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Clinical Cancer Research 13, 7003, December 1, 2007. doi: 10.1158/1078-0432.CCR-07-1263
© 2007 American Association for Cancer Research
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Imaging, Diagnosis, Prognosis

A Switch from E-Cadherin to N-Cadherin Expression Indicates Epithelial to Mesenchymal Transition and Is of Strong and Independent Importance for the Progress of Prostate Cancer

Karsten Gravdal1, Ole J. Halvorsen1, Svein A. Haukaas2 and Lars A. Akslen1

Authors' Affiliations: 1 The Gade Institute, Section for Pathology and 2 Department of Surgical Sciences, University of Bergen, Haukeland University Hospital, Bergen, Norway

Requests for reprints: Lars A. Akslen, The Gade Institute, Section for Pathology, University of Bergen, Haukeland University Hospital, N-5021 Bergen, Norway. Phone: 47-55-973182/973173; Fax: 47-55-973158; E-mail: Lars.Akslen{at}Gades.uib.no.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: Cell adhesion molecules are of crucial importance in cancer invasion and metastasis. Epithelial to mesenchymal transition, characterized by reduced E-cadherin and increased N-cadherin expression, has been recognized as a feature of aggressive tumors, but the importance of this phenotype has not been settled in human prostate cancer. We here present novel data, with special focus on the independent relationship between an E-cadherin to N-cadherin switch (EN-switch) and patient prognosis.

Experimental Design: Tissue microarray sections from a consecutive series of 104 radical prostatectomies during 1988 to 1994 with detailed clinicopathologic data and long follow-up were studied immunohistochemically for the expression of E-cadherin, N-cadherin, P-cadherin, β-catenin, and p120CTN.

Results: Low E-cadherin expression was significantly associated with adverse clinicopathologic features, whereas other biomarkers were mostly related to Gleason score. In univariate survival analyses, cadherin switching (high N-cadherin and low E-cadherin) showed strong and significant associations with multiple end points of progression and cancer-specific death. Expression of the "basal cell marker" P-cadherin was associated with shorter time to skeletal metastasis (P = 0.036). In multivariate analysis of time to clinical recurrence, the "EN-switch" (hazard ratio, 4.3; P < 0.0005) had strong and independent prognostic effect, together with Gleason score.

Conclusion: These novel data unravel the importance of epithelial to mesenchymal transition for prostate cancer progression, and demonstration of a switch from E-cadherin to N-cadherin expression could have significant effect on the care of prostate cancer patients.

There is currently a need for improved prediction of long-term outcome in patients with clinically localized prostate cancer (1, 2). Among important molecular determinants, alterations in cell adhesion molecules are involved in both embryologic development and tumor progression (3). The classic cadherins (E-cadherin, N-cadherin, and P-cadherin) are transmembrane adhesion glycoproteins (4), which link to the actin cytoskeleton by different catenins (5). As a feature of aggressive tumors, epithelial to mesenchymal transition (EMT) is characterized by reduced E-cadherin and increased N-cadherin expression, contributing to a stroma-oriented cellular adhesion profile with increased tumor cell motility and invasive properties, and this molecular profile has recently been reported in several tumors (6–8). However, it is not known whether the EMT phenotype is important for the progress and prognosis of human prostate cancer. Some studies have indicated reduced E-cadherin expression in subgroups of aggressive prostate cancer (9, 10). One study showed N-cadherin positivity in only 5% of prostatic cancers, but with no clinicopathologic correlations (11), whereas another report showed no expression (12). Simultaneous up-regulation of N-cadherin and down-regulation of E-cadherin have been found in more aggressive prostate cancer cell lines (6, 13, 14), but survival data related to the EMT profile are lacking.

P-cadherin is expressed mostly in basal and proliferating layers of epithelia and decreases with cellular differentiation (15). In breast cancer, increased expression has been related to the "basaloid phenotype" and a worse prognosis (16). In benign prostate tissue, P-cadherin has been promoted as a novel basal cell marker (17, 18) but has also been variably detected in subgroups of prostate cancers (12, 18, 19). Prognostic implications of this finding are not known.

β-Catenin and p120CTN are attached to the cadherin complex (5, 20) and are required for the adhesive properties of classic cadherins (20). Reduced membranous β-catenin and p120CTN, and increased expression of nuclear β-catenin, have been associated with aggressive prostate cancer (11, 21–24), but no significant survival differences were noted for p120CTN (11, 24).

On this background, the aim of our study was to examine a panel of cell adhesion molecules (E-cadherin, N-cadherin, P-cadherin, β-catenin, and p120CTN) with reference to clinicopathologic phenotype and prognostic information in prostate cancer and with special focus on the significance of EMT.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Patients
As described previously (25, 26), a consecutive series of 104 men treated by radical prostatectomy for clinically localized prostate cancer during 1988 to 1994, with long and complete follow-up, was included. Clinical stage T1/T2 disease, negative bone scan, and generally good health were the prerequisites for radical retropubic prostatectomy. The majority of cancers in this series are clinical stage T2 and presented before the prostate-specific antigen (PSA) era started in Norway in the mid-1990s. Consequently, the prevalence of adverse prognostic factors, such as capsular penetration, seminal vesicle invasion, and positive surgical margins, is rather high compared with most contemporary series. No patients treated by radical prostatectomy received radiotherapy before biochemical failure or clinical recurrence.

Clinicopathologic variables
Two separate Gleason scores were recorded: one standard score from radical prostatectomy specimens and one local score on the 1 to 2 cm2 tumor area from which tissue microarray samples were punched. Further, WHO histologic grade (26), largest tumor dimension, capsular penetration, seminal vesicle invasion, involvement of surgical margins, presence of lymph node and skeletal metastasis, clinical and pathologic stage, and serum PSA (s-PSA) level before and after surgical treatment were recorded. Tumor cell proliferation (Ki-67; ref. 27), microvessel density (26), vascular proliferation index (25), glomeruloid microvascular proliferation (28), and expression of PTEN (29) and p27 (29) were included from previous studies for comparison.

Tissue sampling
The entire prostate was cut into 5-mm transverse serial sections. Based on H&E-stained slides, the area of highest histologic tumor grade was identified and cut out of the paraffin blocks, reembedded in paraffin, and sectioned for immunohistochemistry for estimation of Ki-67 (27), microvessel density (26), vessel proliferation by Ki-67/F-VIII double staining (25), and glomeruloid microvascular proliferation (28).

Tissue microarrays
The tissue microarray technique has been described and validated in several studies (30–33). This method has been used in our studies of prostate cancers (25, 29) and expression of cell adhesion markers in other tumors (34, 35). Representative tumor areas were identified on H&E slides, and three tissue cylinders (diameter of 0.6 mm) were punched from the donor block and mounted into a recipient paraffin block (30).

Immunohistochemistry
Immunohistochemical staining was done on formalin-fixed and paraffin-embedded tissue using 5-µm sections from tissue microarray blocks as described (25). Western blot analysis confirming the specificity of the antibodies against E-cadherin, N-cadherin, P-cadherin, and β-catenin has been done and described in a recent report from our research group (35).

E-cadherin. After microwave antigen retrieval (boiling for 15 min at 350 W) in citrate buffer (pH 6.0), slides were incubated overnight at 4°C with the monoclonal mouse E-cadherin antibody M3612 (diluted 1:400; DAKO). Staining was done on TechMate 500 automated slide processing equipment (DAKO).

N-cadherin. After boiling in Tris-EDTA buffer (pH 9.0) for 20 min at 350 W, sections were incubated for 1 h at room temperature with the monoclonal mouse antibody M3613 (diluted 1:25; DAKO).

P-cadherin. After boiling for 20 min at 350 W in target retrieval solution (DAKO) buffer (pH 6.0), an autostainer (DAKO) was used for staining, with incubation for 1 h at room temperature with the monoclonal mouse antibody C24120 (diluted 1:100; BD Transduction Laboratories).

β-catenin. After microwave retrieval in citrate buffer (pH 6.0; boiling for 15 min at 350 W), tissue microarray slides were incubated for 25 min at room temperature with the monoclonal mouse antibody (clone 14; diluted 1:800; BD Transduction Laboratories) using TechMate 500 automated slide processing equipment for staining.

p120CTN. After boiling for 15 min at 500 W in target retrieval solution buffer (pH 6.0), an autostainer was used with incubation for 1 h at room temperature with a monoclonal mouse antibody (clone 98; diluted 1:3,000; BD Transduction Laboratories).

Staining for N-cadherin, P-cadherin, and p120CTN was done using the EnVision-labeled polymer method, with commercial kits (DAKO). For E-cadherin and β-catenin, the standard avidin-biotin method was used. The peroxidase was localized by the diaminobenzidine tetrachloride peroxidase reaction and counterstained with Mayer's hematoxylin. Negative controls were obtained using isotypic mouse immunoglobulin (IgG1). Samples with known reactivity were used as positive controls (e.g., liver, colon, epidermis, endometrium, and multitissue sections).

Evaluation of staining results in prostate tissues
E-cadherin stained cell membranes consistently in benign and variably in malignant epithelium (Fig. 1A and B ). N-cadherin was negative in benign epithelium; mostly incomplete but distinct membranous staining was found in a subgroup of cancers (Fig. 1C and D). Cytoplasmic N-cadherin staining with variable intensity was also recorded. P-cadherin stained basal cells. In malignant cells, positive cases showed mixed cytoplasmic and membranous staining (Fig. 1F); other cases were weak or negative (Fig. 1E). β-Catenin showed a mixed cytoplasmic and membranous staining in benign epithelium; both membranous and nuclear staining were found in malignant epithelium (Fig. 1G and H), and these were positively correlated (P = 0.008). p120CTN showed membranous staining particularly in basal cells, and variable membranous staining was recorded in malignant epithelium (Fig. 1I and J). No nuclear staining was observed.


Figure 1
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  		Fig. 1. Left, immunohistochemical staining of prostatic carcinomas. Strong membrane E-cadherin (A) and weak E-cadherin (B) in tumor cells surrounding a benign gland. C, negative N-cadherin. D, positive membranous N-cadherin. E, weak P-cadherin. F, strong membranous and cytoplasmic P-cadherin. G, strong membranous expression of β-catenin. H, weak β-catenin. I, strong membranous expression of p120CTN. J, negative p120CTN. Magnification, x400. Bar, 50 µm. Right, univariate survival analyses according to the Kaplan-Meier method by the "EN-switch" (subgroup with combined weak E-cadherin and strong N-cadherin expression) with biochemical failure (K), clinical recurrence (L), locoregional recurrence (M), skeletal metastases (N), and cancer-specific patient survival (O) as end points.

 
For all factors, a staining index (SI; values 0-9) was calculated as a product of staining intensity (0-3) and proportion of positive cells (0% = 0, 1-10% = 1, 11-50% = 2, >50% = 3; ref. 36). Cutoff points for SI categories were mostly based on median values, considering the frequency distribution for each marker; categories with similar survival estimates were merged when appropriate. E-cadherin, membranous β-catenin, and p120CTN were categorized by median values as strong (SI > 4) or weak (0-4). Membranous N-cadherin and P-cadherin as well as nuclear β-catenin expression were divided by negative (SI = 0) or positive (SI ≥ 1) staining, and cytoplasmic N-cadherin and cytoplasmic P-cadherin were divided by their median values as strong (SI > 3) or weak (0-3).

Follow-up
Postoperatively, s-PSA, locoregional tumor recurrences, distant metastases, and patient survival were recorded (26). Time from surgery until biochemical failure (defined as persistent or rising s-PSA level of >0.5 ng/mL in two consecutive blood samples) was noted. Further, a tumor in the prostatic fossa or evidence of distant metastasis on bone scan, X-ray, or magnetic resonance imaging was recorded as clinical recurrence. The last time of follow-up was December 2001 (25). Median follow-up time was 95 months (7.9 years). No patients were lost because of insufficient data. Sixty-seven patients experienced biochemical failure, 31 patients had clinical recurrence, and 9 patients died of prostate cancer.

Statistics
Associations between variables were assessed by Pearson's {chi}2 test or the Mann-Whitney U test. Univariate survival analysis was done by the Kaplan-Meier method (log-rank test), and multivariate survival analysis was done by the proportional hazards method (likelihood ratio test). Model assumptions were examined by log-log plots. The Statistical Package for the Social Sciences statistical package 13.0 (SPSS, Inc.) was used.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Clinicopathologic characteristics
Largest tumor dimension (median) was 28 mm (range, 10-45 mm). Fifteen tumors (14.4%) had a standard Gleason score of 0 to 6, 34 tumors (32.7%) had a Gleason score of 3 + 4, 33 tumors (31.7%) had a Gleason score of 4 + 3, and 22 tumors (21.2%) had score of 8 to 10. Standard Gleason score was significantly correlated with local Gleason score (Spearman's rho = 0.65; P < 0.0005). Capsular penetration was shown in 72 cases (69.2%), seminal vesicle invasion in 35 cases (33.7%), and positive surgical margins in 55 cases (52.9%). Pelvic lymph node infiltration was found in seven patients (6.7%) at time of surgery. The median preoperative s-PSA was 11.2 ng/mL (range, 1.8-70.0). More details are available (26).

Cell adhesion markers
E-cadherin. Weak membrane expression (36%) was significantly associated with all adverse clinicopathologic variables (Table 1 ), including poor WHO histologic grade (P = 0.001).


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  		Table 1. Associations between E-cadherin, N-cadherin, and P-cadherin expression and clinicopathologic features in 104 patients with clinically localized prostatic adenocarcinoma (radical prostatectomies)

 
N-cadherin. Positive membranous expression (34%) was associated with poor WHO histologic differentiation (P = 0.030), seminal vesicle invasion (P = 0.006), and pelvic lymph node infiltration (P = 0.029; Table 1). Local Gleason score ≥4 + 3 showed a trend (P = 0.083). Cytoplasmic N-cadherin expression was associated with increased proliferation by Ki-67 (P = 0.012).

P-cadherin. Positive membranous expression (44%) was significantly related to increased local Gleason score ≥4 + 3 (P = 0.002) and to the poorly differentiated group by WHO (P = 0.04).

β-catenin. Weak membranous expression (44%) was significantly related to standard Gleason score ≥4 + 3 (P = 0.008; Table 2 ), poor WHO histologic grade (P = 0.036), and increased preoperative s-PSA (P = 0.019). Positive nuclear expression (47%) was related to the poorly differentiated group by WHO (P = 0.033) and presence of glomeruloid microvascular proliferations (P = 0.05).


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  		Table 2. Associations between membranous and nuclear β-catenin expression, p120CTN, and clinicopathologic features in 104 patients with clinically localized prostatic adenocarcinoma (radical prostatectomies)

 
p120CTN. Weak membranous expression (50%) was significantly associated with standard Gleason score ≥4 + 3 (P = 0.003), pelvic lymph node infiltration (P = 0.013; Table 2), and advanced clinical stage (P = 0.047).

Associations among cell adhesion markers
Weak expression of membranous E-cadherin was strongly associated with presence of membranous N-cadherin (P < 0.0005), presence of membranous P-cadherin (P < 0.0005), weak membranous expression of β-catenin (P < 0.0005), and weak expression of membranous p120CTN (P < 0.0005). A nonsignificant trend was observed between presence of membranous P-cadherin and presence of membranous N-cadherin (P = 0.14). Both presence of membranous N-cadherin (P = 0.002) and presence of P-cadherin (P = 0.006) were related to weak expression of membranous p120CTN. Weak membrane staining of β-catenin was significantly associated with weak membrane expression of p120CTN (P < 0.0005).

Associations with other biomarkers and tumor-associated angiogenesis
Significant alterations of p27 and PTEN have previously been reported in this series (29). Weak E-cadherin (P < 0.0005) and weak membranous β-catenin expression (P < 0.0005), as well as positive N-cadherin (P = 0.001) and P-cadherin expression (P = 0.006), were all related to low expression of p27. Weak E-cadherin (P = 0.015) and positive membranous P-cadherin expression (P = 0.039) were associated with low PTEN expression.

The prognostic significance of microvessel density and vascular proliferation index has previously been studied in this material (25, 26), and these angiogenic markers were not associated with any of the five cell adhesion proteins.

Univariate survival analysis
E-cadherin. Weak membrane expression was strongly associated with shorter time to biochemical failure, clinical recurrence (Table 3 ; Fig. 2 ), locoregional recurrence (P = 0.011), skeletal metastasis (P = 0.003), and cancer-specific death (P = 0.012).


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  		Table 3. Univariate survival analysis (Kaplan-Meier method) by expression of E-cadherin, N-cadherin, P-cadherin, β-catenin, and p120CTN in tumor cells using time to biochemical failure or clinical recurrence after radical prostatectomy in 104 prostatic cancer patients

 

Figure 2
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  		Fig. 2. Univariate survival analyses according to the Kaplan-Meier method by E-cadherin (A), N-cadherin (B), P-cadherin (C), β-catenin (D), and p120CTN (E), with clinical recurrence in prostate cancer as end point.

 
N-cadherin. Positive membrane expression was associated with shorter time to biochemical failure, clinical recurrence (Table 3; Fig. 2), and skeletal metastasis (P = 0.046). No significant differences were found for cytoplasmic expression.

EN-switch. Univariate survival analyses were also done for the EN-switch (weak E-cadherin and positive N-cadherin, n = 23; 22%). This subgroup was strongly associated with shorter time to all five end points (Fig. 1).

P-cadherin. Positive membrane staining was significantly associated with shorter time to skeletal metastases (P = 0.036), and nonsignificant trends with shorter time to biochemical failure and clinical recurrence (Table 3; Fig. 2) were observed. No significant differences were found for cytoplasmic expression.

β-Catenin. No significant survival differences were observed (Table 3; Fig. 2).

p120CTN. Weak membrane expression was associated with shorter time to biochemical failure, clinical recurrence (Table 3; Fig. 2), locoregional recurrence (P = 0.034), and cancer-specific death (P = 0.023).

Multivariate survival analysis
Cell adhesion markers (E-cadherin, N-cadherin, P-cadherin, β-catenin, and p120CTN) with P values of <0.15 in univariate survival analyses were included together with preoperative s-PSA, standard Gleason score (≤3 + 4 versus ≥4 + 3), and pathologic stage.

When including individual variables in a simultaneous model (excluding the combined EN-status), E-cadherin [hazard ratio (HR), 2.5; P = 0.019], N-cadherin (HR, 5.6; P = 0.003), and standard Gleason score (HR, 4.3; P = 0.002) were all independent predictors of time to clinical recurrence, whereas E-cadherin (HR, 1.8; P = 0.02), standard Gleason score (HR, 2.9; P < 0.0005), and pathologic stage (HR, 2.7; P = 0.001) all had an independent prognostic effect on time to biochemical failure. In contrast, P-cadherin, β-catenin, or p120CTN did not show independent prognostic effect for any of these end points.

In a final simultaneous model, excluding E-cadherin and N-cadherin, the EN-status (weak E-cadherin and strong N-cadherin), as an indication of EMT in prostate cancers, consistently showed an independent prognostic effect, stronger than for E-cadherin and N-cadherin separately, together with Gleason score (≤3 + 4 versus ≥4 + 3) using both biochemical failure and clinical recurrence as end points (Table 4 ).


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  		Table 4. Final multivariate survival analysis according to Cox proportional hazards method for patients with clinically localized prostate cancer using biochemical failure or clinical recurrence as end points

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
The prognosis of patients with clinically localized prostate cancer cannot be accurately predicted by standard variables such as preoperative s-PSA, Gleason score, and pathologic stage alone, and there is a need for supplementary prognostic factors (2). The aim of the present study was to explore the significance of cell adhesion markers in comparison with the above-mentioned "triad." As a novel finding, increased expression of N-cadherin was a strong and independent predictor of clinical recurrence after radical prostatectomy.

We here show an independent prognostic significance of reduced E-cadherin expression as found by others (9–11, 37–40). Reduced expression of E-cadherin in prostate cancer may be caused by DNA hypermethylation (41) and transcriptional (42) and posttranslational mechanisms (43) but probably not DNA mutations (38). E-cadherin repression seems to be a dynamic and partly reversible process, and reexpression has been observed in metastatic prostate cancer (38, 43).

In our series, E-cadherin was not associated with preoperative s-PSA. One explanation might be that lowered E-cadherin is a marker of biological aggressiveness, whereas s-PSA is only a marker of tumor volume. Indeed, high preoperative s-PSA predicted advanced pathologic stage (pT3) but was without independent prognostic effect in predicting clinical recurrence after surgical treatment.

Importantly, a "cadherin switch" with increased N-cadherin and reduced E-cadherin expression had an independent prognostic effect on time to both biochemical failure and clinical recurrence in multivariate survival analyses, stronger than for E-cadherin or N-cadherin separately. Survival data for N-cadherin have not been previously reported for prostate cancer. N-cadherin expression contributes to a stroma-oriented cellular adhesion profile with increased tumor cell motility and invasive properties, indicating a possible EMT (6–8). Thus, cell adhesion molecules might add prognostic information beyond that presently given by histologic evaluation alone (44). Supporting our findings, soluble E-cadherin and N-cadherin were recently studied as serum biomarkers in prostate cancer, suggesting increased level of N-cadherin as a marker of ongoing EMT and tumor progress (45, 46). The higher frequency of positive N-cadherin staining compared with two other studies (11, 12) may be a result of increased detection using a different antibody validated by Western blot (35) in our lab.

Strong P-cadherin staining was found in the basal cell compartment, and this is in concert with earlier studies (12, 17–19). Further, P-cadherin was found to be reexpressed in a subset of prostate cancers, indicating a worse outcome although without independent prognostic power. This seems to be similar to P-cadherin as a myoepithelial marker in benign breast tissues, being reexpressed in the basaloid phenotype of more aggressive breast cancer (16). According to our demonstration of significant associations between both N-cadherin and P-cadherin with reduced E-cadherin-expression, the term cadherin switch should also include reexpression of P-cadherin in some prostate cancers. However, no independent prognostic effect was observed for P-cadherin, β-catenin, or p120CTN, and these factors seem to be less important for prognostication.

In the present study, we asked whether there was an association between alterations of cell adhesion molecules, as evidence of EMT, and activation of the vascular system. Interestingly, one study showed a correlation between increased hypoxia-inducible factor and down-regulated E-cadherin in renal cell carcinoma (47), indicating a relationship between these pathways. However, we could not find any evidence for such a relationship, as none of the cadherins were linked to vascular related factors, such as microvessel density or vascular proliferation.

As a novel finding, our present data strongly suggest the importance of EMT (increased N-cadherin and decreased E-cadherin expression) for the progression and patient prognosis of human prostate cancer. Whereas previous findings have indicated reduced E-cadherin expression in prostate cancer subgroups (9, 10), an EMT phenotype and its association with outcome data have not been presented. Because this marker could have significant effect on the care of prostate cancer patients, including prospects of targeted therapy (48, 49), we suggest larger prospective studies to further validate our findings.


   Acknowledgments
 
We thank Karen Bøhm-Nilsen, Gerd Lillian Hallseth, Bendik Nordanger, and Grethe Waaler for excellent technical assistance.


   Footnotes
 
Grant support: Cancer Society of Norway, Norwegian Research Council, and Helse Vest Research Fund.

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.

Note: This study was approved by The Regional Ethical Committee for Medical Research.

Received 5/22/07; revised 7/18/07; accepted 8/16/07.


   References
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

  1. Quinn DI, Henshall SM, Sutherland RL. Molecular markers of prostate cancer outcome. Eur J Cancer 2005;41:858–87.[CrossRef][Medline]
  2. Albertsen PC, Hanley JA, Fine J. 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA 2005;293:2095–101.[Abstract/Free Full Text]
  3. Hirohashi S, Kanai Y. Cell adhesion system and human cancer morphogenesis. Cancer Sci 2003;94:575–81.[CrossRef][Medline]
  4. Gumbiner BBM. Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell 1996;84:345–57.[CrossRef][Medline]
  5. Kemler R. From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet 1993;9:317–21.[CrossRef][Medline]
  6. Tran NL, Nagle RB, Cress AE, Heimark RL. N-cadherin expression in human prostate carcinoma cell lines. An epithelial-mesenchymal transformation mediating adhesion with stromal cells. Am J Pathol 1999;155:787–98.[Abstract/Free Full Text]
  7. Christiansen JJ, Rajasekaran AK. Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 2006;66:8319–26.[Abstract/Free Full Text]
  8. Kang Y, Massague J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 2004;118:277–9.[CrossRef][Medline]
  9. Richmond PJ, Karayiannakis AJ, Nagafuchi A, Kaisary AV, Pignatelli M. Aberrant E-cadherin and {alpha}-catenin expression in prostate cancer: correlation with patient survival. Cancer Res 1997;57:3189–93.[Abstract/Free Full Text]
  10. Umbas R, Isaacs WB, Bringuier PP, et al. Decreased E-cadherin expression is associated with poor prognosis in patients with prostate cancer. Cancer Res 1994;54:3929–33.[Abstract/Free Full Text]
  11. Kallakury BV, Sheehan CE, Ross JS. Co-downregulation of cell adhesion proteins {alpha}- and β-catenins, p120CTN, E-cadherin, and CD44 in prostatic adenocarcinomas. Hum Pathol 2001;32:849–55.[CrossRef][Medline]
  12. Soler AP, Harner GD, Knudsen KA, et al. Expression of P-cadherin identifies prostate-specific-antigen-negative cells in epithelial tissues of male sexual accessory organs and in prostatic carcinomas. Implications for prostate cancer biology. Am J Pathol 1997;151:471–8.[Abstract]
  13. Jennbacken K, Gustavsson H, Welen K, Vallbo C, Damber JE. Prostate cancer progression into androgen independency is associated with alterations in cell adhesion and invasivity. Prostate 2006;66:1631–40.[CrossRef][Medline]
  14. Bussemakers MJ, Van Bokhoven A, Tomita K, Jansen CF, Schalken JA. Complex cadherin expression in human prostate cancer cells. Int J Cancer 2000;85:446–50.[CrossRef][Medline]
  15. Shimoyama Y, Hirohashi S, Hirano S, et al. Cadherin cell-adhesion molecules in human epithelial tissues and carcinomas. Cancer Res 1989;49:2128–33.[Abstract/Free Full Text]
  16. Arnes JB, Brunet JS, Stefansson I, et al. Placental cadherin and the basal epithelial phenotype of BRCA1-related breast cancer. Clin Cancer Res 2005;11:4003–11.[Abstract/Free Full Text]
  17. Jarrard DF, Paul R, van Bokhoven A, et al. P-cadherin is a basal cell-specific epithelial marker that is not expressed in prostate cancer. Clin Cancer Res 1997;3:2121–8.[Abstract]
  18. Wang J, Krill D, Torbenson M, et al. Expression of cadherins and catenins in paired tumor and non-neoplastic primary prostate cultures and corresponding prostatectomy specimens. Urol Res 2000;28:308–15.[CrossRef][Medline]
  19. Arenas MI, Romo E, Royuela M, Fraile B, Paniagua R. E-, N- and P-cadherin, and {alpha}-, β- and {gamma}-catenin protein expression in normal, hyperplastic and carcinomatous human prostate. Histochem J 2000;32:659–67.[CrossRef][Medline]
  20. Behrens J, Vakaet L, Friis R, et al. Loss of epithelial differentiation and gain of invasiveness correlates with tyrosine phosphorylation of the E-cadherin/β-catenin complex in cells transformed with a temperature-sensitive v-SRC gene. J Cell Biol 1993;120:757–66.[Abstract/Free Full Text]
  21. Jaggi M, Johansson SL, Baker JJ, Smith LM, Galich A, Balaji KC. Aberrant expression of E-cadherin and β-catenin in human prostate cancer. Urol Oncol 2005;23:402–6.[Medline]
  22. Aaltomaa S, Karja V, Lipponen P, et al. Reduced {alpha}- and β-catenin expression predicts shortened survival in local prostate cancer. Anticancer Res 2005;25:4707–12.[Abstract/Free Full Text]
  23. Lu Q, Dobbs LJ, Gregory CW, et al. Increased expression of {delta}-catenin/neural plakophilin-related armadillo protein is associated with the down-regulation and redistribution of E-cadherin and p120ctn in human prostate cancer. Hum Pathol 2005;36:1037–48.[CrossRef][Medline]
  24. Kallakury BV, Sheehan CE, Winn-Deen E, et al. Decreased expression of catenins ({alpha} and β), p120 CTN, E-cadherin cell adhesion proteins and E-cadherin gene promoter methylation in prostatic adenocarcinomas. Cancer 2001;92:2786–95.[CrossRef][Medline]
  25. Gravdal K, Halvorsen OJ, Haukaas SA, Akslen LA. Expression of bFGF/FGFR-1 and vascular proliferation related to clinicopathologic features and tumor progress in localized prostate cancer. Virchows Archiv 2006;448:68–74.[CrossRef][Medline]
  26. Halvorsen OJ, Haukaas S, Hoisaeter PA, Akslen LA. Independent prognostic importance of microvessel density in clinically localized prostate cancer. Anticancer Res 2000;20:3791–9.[Medline]
  27. Halvorsen OJ, Haukaas S, Hoisaeter PA, Akslen LA. Maximum Ki-67 staining in prostate cancer provides independent prognostic information after radical prostatectomy. Anticancer Res 2001;21:4071–6.[Medline]
  28. Straume O, Chappuis PO, Salvesen HB, et al. Prognostic importance of glomeruloid microvascular proliferation indicates an aggressive angiogenic phenotype in human cancers. Cancer Res 2002;62:6808–11.[Abstract/Free Full Text]
  29. Halvorsen OJ, Haukaas SA, Akslen LA. Combined loss of PTEN and p27 expression is associated with tumor cell proliferation by Ki-67 and increased risk of recurrent disease in localized prostate cancer. Clin Cancer Res 2003;9:1474–9.[Abstract/Free Full Text]
  30. Hoos A, Urist MJ, Stojadinovic A, et al. Validation of tissue microarrays for immunohistochemical profiling of cancer specimens using the example of human fibroblastic tumors. Am J Pathol 2001;158:1245–51.[Abstract/Free Full Text]
  31. Straume O, Akslen LA. Importance of vascular phenotype by basic fibroblast growth factor, and influence of the angiogenic factors basic fibroblast growth factor/fibroblast growth factor receptor-1 and ephrin-A1/EphA2 on melanoma progression. Am J Pathol 2002;160:1009–19.[Abstract/Free Full Text]
  32. Kononen J, Bubendorf L, Kallioniemi A, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 1998;4:844–7.[CrossRef][Medline]
  33. Nocito A, Bubendorf L, Maria Tinner E, et al. Microarrays of bladder cancer tissue are highly representative of proliferation index and histological grade. J Pathol 2001;194:349–57.[CrossRef][Medline]
  34. Stefansson IM, Salvesen HB, Akslen LA. Prognostic impact of alterations in P-cadherin expression and related cell adhesion markers in endometrial cancer. J Clin Oncol 2004;22:1242–52.[Abstract/Free Full Text]
  35. Bachmann IM, Straume O, Puntervoll HE, Kalvenes MB, Akslen LA. Importance of P-cadherin, β-catenin, and Wnt5a/frizzled for progression of melanocytic tumors and prognosis in cutaneous melanoma. Clin Cancer Res 2005;11:8606–14.[Abstract/Free Full Text]
  36. Aas T, Borresen AL, Geisler S, et al. Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med 1996;2:811–4.[CrossRef][Medline]
  37. Cheng L, Nagabhushan M, Pretlow TP, Amini SB, Pretlow TG. Expression of E-cadherin in primary and metastatic prostate cancer. Am J Pathol 1996;148:1375–80.[Abstract]
  38. De Marzo AM, Knudsen B, Chan-Tack K, Epstein JI. E-cadherin expression as a marker of tumor aggressiveness in routinely processed radical prostatectomy specimens. Urology 1999;53:707–13.[CrossRef][Medline]
  39. Koksal IT, Ozcan F, Kilicaslan I, Tefekli A. Expression of E-cadherin in prostate cancer in formalin-fixed, paraffin-embedded tissues: correlation with pathological features. Pathology 2002;34:233–8.[CrossRef][Medline]
  40. Wu TT, Hsu YS, Wang JS, Lee YH, Huang JK. The role of p53, bcl-2 and E-cadherin expression in predicting biochemical relapse for organ confined prostate cancer in Taiwan. J Urol 2003;170:78–81.[CrossRef][Medline]
  41. Graff JR, Herman JG, Lapidus RG, et al. E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res 1995;55:5195–9.[Abstract/Free Full Text]
  42. Elloul S, Elstrand MB, Nesland JM, et al. Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer 2005;103:1631–43.[CrossRef][Medline]
  43. Rubin MA, Mucci NR, Figurski J, Fecko A, Pienta KJ, Day ML. E-cadherin expression in prostate cancer: a broad survey using high-density tissue microarray technology. Hum Pathol 2001;32:690–7.[CrossRef][Medline]
  44. Ohmori H, Fujii K, Sasahira T, et al. Determinants for prediction of malignant potential by metalloproteinase:E-cadherin ratio in prostate core needle biopsy. Pathobiology 2006;73:98–104.[CrossRef][Medline]
  45. Kuefer R, Hofer MD, Zorn CS, et al. Assessment of a fragment of e-cadherin as a serum biomarker with predictive value for prostate cancer. Br J Cancer 2005;92:2018–23.[CrossRef][Medline]
  46. Derycke L, De Wever O, Stove V, et al. Soluble N-cadherin in human biological fluids. Int J Cancer 2006;119:2895–900.[CrossRef][Medline]
  47. Esteban MA, Tran MG, Harten SK, et al. Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer Res 2006;66:3567–75.[Abstract/Free Full Text]
  48. Mariotti A, Perotti A, Sessa C, Ruegg C. N-cadherin as a therapeutic target in cancer. Expert Opin Investig Drugs 2007;16:451–65.[CrossRef][Medline]
  49. Cavallaro U. N-cadherin as an invasion promoter: a novel target for antitumor therapy? Curr Opin Investig Drugs 2004;5:1274–8.[Medline]



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