-catenin (46) . The function of APC as a tumor-suppresser gene might bind and limit cytoplasmic-free ß-catenin. ß-catenin in this status binds to T-cell factor and lymphoid enhancer factor transcription factors, which play key roles downstream of the Wingless signals (14 , 15 , 47) . Colorectal tumors with intact APC genes were found to contain activating mutations of ß-catenin that altered functionally significant phosphorylation sites (14) . In 122 cases of reduced expression, 34 (28%) showed cytoplasmic expression of the ß-catenin, and the other 88 (72%) showed noncytoplasmic expression. There was no significant correlation between the cytoplasmic expression and various clinicopathological factors. The 5-year survival rate was 52.1% for patients with cytoplasmic expression and 40.6% for those with noncytoplasmic expression, with no statistical difference (P = 0.7822; data not shown). In our data, lung cancer with the cytoplasmic expression of ß-catenin is not as significant, as seen in cases of colon cancer.
In conclusion, the cadherin-catenin complex may have a major role in cell-cell adhesion systems, and down-regulation of E-cadherin and ß-catenin indicates an unfavorable prognosis. This is a useful prognostic factor in NSCLC with ß-catenin expression. For patients with a reduced expression of the cadherin-catenin complex, follow-up should be close because optional chemotherapy or radiation may be required.
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FOOTNOTES |
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1 Supported in part by a Grant-in-Aid for cancer
research from the Ministry of Education, Science, Sports and Culture,
Japan. 
2 To whom requests for reprints should be
addressed, at Department of Surgery and Science, Graduate School of
Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku,
Fukuoka 812-8582, Japan. Phone: 81-92-642-5466; Fax: 81-92-642-5482;
E-mail: sugio{at}surg2.med.kyushu-u.ac.jp
3 The abbreviations used are: APC, adenomatous
polyposis coli; NSCLC, non-small cell lung cancer.
Received 4/25/00; revised 10/ 3/00; accepted 10/10/00.
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