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Tumor Biology |
Urology Research Laboratory [K. T., A. v. B., C. F. J. J., M. J. G. B., J. A. S.] and Department of Pathology [G. J. L. H. v. L., E. T. G. R.], University Hospital Nijmegen, 6500 HB Nijmegen, the Netherlands
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Recently, a number of papers have been published that describe the
inappropriate expression of nonepithelial cadherins by epithelial cells
as a putative novel mechanism for promoting the interaction with the
stroma, thereby facilitating invasion and metastasis
(13, 14, 15, 16)
. Indeed, we were able to show that human prostate
cancer cell lines, which lack expression of either E-cadherin or the
catenins and, therefore, lack an E-cadherin-mediated cell-cell
adhesion, show expression of several other cadherins (17)
.
Most prominent is the expression of the mesenchymal N-cadherin and
cadherin-11 in these cell lines. Moreover, in other epithelial-tissue
derived cancer cell lines, e.g., human bladder, melanoma,
and breast cancer cell lines (15
, 16
, 18, 19, 20)
, which lack
functional E-cadherin-mediated adhesion, expression of other cadherins
is observed. Considering that the de novo expression of
N-cadherin and cadherin-11 may distinguish changes in
cell-adhesion processes that are important for the invasive and
metastatic capacity of the prostate cancer cells, we decided to
investigate the expression of N-cadherin and cadherin-11 in human
prostate cancer specimens by single- and two-parameter
immunofluorescence. By analyzing the protein expression patterns of
these cadherins and correlating them to the expression patterns of
E-cadherin or 
-catenin, we aimed at establishing the pathological
role of induced expression of N-cadherin and cadherin-11 in prostate
cancer progression.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Immunofluorescence.
Sections were fixed using paraformaldehyde (3%) for E-cadherin,
N-cadherin, cadherin-11, and -catenin staining. On preincubation
with normal sheep serum (diluted 1:20 in PBS) for 30 min.; the
sections were incubated for 1 h with the primary antibody. Next,
the sections were incubated with biotin-labeled secondary antibody,
followed by a streptavidin-fluorescein detection step (Amersham).
Antibodies against E-cadherin [HECD-1 (mouse monoclonal antibody,
Takara)] and N-cadherin [GC4 (mouse monoclonal antibody, Sigma)], an
N-cadherin rabbit polyclonal antibody (Takara), cadherin-11 mouse
monoclonal antibody (Ref. 17
, clone No.16a), and a
rabbit polyclonal antibody against -catenin, C2081 (Sigma), were
used at a dilution of 1:100, 1:30, 1:30, 1:100, and 1:1000,
respectively.
Specificity of the antibodies against N-cadherin and Cadherin-11 was determined by the comparison of steady-state mRNA levels assessed by Northern analysis with immunofluorescence, using a panel of cell lines (17) . There was a full correlation between mRNA and immunofluorescence results. Moreover, Western analysis using these antibodies identified proteins of the expected MW (Mr 135,000 for N-cadherin (17) and Mr 120,000 for Cadherin-11.
N-cadherin, cadherin-11, and E-cadherin staining using the mouse monoclonal antibodies was performed for all of the samples and scored by three independent observers (K. T., A. v. B., and E. T. G. R.). E-cadherin was scored as either normal (membrane staining) or aberrant (negative or heterogeneous staining) as previously described by Schipper et al. (22) and Umbas et al. (23) . N-cadherin staining was judged negative when <5% of the prostate cells were positive for N-cadherin, or when no significant N-cadherin staining was observed. N-cadherin staining was considered positive when 61 5% of the prostate cancer cells showed expression. Furthermore, the staining pattern was scored, i.e., membranous, or dotted. Cadherin-11 staining was scored negative when weak diffuse staining was observed, particularly in the stroma surrounding cancer cells, or when no significant staining was observed. Cadherin-11 staining was considered positive when 61 5% of the prostate cancer cells showed expression, typically in a dotted pattern.
Double staining, using FITC- and
TRITC2
-labeled secondary antibodies were performed to investigate relative
localization of E-cadherin and N-cadherin (rabbit polyclonal) and
-catenin and cadherin-11. The samples were visualized by either
standard epiluminescence fluorescence microscopy (Zeiss,
axioscop) using the appropriate filter combinations or CSLM
(Leitz DMIRBE, Leica).
Statistical Analyses.
The 
2 test was used to determine the
correlation between staining and Gleason score. The odds ratio was used
to determine the correlation of N-cadherin or cadherin-11 with
E-cadherin.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-catenin complexes (17)
. In
particular, N-cadherin and cadherin-11, the expression of which was
confirmed by Western blot analysis, seemed to be of potential relevance
for prostate cancer progression. To gain insight into the role of
N-cadherin and cadherin-11 in human prostate cancer progression, we
used immunofluorescence analysis to study the expression patterns of
these cadherins in human primary and metastatic prostate cancer. In nonmalignant preexisting acini, we never found expression of N-cadherin, i.e., none of the 12 samples analyzed showed positive staining. For cadherin-11, we occasionally found a very weak diffuse staining in the stromal cells, which is in agreement with the putative mesenchymal nature of cadherin-11 (13) .
In cancer specimens, particularly high-grade (Gleason score: >7;
see next section on "Increased Expression ... "), we found
expression of N-cadherin in the carcinoma cells (Fig. 1, A, D, and G)
. In the primary cancer
specimens, the expression pattern is heterogeneous, with a predominant
expression at the membrane (Fig. 1, A and D)
.
Interestingly, in the high-grade tumors, N-cadherin was expressed more
homogeneously, and, moreover, the pattern of staining changed from a
membranous honeycomb-like staining to a dotted pattern (Fig. 1D)
. Because we performed double-label immunofluorescence
(FITC for N-cadherin and TRITC for E-cadherin), we were able to study
the expression of both cadherins simultaneously. On comparison of the
individual fluorescent dyes, it became evident that, in the
heterogeneously staining primary tumors, the pattern of staining was
complementary, i.e., cells showed either a predominant
expression of E-cadherin or N-cadherin at the membrane (Fig. 1A versus 1B
, and Fig. 1D
versus 1E
). In the undifferentiated tumors
(Gleason score: 9, 10) and metastases, E-cadherin was
mostly negative; and all of the cancer cells were positive for
N-cadherin albeit in two patterns, a membranous and a dotted one (Fig. 1, G, H, and I)
. The complementary
staining pattern is best illustrated in the double exposures of
N-cadherin and E-cadherin-associated immunofluorescence (Fig. 1, C and F)
.
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, we see—besides E-cadherin- and N-cadherin-positive cell
clusters—cell-cell contacts where E-cadherin staining and N-cadherin
staining are juxtaposed (arrowheads), i.e., not
colocalized. In this case, the pattern of N-cadherin staining is
similar to that for E-cadherin. However, occasionally we found
processes in which E-cadherin and N-cadherin were expressed in the same
cell, albeit in different structures (Fig. 2B)
. This figure
also clearly illustrates that the cells that do express N-cadherin have
a marked decrease in E-cadherin immunoreactivity.
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. Interestingly, the expression of cadherin-11 was strongly
induced in cancer areas with a typical dotted pattern (Fig. 3B)
, which was very similar to that observed for N-cadherin.
In high-grade cancers and metastases, the expression was no longer
confined to the stromal cells but was clearly observed in the cancer
cells (Fig. 3, C and D)
. Sometimes the expression
seemed to be at the stromal-epithelial interface, but coexpression of
E-cadherin/-catenin and cadherin-11 was also found in the
typical dotted pattern. In the cells coexpressing
E-cadherin/-catenin and cadherin-11, the de novo
expression of cadherin-11 was associated with a decreased expression of
E-cadherin.
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. The membranous expression of N-cadherin increased from 5% of
low-grade cases (Gleason score: 4–6) to 50% in intermediate- and
high-grade cases (Gleason score: 7 and 8–10, respectively). This
correlation was statistically significant, as was the correlation with
decreased expression of E- cadherin (Table 2)
. In other words, there was a significant correlation between decreased
expression of E-cadherin and increased expression of N-cadherin.
Moreover, there was a trend toward a change of localization of the
cadherin complexes from a typical pattern associated with the adhesion
belt to a dotted pattern. We found the highest percentage of tumor
cells expressing N-cadherin in the dotted pattern in the metastases
(Table 1)
.
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. Moreover, in 9 (60%) of 15 of the metastatic lesions, (homogeneous)
expression of cadherin-11 in the typical dotted pattern was also found.
As is illustrated by Table 4
, the most commonly observed pattern is that of mutual exclusiveness:
when E-cadherin is expressed, there is no expression of cadherin-11 in
the carcinoma cells, and when the E-cadherin staining pattern is
aberrant, cadherin-11 is expressed in a dotted pattern in the cancer
cells.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Recently, the first reports appeared that described inappropriate expression of nonepithelial cadherins by epithelial cells as functionally related to disrupted cell-cell adhesion. A human squamous carcinoma cell line that displayed a scattered fibroblastic phenotype was found to express N-cadherin along with a decreased expression of E- and P-cadherin (24) . In addition, in several breast cancer cell lines that showed a reduced expression of E-cadherin, high levels of N-cadherin expression were found (15) . Temporary, up-regulation of expression of N-cadherin has also been suggested to play an important role in the migration of melanoma cells through the endothelium (16 , 25) . For prostate cancer, we previously found that cell lines that lack functional E-cadherin complexes do express N-cadherin and cadherin-11 (17) . In this report, for the first time, we describe the de novo expression of N-cadherin and cadherin-11 using two parameter immunofluorescence. N-cadherin was expressed in high-grade human prostate cancers, whereas no expression was found in normal prostatic tissue. The technique used, i.e., double-label immunofluorescence, allowed us to assess the expression pattern of N-cadherin and E-cadherin simultaneously. In most cases, expression of N-cadherin was observed in tumor cells that showed reduced or no staining for E-cadherin; hence, the expression seemed to be mutually exclusive. Further detailed analysis by CSLM showed that "intermediate" patterns were occasionally observed putatively representing the transition from E-cadherin to N-cadherin expression. These analyses, furthermore, illustrated a change in pattern of N-cadherin staining, which suggested a change in the adherens junction mediated by these cadherins.
The typical honeycomb pattern associated with localization in a belt-like structure disappeared, and a dotted pattern emerged. This pattern is remarkably similar to that observed for cadherin-11 in the stromal cells, and it is tempting to speculate that this dotted pattern represents an as yet poorly characterized junctional complex mediating interaction between mesenchymal cells.
Moreover, cadherin-11 has been suggested to be up-regulated during
tumor progression: it may play a role in stromal-epithelial
interactions and, thus, may be involved in migration. This would be in
agreement with the interaction of stromal and cancer cells in a subtype
of gastric cancer that is characterized by overexpression of
cadherin-11 (26)
. A role for cadherin-11 in tumor cell
invasion and metastasis is, furthermore, suggested for breast cancer:
in most invasive breast cancer cell lines, expression of cadherin-11 is
observed, whereas no expression can be detected in any noninvasive cell
line (27)
. In prostate cancer cell lines, expression of
cadherin-11 is found in those lines that have lost functional
expression of E-cadherin, attributable to loss of expression of
-catenin (17)
.
Double-label immunofluorescence analysis of cadherin-11 expression revealed no expression of cadherin-11 in nonmalignant prostate tissue. However, all of the prostate cancer specimens did show a dotted staining pattern in the stromal cells surrounding the tumor cells and at the interface of stroma and tumor cells. Further detailed analysis of the expression of cadherin-11 provided unequivocal evidence that in high-grade cancers, the tumor cells also express cadherin-11. Even more interesting is the homogeneous expression of cadherin-11 in the prostate metastatic lesions. The striking resemblance of the pattern of N-cadherin and cadherin-11 staining, i.e., in a dotted pattern, indicates that the switch in cadherin expression and concomitant change of pattern is, in fact, related to the functional interaction between cancer and stromal cells. This, in turn, could be an essential step in the metastatic cascade. Clearly, we can at this point only speculate about the biological functional relation of the cadherin switch and increased metastatic propensity. However, the significant correlation with histological grade together with the fact that we find enrichment of this effect in the metastases (i.e., the metastases show a rather homogeneous pattern for both cadherin-11 and N-cadherin expression) corroborates the hypothesis that N-cadherin/cadherin-11-positive cells have a selective advantage to metastasize. It is noteworthy, however, that up-regulation of E-cadherin in metastases has also been reported (1 , 28) , which in fact could mean that cadherin switching is a dynamic process. The functional role of reexpression of E-cadherin is yet poorly understood. Cadherin-11, also termed osteoblast(OB-)cadherin is expressed at high levels in osteoblasts, which makes it, furthermore, tempting to speculate that there is a potential role of cadherin-11 in homing toward secondary sites, particularly bone.
We, therefore, conclude that we for the first time were able to provide evidence of cadherin switching in advanced human prostate cancer. The change in pattern—resembling the pattern of cadherin expression in stromal cells—suggests a functional role of homotypic cadherin-mediated interactions, in the later stages of cancer progression.
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FOOTNOTES |
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1 To whom requests for reprints should be
addressed, at Urology Research Laboratory, University Hospital
Nijmegen, P. O. Box 9101, 6500 HB Nijmegen, the Netherlands. Phone:
31-24-3614146; Fax: 31-24-3541222; E-mail: J.Schalken{at}uro.azn.nl 
2 The abbreviations used are: TRITC, Texas Red
isothiocyanate; CSLM, confocal scanning laser microscopy.
Received 11/19/99. Accepted 4/27/00.
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E. H. Van Aken, O. De Wever, L. Van Hoorde, E. Bruyneel, J.-J. De Laey, and M. M. Mareel Invasion of Retinal Pigment Epithelial Cells: N-cadherin, Hepatocyte Growth Factor, and Focal Adhesion Kinase Invest. Ophthalmol. Vis. Sci., February 1, 2003; 44(2): 463 - 472. [Abstract] [Full Text] [PDF]
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S. K. Green, M. C. I. Karlsson, J. V. Ravetch, and R. S. Kerbel Disruption of Cell-Cell Adhesion Enhances Antibody-dependent Cellular Cytotoxicity: Implications for Antibody-based Therapeutics of Cancer Cancer Res., December 1, 2002; 62(23): 6891 - 6900. [Abstract] [Full Text] [PDF]
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 R. Lin, Y. Nagai, R. Sladek, Y. Bastien, J. Ho, K. Petrecca, G. Sotiropoulou, E. P. Diamandis, T. J. Hudson, and J. H. White Expression Profiling in Squamous Carcinoma Cells Reveals Pleiotropic Effects of Vitamin D3 Analog EB1089 Signaling on Cell Proliferation, Differentiation, and Immune System Regulation Mol. Endocrinol., June 1, 2002; 16(6): 1243 - 1256. [Abstract] [Full Text] [PDF]
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E. H. Van Aken, P. Papeleu, Patrick De Potter, E. Bruyneel, J. Philippe, S. Seregard, A. Kvanta, J.-J. De Laey, and M. M. Mareel Structure and Function of the N-Cadherin/Catenin Complex in Retinoblastoma Invest. Ophthalmol. Vis. Sci., March 1, 2002; 43(3): 595 - 602. [Abstract] [Full Text] [PDF]
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A. Zeitvogel, R. Baumann, and A. Starzinski-Powitz Identification of an Invasive, N-Cadherin-Expressing Epithelial Cell Type in Endometriosis Using a New Cell Culture Model Am. J. Pathol., November 1, 2001; 159(5): 1839 - 1852. [Abstract] [Full Text] [PDF]
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 K M Rieger-Christ, J A Pezza, J M Dugan, J W Braasch, K S Hughes, and I C Summerhayes Disparate E-cadherin mutations in LCIS and associated invasive breast carcinomas Mol. Pathol., April 1, 2001; 54(2): 91 - 97. [Abstract] [Full Text]
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L. Kotelevets, J. van Hengel, E. Bruyneel, M. Mareel, F. van Roy, and E. Chastre The lipid phosphatase activity of PTEN is critical for stabilizing intercellular junctions and reverting invasiveness J. Cell Biol., December 24, 2001; 155(7): 1129 - 1136. [Abstract] [Full Text] [PDF]
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