Abstract
Background
We analyzed immunoexpression of Dysadherin, E-cadherin and ß-catenin proteins in prostate.
Methods
53 radical prostatectomy specimens were included. Dysadherin, E-cadherin and ß-catenin were evaluated in prostatic adenocarcinoma and in adjacent non–tumorous tissue, and correlated with clinicomorphological features in prostatic adenocarcinoma.
Results
We report cytoplasmic/membraneous and nuclear staining for Dysadherin in prostatic tissue. Cytoplasmic/membraneous expression was stronger in prostatic adenocarcinoma when compared to adjacent non-tumorous prostatic tissue (p < 0.001).
Dysadherin positively correlated with T status (rho = 0.326, P = 0.017) and Grade Group (rho = 0.278, P = 0.044). We report no correlation with recurrence, surgical margins status, sPSA and N status. E-cadherin was negatively correlated with recurrence (rho = −0.297, P = 0.031), T status (rho = −0.430, P = 0.001), Grade Group (rho = −0.558, P < 0.001) and positive surgical margins (rho = −0.404, P = 0.003). ß-catenin negatively correlated with Grade Group (rho = −0.557, P < 0,001). No correlation was observed between Dysadherin and E-cadherin and Dysadherin and ß-catenin expression.
Conclusion
Our results suggest a potential role for Dysadherin in tumor progression. No significant correlation between Dysadherin and E-cadherin or ß-catenin indicates potential independence of Dysadherin in its regulatory role in prostatic adenocarcinoma.
Keywords: Dysadherin, E-cadherin, ß-catenin, prostate, adenocarcinoma, cell adhesion
ARTICLE HIGHLIGHTS
Dysadherin as a Biomarker in Prostate Cancer: This study investigates the expression of Dysadherin in prostatic adenocarcinoma and its adjacent non-tumorous tissue, highlighting its role in tumor aggressiveness and progression. Dysadherin is identified as a potential biomarker due to its association with higher Grade Group and T stage.
Differential Expression Patterns: Dysadherin showed significantly higher cytoplasmic/membranous expression in prostatic adenocarcinoma compared to adjacent non-tumorous tissue (p < 0.001). Nuclear Dysadherin expression was observed in both tumor and non-tumorous tissues, with no significant difference, indicating potential alternative roles beyond cell adhesion.
E-cadherin as a Prognostic Marker: E-cadherin expression was inversely correlated with tumor aggressiveness. Reduced E-cadherin levels were associated with higher Grade Group (rho = −0.558, p < 0.001), T status (rho = −0.430, P = 0.001), surgical margin positivity (rho = −0.404, P = 0.003), and biochemical recurrence (rho = −0.297, P = 0.031). Strong E-cadherin expression was linked to longer recurrence-free survival (77.9 months) compared to weak or negative expression (52.7 months; P = 0.028).
β-Catenin and Tumor Aggressiveness: β-catenin expression demonstrated a significant negative correlation with tumor Grade Group (rho = −0.557, p < 0.001). Its cooperative role with E-cadherin in maintaining epithelial polarity and suppressing tumorigenesis was evident.
Lack of Correlation Between Dysadherin and Cell Adhesion Molecules: Dysadherin expression did not show a significant correlation with E-cadherin or β-catenin levels in prostatic adenocarcinoma. This suggests Dysadherin may function independently or through distinct mechanisms in modulating cell adhesion and tumor microenvironment dynamics.
Prognostic and Therapeutic Implications: Dysadherin’s expression profile aligns with markers of aggressive disease, yet its lack of direct correlation with survival underscores the complexity of its role in prostate cancer biology. The findings support Dysadherin’s potential as a biomarker while calling for larger, multicenter studies to validate its prognostic utility.
Emerging Mechanisms of Dysadherin: Beyond its established role in modulating cell adhesion, growing evidence suggests Dysadherin’s involvement in extracellular matrix remodeling, chemokine secretion, and immune modulation in the tumor microenvironment.
Epithelial-to-Mesenchymal Transition (EMT): Dysadherin’s relation with EMT-related pathways highlights its contribution to cancer cell invasiveness and metastasis. However, its relationship with key EMT markers in prostate cancer, such as E-cadherin and β-catenin, warrants further exploration.
Study Significance: This research is the first to analyze Dysadherin expression in prostate cancer in correlation with key clinicopathological parameters. The findings provide a foundation for future studies on Dysadherin’s role in cancer progression, with potential implicati patient stratification and targeted therapies.
Future Directions: Further research is needed to establish Dysadherin’s role in androgen receptor signaling, therapy resistance, and its interaction with the immune microenvironment. These insights could open avenues for novel biomarker-driven strategies in prostate cancer management.
1. Introduction
Recent advancements in cancer biology have underscored the importance of molecular markers in understanding tumor progression and metastasis. Dysadherin also known as FXYD5 protein is a member of the FXYD family of transmembrane proteins which regulate ion transport across cell membranes [1]. It is encoded by a cDNA that includes 178 amino acids, featuring a putative signal sequence, a potential O-glycosylated extracellular domain, a single transmembrane domain, and a short cytoplasmic tail.
In non-tumorous cells, Dysadherin has been identified through immunohistochemistry in lymphocytes, endothelial cells, and basal cells of the squamous epithelium. Through Western blotting analysis, Dysadherin was also detected in multiple epithelial tissues, and notably, it displayed increased abundance in the kidney cortex, intestinal duodenum, spleen, and lung [1]. In normal cellular contexts, dysadherin is not typically expressed at significant levels. Its expression is largely associated with malignant transformation and cancerous tissues. Dysadherin exhibits increased expression in a range of human cancers, including breast, lung, ovarian, pancreatic, gastric, thyroid, esophageal, colorectal, endometrial, cervical, testicular, malignant melanoma, and head and neck cancers [2–10]. Multiple studies have reported a significant correlation between Dysadherin upregulated expression and various clinicopathological characteristics, including distant metastasis, recurrence, and lower survival rates in cancer, associating it with cancer progression, as well as with the enhancement of cell migration and invasion [2–10]. As of now, it is understood that in cancer Dysadherin functions by modulating cell adhesion, extracellular matrix (ECM) remodeling, mechanotransduction, chemokine production, and key signaling pathways [1,11–14]. Dysadherin is considered to act as auxiliary subunits of the sodium pump (Na+/K+-ATPase). Ever since its initial report there has been substantial advocacy for Dysadherin’s role in altering cell-cell adhesion and, consequently, the architecture of epithelial tissues. One of the mechanisms through which Dysadherin affects cell-cell adhesion is believed to involve the downregulation of E-cadherin [1]. Nevertheless, in breast cancer cell lines expressing E-cadherin, even in cells lacking functional E-cadherin, knockdown of Dysadherin was found to suppress cell invasiveness, indicating the presence of a novel mechanism at play. Through global gene expression analysis, it was discovered that Dysadherin knockdown notably affected the expression of chemokine (C-C motif) ligand 2 (CCL2) transcripts in MDA-MB-231 cells. Furthermore, Dysadherin was found to regulate CCL2 expression, at least partially, by activating the nuclear factor-kappaB pathway [4,11]. Upregulation of CCL2 promotes tumor cell invasion and metastasis through autocrine and paracrine mechanisms and also is considered to contribute to the immunosuppressive and proangiogenic tumor microenvironment.
Recently is has been reported that Dysadherin interacts with matrix metalloproteinase 9 (MMP9), leading to ECM remodeling and thus enhances cancer cell invasiveness and activates cancer-associated fibroblasts, contributing to a pro-tumorigenic microenvironment [12]. It also binds to fibronectin, facilitating cancer cell adhesion and activating integrin-mediated mechanotransduction pathways [13], as well as activates Focal Adhesion Kinases (FAK), enhancing cell migration and invasion by modulating actin dynamics and focal adhesion turnover a signaling pathway which is critical for the formation of protrusive structures necessary for cell motility [14].
E-cadherin on the othe side acts as a tumor suppressor in epithelial tissue by maintaining cell-cell adhesion and tissue integrity. E-cadherin molecules on adjacent epithelial cells bind to each other through their extracellular domains, forming homotypic interactions that mediate strong cell-cell adhesion [15].
Its downregulation or loss is frequently observed in advanced stages of several epithelial carcinomas including prostatic adenocarcinoma. Reduced E-cadherin expression correlates with tumor invasion, migration, and the acquisition of a mesenchymal phenotype, indicative of epithelial-to-mesenchymal transition (EMT), a critical process in cancer progression and is reported to be associated with increased tumor aggressiveness, metastasis, and poor prognosis [15–18].
ß-catenin is a critical component of cell-cell adhesion complexes. The cytoplasmic tail of E-cadherin binds to ß-catenin, linking the cadherin complex to the actin cytoskeleton, stabilizing cell-cell junctions and contributing this way to tissue integrity and organization [15–19]. Moreover, ß-catenin is a key component of the Wnt signaling pathway [19]. E-cadherin and ß-catenin function cooperatively to suppress tumorigenesis by maintaining epithelial polarity and inhibiting cell motility and invasion in prostatic tissue.
The exploration of Dysadherin’s role in cancer biology has expanded significantly in recent years, with growing evidence pointing to its involvement in tumor progression and metastasis.
While there have been partial reports of Dysadherin expression in prostatic tissue in abstract form [20], its correlation with clinical and morphological characteristics in prostatic cancer has not been well documented. In our study, we aimed to address this gap and to elucidate Dysadherin’s role in prostatic adenocarcinoma tumor progression and its potential as a biomarker or therapeutic target. We evaluated Dysadherin expression in prostatic adenocarcinoma and adjacent non-tumorous tissue, and correlated its expression with structural proteins of cell junctions E-cadherin and ß-catenin as well as with tumor Grade Group, preoperative prostate specific antigen (sPSA), surgical margin status, biochemical recurrence (BCR) and the TNM staging in prostatic adenocarcinoma.
The dynamic interplay between Dysadherin, E-cadherin, and β-catenin in prostatic adenocarcinoma could provide clues about the mechanisms underpinning EMT in this specific cancer type. Furthermore, there is a potential role for Dysadherin in the context of targeted treatments and immune checkpoint inhibitors considering Dysadherin’s ability to influence chemokine secretion and modulate the tumor microenvironment which positions it as a potential mediator of immune evasion.
2. Patients and methods
2.1. Participants
The research was conducted in archival tissue specimens of prostatic adenocarcinoma and the adjacent non tumorous prostatic tissue, obtained by radical prostatectomy in the Department of Pathology «Ljudevit Jurak» of the Clinical Hospital Center «Sestre milosrdnice» in Zagreb, Croatia.
To safeguard patient confidentiality, we substituted patient identifiers with study numbers. We conducted the analysis on a total of 53 prostate samples that had been morphologically identified as prostatic adenocarcinoma, along with the adjacent non-tumorous tissue. Our selection criteria for including a tissue block in the study involved two key factors: the presence of identifiable prostatic adenocarcinoma and the availability of adjacent non-tumorous prostatic tissue. None of the patients had undergone preoperative hormonal therapy or radiotherapy. Additionally, the postoperative administration of hormonal therapy and/or radiotherapy did not influence our study results, as all samples were collected prior to the initiation of such treatments. This retrospective study was approved by the Ethical Committee School of Medicine, University of Zagreb, Croatia.
2.2. Methods
2.2.1. Hematoxilin and eosin
5 µm thick sections were cut from paraffin blocks containing prostatic lesional tissue fixed in 10% buffered formalyn, deparaffinized and stained with hematoxylin and eosin (H&E) for light microscope analysis.
2.2.2. Immunohistochemistry
Immunohistochemical analysis of the expression of Dysadherin (ab190957, polyclonal, 1:500 dilution, Abcam Cambridge, MA), E-cadherin (M3612, clone NCH-38, dilution 1:50, Dako, Glostrup, Denmark) and β-catenin (M3539, clone β-catenin-1, dilution 1:200, Dako, Glostrup, Denmark), proteins in tumorous and the adjacent non-tumorous prostatic tissue was performed using the EnVision Flex-system on a DakoTechMate TM immunohistochemical autostainer. Intratumoral lymphocytes and endothelial cells were used as a positive control for Dysadherin expression, and breast cancer tissue was used as a positive control for E-cadherin and β-catenin. Whereas, Mouse IgG1 (code X0931) was used as a negative control for all three biomarkers.
Expression of Dysadherin, E-cadherin and ß-catenin was assessed semi quantitatively as 0 (no staining), 1+ (weak), 2+ (moderate), and 3+ (strong). Dysadherin expression was evaluated based on its intensity and distribution in both cytoplasmic/membranous and nuclear compartments. Staining intensity was categorized as follows: 0: No detectable staining; 1+: Weak intensity staining present comparable to the positive control (adjacent lymphocytes/endothelial cells); 2+: Moderate intensity staining observed comparable to the positive control (adjacent lymphocytes/endothelial cells) control; 3+: Strong intensity staining, comparable to the positive control (adjacent lymphocytes/endothelial cells).
We defined positive Dysadherin expression as cells exhibiting staining intensity equal to or stronger than adjacent lymphocytes and endothelial cells, affecting more than 50% of the cell population. Negative or reduced expression was defined when fewer than 50% of cells exhibited staining or if the intensity was weaker than the positive control.
E-cadherin and ß-catenin expression was considered positive when more than 70% of tumor cells stained as strongly 3+ as normal epithelial cells adjacent to the tumor. Whereas it was considered negative when fewer than 70% of tumor cells were 3+ positive or when tumor cells stained more weakly than normal epithelial cells.
Dysadherin, E-cadherin and ß-catenin expression was evaluated in prostatic adenocarcinoma tissue and correlated with the expression in the adjacent non-tumorus tissue as well as with tumor Grade Group, sPSA, surgical margin status, BCR and the TNM staging in prostatic adenocarcinoma. BCR was defined specifically as a PSA level of ≥0.2 ng/mL following surgery.
2.3. Statistical methods
Data are presented as tables and graphs.
For all categorical variables, in addition to the absolute values and corresponding shares, the corresponding 95% confidence intervals were calculated. The critical z-score value for calculating the 95% confidence interval was 1.96. Differences in categorical variables were analyzed using the chi-square test. Spearman correlation coefficients were used for the correlations between the expression of Dysadherin, E-cadherin and ß-catenin with each other and with other clinical parameters. Kaplan-Meier curves with associated log-rank tests were used for survival analysis. All P-values less than 0.05 were considered significant. The MedCalc® Statistical Software version 20.022 software support (MedCalc Software Ltd, Ostend, Belgium; https://www.medcalc.org; 2021) was used in the analysis.
3. Results
The descriptive statistics (prevalence with 95% confidence intervals) of the categorical clinical variables analyzed are shown in Table 1. Recurrence of the disease was present in 19/53 patients (35.8%). The most prevalent Grade Group of prostatic adenocarcinoma was Grade group 2 (24/53; 45.3%). Positive margins were present in 13/53; 24.5% of the patients. The descriptive statistics of the quantitative clinical variables analyzed are shown in Table 2. The median age (interquartile range) of the participants was 65.0 (62.0–69.0) years. The median PSA level was 10.0 (6.5–13.1) with a median follow-up time of 64.0 (38.0–69.0) months. The median time to BCR was 17.0 (8.0–34.0) months. The correlation coefficients of the expression of Dysadherin, E-cadherin and ß-catenin in prostatic adenocarcinoma with clinical characteristics are shown in Table 3. Dysadherin expression was noted to be nuclear and cytoplasmic/membraneous in prostatic tissue (Figure 1). As illustrated in Figure 1A, non-tumorous prostatic glands demonstrated strong nuclear Dysadherin expression without significant cytoplasmic staining. In contrast, prostatic adenocarcinoma tissues exhibited cytoplasmic/membranous Dysadherin staining , clearly visible in Figure 1B. Notably, Figure 1C shows lower-grade adenocarcinoma (Grade Group 1), characterized by weaker Dysadherin staining, while Figure 1D highlights a higher-grade adenocarcinoma (Grade Group 4), where markedly stronger cytoplasmic/membranous Dysadherin staining is seen.
Table 1.
Descriptive statistics of analyzed clinical categorical variables (N = 53).
| N | % | 95% CI | |||
|---|---|---|---|---|---|
| Recurrence | No | 34 | 64.2% | 50.8% | 76.0% |
| Yes | 19 | 35.8% | 24.0% | 49.2% | |
| T status | 2 | 35 | 66.0% | 52.7% | 77.7% |
| 3 | 18 | 34.0% | 22.3% | 47.3% | |
| N status | 0 | 50 | 94.3% | 85.7% | 98.4% |
| 1 | 3 | 5.7% | 1.6% | 14.3% | |
| M status | X | 53 | 100.0% | ||
| Grade Group | 1 | 12 | 22.6% | 13.0% | 35.2% |
| 2 | 24 | 45.3% | 32.4% | 58.6% | |
| 3 | 14 | 26.4% | 16.0% | 39.3% | |
| 4 | 1 | 1.9% | 0.2% | 8.5% | |
| 5 | 2 | 3.8% | 0.8% | 11.6% | |
| Positive surgical margins | No | 40 | 75.5% | 62.8% | 85.5% |
| Yes | 13 | 24.5% | 14.5% | 37.2% | |
| Dysadherin expression in prostatic adenocarcinoma –cytoplasmic/membraneous | 0 | 17 | 32.1% | 20.7% | 45.3% |
| 1 | 23 | 43.4% | 30.7% | 56.8% | |
| 2 | 13 | 24.5% | 14.5% | 37.2% | |
| Dysadherin expression in prostatic adenocarcinoma – nuclear | 0 | 7 | 13.2% | 6.1% | 24.2% |
| 1 | 21 | 39.6% | 27.3% | 53.1% | |
| 2 | 25 | 47.2% | 34.2% | 60.5% | |
| Dysadherin expression in adjacent non-tumorous tissue – cytoplasmic/membraneous | 0 | 49 | 92.5% | 83.0% | 97.4% |
| 1 | 3 | 5.7% | 1.6% | 14.3% | |
| 2 | 1 | 1.9% | 0.2% | 8.5% | |
| Dysadherin expression in adjacent non-tumorous tissue – nuclear | 0 | 16 | 30.2% | 19.1% | 43.3% |
| 1 | 23 | 43.4% | 30.7% | 56.8% | |
| 2 | 14 | 26.4% | 16.0% | 39.3% | |
| E-cadherin expression in prostatic adenocarcinoma | 1 | 35 | 66.0% | 52.7% | 77.7% |
| 2 | 15 | 28.3% | 17.6% | 41.3% | |
| 3 | 3 | 5.7% | 1.6% | 14.3% | |
| E-cadherin expression in adjacent non-tumorous tissue | 2 | 5 | 9.4% | 3.7% | 19.4% |
| 3 | 48 | 90.6% | 80.6% | 96.3% | |
| ß-catenin expression in prostatic adenocarcinoma | 1 | 15 | 28.3% | 17.6% | 41.3% |
| 2 | 22 | 41.5% | 29.0% | 54.9% | |
| 3 | 16 | 30.2% | 19.1% | 43.3% | |
| ß-catenin expression in adjacent non-tumorous tissue | 2 | 7 | 13.2% | 6.1% | 24.2% |
| 3 | 46 | 86.8% | 75.8% | 93.9% | |
Table 2.
Descriptive statistics of the quantitative clinical variables analyzed (N = 53).
| Min | Max | Median | Percentile 25 | Percentile 75 | |
|---|---|---|---|---|---|
| Age (years) | 50.00 | 77.00 | 65.00 | 62.00 | 69.00 |
| PSA level | 3.20 | 39.30 | 10.00 | 6.50 | 13.1 |
| Follow up (months) | 6.00 | 87.00 | 64.00 | 38.00 | 69.00 |
| PSA in recurrence | 0.30 | 3.30 | 0.95 | 0.58 | 1.72 |
| TIME to BCR (months) | 6.00 | 63.00 | 17.00 | 8.00 | 34.00 |
Table 3.
Correlation coefficients of the expression of dysadherin (cytoplasmic/membraneous and nuclear), E-cadherin and ß-catenin in prostatic adenocarcinoma with clinical characteristics (N = 53): spearman correlation coefficients rho.
| Dysadherin cytoplasmic/ membraneous | Dysadherin nuclear | E-cadherin | ß-catenin | ||
|---|---|---|---|---|---|
| Age (years) | Correlation Coefficient | 0.004 | −0.252 | −0.004 | 0.084 |
| P | 0.977 | 0.069 | 0.976 | 0.550 | |
| PSA level | Correlation Coefficient | 0.203 | 0.241 | −0.008 | −0.086 |
| P | 0.145 | 0.082 | 0.957 | 0.538 | |
| Follow up (months) | Correlation Coefficient | 0.000 | −0.254 | 0.273 | 0.199 |
| P | 0.999 | 0.066 | 0.048 | 0.154 | |
| Recurrence | Correlation Coefficient | 0.083 | 0.192 | −0.297 | −0.225 |
| P | 0.556 | 0.169 | 0.031 | 0.105 | |
| PSA in recurrence | Correlation Coefficient | 0.178 | −0.055 | −0.317 | −0.349 |
| P | 0.466 | 0.825 | 0.186 | 0.144 | |
| TIME BCR (months) | Correlation Coefficient | −0.193 | −0.187 | 0.528 | 0.226 |
| P | 0.429 | 0.444 | 0.020 | 0.352 | |
| T status | Correlation Coefficient | 0.179 | 0.326 | −0.430 | −0.225 |
| P | 0.201 | 0.017 | 0.001 | 0.105 | |
| N status | Correlation Coefficient | −0.092 | 0.111 | −0.174 | −0.219 |
| P | 0.515 | 0.428 | 0.214 | 0.115 | |
| Grade group | Correlation Coefficient | 0.130 | 0.278 | −0.558 | −0.557 |
| P | 0.354 | 0.044 | <0.001 | <0.001 | |
| Positive margins | Correlation Coefficient | 0.006 | 0.050 | −0.404 | −0.128 |
| P | 0.965 | 0.720 | 0.003 | 0.359 | |
Figure 1.
Dysadherin immunohistochemical expression in prostatic tissue. A. Dysadherin exhibits nuclear expression in non-tumorous prostatic tissue, with no expression in the cytoplasm/membrane of the non-tumorous acini (200x magnification). B. Dysadherin cytoplasmic/membraneous and nuclear expression is seen in Prostatic Adenocarcinoma, while negative cytoplasmic/membraneous expression and strong nuclear expression are observed in the adjacent non-tumorous prostatic tissue (100x magnification). C. Dysadherin shows weak cytoplasmic/membraneous expression in Prostatic Adenocarcinoma with Gleason Score 3 + 3 = 6 (Grade Group 1) (200x magnification). D. Dysadherin displays strong cytoplasmic/membraneous and nuclear expression in Prostatic Adenocarcinoma with Gleason Score 4 + 4 = 8 (Grade Group 4) (100x magnification).
Cytoplasmic/membraneous Dysadherin expression in prostatic adenocarcinoma was positively correlated with Grade Group (rho = 0.278, P = 0.044) and the T status (rho = 0.326, P = 0.017). E-cadherin and ß-catenin expression was membraneous and weakly cytoplasmic in prostatic tissue (Figure 2). Figure 2A clearly depicts strong membranous E-cadherin expression, typical of lower-grade adenocarcinoma (Grade Group 1) and adjacent normal glands, indicating intact epithelial adhesion. In Figure 2B, reduced E-cadherin staining is seen in Prostatic Adenocarcinoma (black arrow) compared to the adjacent normal glands (red arrow). Whereas Figure 2C shows intermediate-grade adenocarcinoma with reduced E-cadherin staining, suggesting compromised cell-cell adhesion. Similarly, Figures 2D–F illustrate β-catenin expression, where strong membranous staining in low-grade adenocarcinoma (Grade Group 1) contrasts with the weak staining pattern observed in higher-grade adenocarcinoma (Grade Group 4), consistent with progression-associated loss of cellular adhesion.
Figure 2.
E-cadherin and ß-catenin immunohistochemical expression in prostatic tissue. A. E-cadherin exhibits strong expression in Prostatic Adenocarcinoma Gleason Score 3 + 3 = 6 (Grade Group 1), as well as in the adjacent non-tumorous tissue (100x magnification). B. Weak E-cadherin expression is observed in Prostatic Adenocarcinoma (black arrow) and strong E-cadherin expression in the adjacent non-tumorous tissue (red arrow) (100x magnification). C. Weak E-cadherin expression is observed in Prostatic Adenocarcinoma Gleason Score 3 + 4 = 7 (Grade Group 2) (100x magnification). D. ß-catenin displays strong expression in Prostatic Adenocarcinoma Gleason Score 3 + 3 = 6 (Grade Group 1) and in the adjacent non-tumorous tissue (100x magnification). E. Weak ß-catenin expression is observed in Prostatic Adenocarcinoma (black arrow) and strong ß-catenin expression in the adjacent non-tumorous tissue (red arrow) (100x magnification). F. Weak ß-catenin expression is seen in Prostatic Adenocarcinoma with Gleason Score 4 + 4 = 8 (Grade Group 4) (200x magnification).
E-cadherin was negatively correlated with Grade Group (rho = −0.558, P < 0.001), recurrence (rho = −0.297, P = 0.031), T status (rho = −0.430, P = 0.001), and positive surgical margins (rho = −0.404, P = 0.003). ß-catenin in prostatic adenocarcinoma was significantly negatively correlated with the Grade Group (rho = −0.557, P < 0.001). The correlation coefficients for the expression of Dysadherin, E-cadherin and ß-catenin in prostatic adenocarcinoma with each other are shown in Table 4. There was no correlation between Dysadherin cytoplasmic/membraneous and/or nuclear expression and E-cadherin and ß-Catenin expression in prostatic adenocarcinoma, whereas E-cadherin expression was significantly positively correlated with ß-catenin expression in prostatic adenocarcinoma (rho = 0.473, P < 0.001).
Table 4.
Correlation coefficients of expression of dysadherin (cytoplasmic/membraneous and nuclear), E-cadherin and ß-catenin in prostatic adenocarcinoma with each other and between prostatic adenocarcinoma and the adjacent non-tumorous tissue (N = 53): spearman correlation coefficients rho.
| Dysadherin cytoplasmic/ membraneous | Dysadherin nuclear | E-cadherin | ß-catenin | |||
|---|---|---|---|---|---|---|
| Dysadherin nuclear | Correlation Coefficient | 0.511 | 1.000 | −0.180 | −0.203 | |
| P | <0.001 | 0.198 | 0.145 | |||
| Dysadherin cytoplasmic/membraneous | Correlation Coefficient | 1.000 | 0.511 | −0.063 | −0.163 | |
| P | <0.001 | 0.656 | 0.244 | |||
| E-cadherin | Correlation Coefficient | −0.063 | −0.180 | 1.000 | 0.473 | |
| P | 0.656 | 0.198 | <0.001 | |||
| ß-catenin | Correlation Coefficient | −0.163 | −0.203 | 0.473 | 1.000 | |
| P | 0.244 | 0.145 | <0.001 | |||
| |
Adjacent non-tumorous tissue expression |
|||||
| |
Dysadherin nuclear | Dysadherin cytoplasmic/membraneous | E-cadherin | B-catenin | ||
| Prostatic adenocarcinoma expression | Dysadherin nuclear | Correlation Coefficient | 0.548 | −0.015 | 0.060 | 0.068 |
| P | <0.001 | 0.917 | 0.669 | 0.629 | ||
| Dysadherin cytoplasmic/membraneous | Correlation Coefficient | 0.260 | 0.214 | 0.054 | −0.039 | |
| P | 0.060 | 0.125 | 0.700 | 0.781 | ||
| E-cadherin | Correlation Coefficient | −0.215 | −0.064 | 0.102 | −0.202 | |
| P | 0.122 | 0.646 | 0.469 | 0.147 | ||
| B-catenin | Correlation Coefficient | −0.030 | −0.105 | 0.092 | −0.136 | |
| P | 0.830 | 0.455 | 0.511 | 0.331 | ||
The analysis of Dysadherin, E-cadherin, and β-catenin expression revealed no statistically significant correlations between Dysadherin and E-cadherin and Dysadherin and β-catenin expression in prostatic adenocarcinoma tissue and adjacent non-tumorous tissue (Table 4). The difference in the prevalence of recurrence with respect to the expression of Dysadherin (cytoplasmic/membraneous and nuclear), E-cadherin and ß-catenin in prostatic adenocarcinoma is shown in Table 5. The negative and weak expression of E-cadherin was significantly higher in patients with disease recurrence (45.7% vs 16.7%; P = 0.037). Figure 3. shows the survival analysis of disease recurrence in correlation with E-cadherin expression. Patients with a high expression of E-cadherin in prostatic adenocarcinoma had significantly better survival to recurrence (log rank test, P = 0.028) compared to the negative and weak expression group. In estimated survival times to recurrence patients with high expression of E-cadherin in prostatic adenocarcinoma had 77.9 (95% CI 71.2–84.6) months while those with negative and weak expression had 52.7 (42.2–63.1) months. There were no significant survival to recurrence differences in prostatic adenocarcinoma with respect to the expression of Dysadherin (cytoplasmic/membraneous and nuclear) and ß-catenin.
Table 5.
Difference in the prevalence of biochemical recurrence with respect to the expression of dysadherin (cytoplasmic/membraneous and nuclear), E-cadherin and ß-catenin in prostatic adenocarcinoma: Chi-square test.
| Recurrence |
χ2 | df | P | |||||
|---|---|---|---|---|---|---|---|---|
| No N = 34 |
Yes N = 19 |
|||||||
| N | % | N | % | |||||
| Dysadherin cytoplasmic/membraneous | Negative and weak expression | 25 | 62.5% | 15 | 37.5% | 0.19 | 2 | 0.660 |
| Strong expression | 9 | 69.2% | 4 | 30.8% | ||||
| Dysadherin nuclear | Negative and weak expression | 20 | 71.4% | 8 | 28.6% | 1.37 | 2 | 0.242 |
| Strong expression | 14 | 56.0% | 11 | 44.0% | ||||
| E-cadherin | Negative and weak expression | 19 | 54.3% | 16 | 45.7% | 4.36 | 2 | 0.037 |
| Strong expression | 15 | 83.3% | 3 | 16.7% | ||||
| ß-catenin | Negative and weak expression | 8 | 53.3% | 7 | 46.7% | 1.07 | 2 | 0.302 |
| Strong expression | 26 | 68.4% | 12 | 31.6% | ||||
Figure 3.
Kaplan-Meier survival analysis plot for disease recurrence with respect to E-cadherin expression.
4. Discussion
Prostatic adenocarcinoma, one of the most prevalent malignancies among men, arises from a complex interplay of genetic, hormonal, metabolic and inflammatory factors [21–26]. Metabolic imbalances foster a pro-inflammatory state within the tumor microenvironment that promotes tumor growth by inducing oxidative stress, DNA damage, and epigenetic modifications, which contribute to enhanced tumor aggressiveness. Pro-inflammatory cytokines, such as IL-6 and TNF-α, play pivotal roles by activating signaling pathways like NF-κB and STAT3, which support cell proliferation, angiogenesis, and immune evasion in prostate cancer [21,22]. Hormonal influences, particularly androgen receptor (AR) signaling, further exacerbate these processes. AR signaling synergizes with inflammatory mediators, including interleukins and tumor necrosis factors, to facilitate EMT, a critical step in metastasis [23,24]. Chronic inflammation within the prostate environment not only promotes EMT but also disrupts cellular adhesion and enables invasive behavior, contributing to both local and distant tumor progression [25]. Within this context, Dysadherin is considered a molecule of interest in several human cancers due to its diverse roles in tumor progression, metastasis, and interaction with the microenvironment. Dysadherin is reported to play a crucial role within this dynamic by modulating cellular adhesion and contributing to the destabilization of epithelial architecture. Its involvement with inflammatory signaling pathways, such as the activation of NF-κB, further amplifies its role in creating a pro-tumorigenic environment. Additionally, Dysadherin upregulation has been linked to increased chemokine secretion, such as CCL2, which promotes immune evasion and facilitates metastatic dissemination [4,11]. Our study adds to the growing body of evidence by demonstrating Dysadherin’s differential expression in prostatic adenocarcinoma and adjacent non-tumorous tissue and its association with clinicopathological parameters.
The findings of our study contribute to the understanding of Dysadherin’s immunohistochemical expression in prostatic adenocarcinoma and its relationship with key cell adhesion molecules, E-cadherin and β-catenin.
The interplay between E-cadherin and Dysadherin has been studied in the context of cancer progression and metastasis, where dysregulation of cell adhesion and migration processes is a hallmark feature. Some studies suggest that Dysadherin may influence E-cadherin mediated cell adhesion and migration by modulating intracellular signaling pathways or by directly affecting the stability or localization of E-cadherin at cell junctions [27–30].
Ino et al. [27] in their study reported that Dysadherin downregulates E-cadherin, resulting in decreased cell-cell adhesion and promoting cell motility in epithelial tissue. This observation is supported by multiple other studies that have reported a consistent negative correlation between Dysadherin and E-cadherin expression in cancer tissue, highlighting the significant role of Dysadherin in cancer progression [28–30].
Dysadherin has been shown to promote the internalization and degradation of E-cadherin in breast cancer cells, leading to disrupted cell-cell adhesion and invasiveness [4]. However, the exact mechanisms underlying the interaction between E-cadherin and Dysadherin, and the impact on cell behavior, may vary depending on the cellular context and the specific signaling pathways involved.
Lee et al. [4] demonstrated that Dysadherin enhances motility and survival of breast cancer cells by activating the AKT signaling pathway. Furthermore, they reported that Dysadherin promotes the secretion of CCL2, facilitating the recruitment of macrophages to the tumor microenvironment, which plays a crucial role in establishing a metastatic niche. Thus, confirming Dysadherin’s role in microenvironment modulation. In gastric cancer, Dysadherin’s overexpression correlates with tumor invasion, lymph node metastasis, and poor overall survival. Maehata et al. [8] reported that Dysadherin’s interaction with the extracellular matrix proteins in gastric cancer is central to its function, mediating enhanced migratory potential and invasiveness. Similarly, in colorectal cancer, Dysadherin has been shown to upregulate MMPs that degrade the extracellular matrix, facilitating invasion and metastasis [11]. Batistatou et al. [31] emphasized that Dysadherin’s ability to downregulate E-cadherin in metastatic sites leads to increased cellular detachment, enabling dissemination in colorectal cancer stating that Dysadherin’s expression in lymph node metastases, rather than primary tumors, is a marker for poor prognosis. This selective expression in metastatic sites rather than primary tumors aligns with the hypothesis that Dysadherin’s role is particularly critical during the metastatic cascade. Similarly, in ovarian cancer, Tassi et al. [10] revealed that Dysadherin upregulation is associated with chemoresistance, particularly in ovarian high-grade serous carcinoma. The study showed that Dysadherin confers resistance to platinum-based chemotherapy by altering the expression of apoptosis-related proteins and enhancing cell survival pathways. In thyroid cancer, Dysadherin’s role appears to be linked with tumor dedifferentiation and aggressive phenotypes. Jang et al. [6] developed Dysadherin specific drug conjugates to target aggressive thyroid cancer subtypes, indicating that Dysadherin expression is a hallmark of invasive behavior. Dysadherin’s interaction with chemokine pathways and EMT transition markers in thyroid cancer exemplifies its multifunctional role in tumor progression. A study on head and neck cancer patients showed a significant inverse correlation between Dysadherin and E-cadherin expression. Patients with Dysadherin overexpression had poorer responses to radiation therapy, reinforcing the notion that Dysadherin may play a critical role in tumor progression through its effects on E-cadherin [32].
In our study we evaluated the expression of Dysadherin, E-cadherin and ß-catenin proteins in prostatic adenocarcinoma and in the adjacent non-tumorous prostatic tissue, and we correlated Dysadherin expression with E-cadherin and ß-catenin. Additionally, we correlated the relationship between the expression of Dysadherin, E-cadherin, and ß-catenin with Grade Group, sPSA, surgical margin status, BCR, and TNM staging in prostatic adenocarcinoma. We report a cytoplasmic/membraneous and nuclear staining for Dysadherin in prostatic tissue. Lymphocytes and endothelial cells were also found to exhibit positive Dysadherin expression in our tissue sample. In line with earlier investigations into Dysadherin expression in various cancer tissues [2–10], we observed that Dysadherin’s cytoplasmic/membraneous expression was notably higher in prostatic adenocarcinoma tissue than in the adjacent non-tumorous prostatic tissue (p < 0.001).
Dysadherin cytoplasmic/membraneous expression in prostatic adenocarcinoma positively correlated with Grade Group (rho = 0.278, P = 0.044) and the T status (rho = 0.326, P = 0.017) (Table 3). Whereas, we report no correlation of Dysadherin expression with sPSA, surgical margins status, BCR and the N status in prostatic adenocarcinoma.
Additionally, we observed Dysadherin expression in the nuclei of both prostatic adenocarcinoma and adjacent non-tumorous prostatic tissue. Importantly, there was no statistically significant difference in nuclear Dysadherin expression between the malignant and non-tumorous tissue. Nuclear Dysadherin expression is a finding that has not been widely reported. The nuclear localization of Dysadherin may indicate additional functions beyond its established role in membrane dynamics and cell adhesion suggesting interaction with nuclear signaling pathways.
E-cadherin expression in prostatic adenocarcinoma was negatively correlated with Grade Group (rho = −0.558, P < 0.001), BCR (rho = −0.297, P = 0.031), T status (rho = −0.430, P = 0.001), and positive surgical margins (rho = −0.404, P = 0.003) (Table 3). Whereas, ß-catenin in prostatic adenocarcinoma was significantly negatively correlated with the Grade Group (rho = −0.557, P < 0.001) (Table 3).
We did not reveal any correlation between Dysadherin and E-cadherin expression in prostatic adenocarcinoma. Moreover, our findings diverge from the previously reported results in other studies, which have suggested a negative correlation between Dysadherin and E-cadherin in cancer tissues [27–30]. The research conducted by Batistatou and their group similarly did not uncover any correlation between Dysadherin and E-cadherin immunohistochemical expression in primary colorectal cancer and breast cancer tissues (P > 0.05) [31,33]. Nevertheless, they reported a negative correlation between Dysadherin and E-cadherin expression in the lymph node metastases of colorectal cancer (P < 0.05) [31]. Tamura et al. [34]), did not observe any significant correlation between Dysadherin and E-cadherin expression in non-small cell lung cancer and proposed alternative mechanisms for the decrease in E-cadherin expression that are not related to Dysadherin such as hypermethylation of the E-cadherin gene promotor; regulation by transcriptional repressors as key drivers of the EMT transition that could suppress E-cadherin transcription; and post-translational modifications including proteolytic cleavage or degradation of E-cadherin mediated by enzymes like MMPs or other proteases. The absence of a significant correlation between Dysadherin and E-cadherin in our cohort may be attributable to the complexity of signaling pathways in prostatic adenocarcinoma. Prostate cancer as we previously mentioned is influenced by a myriad of factors, including AR signaling, which has been shown to modulate EMT and cellular adhesion molecules. Dysadherin’s role in this context warrants further investigation to delineate its interplay with AR signaling and other molecular pathways.
Additionally, we report a positive correlation between Dysadherin expression and higher tumor Grade Group and T stage, underscoring its potential role in tumor aggressiveness. This finding is consistent with previous studies that have identified Dysadherin as a marker of poor differentiation and advanced disease in various cancers [2–10]. However, the prognostic value of Dysadherin in prostate cancer, particularly its association with biochemical recurrence and survival outcomes, remains an area of interest for future studies.
While our findings highlight anassociation between Dysadherin expression and higher-grade, more locally advanced prostatic adenocarcinoma, it is important to recognize Dysadherin’s additional roles beyond the impairment of cell–cell adhesion. Several studies indicate that Dysadherin can also promote ECM remodeling by upregulating matrix metalloproteinases (e.g., MMP9), thereby facilitating invasion and metastasis [11]. Moreover, as we mentioned previously Dysadherin has been shown to influence chemokine networks, for instance by enhancing CCL2 production, which in turn can recruit tumor-associated immune cells and promote angiogenesis [14]. Dysadherin may additionally interact with FAK and mechanotransduction pathways, thereby modifying motility and metastatic potential [12,13]. These findings suggest that Dysadherin can drive tumor progression through several molecular events rather than solely via cell adhesion disruption. Further mechanistic work to elucidate Dysadherin’s impact on immune responses, ECM composition, and intracellular signaling in prostate cancer will be crucial for clarifying its precise role and may ultimately guide the development of therapeutic interventions targeting Dysadherin related pathways.
Our study marks a pioneering effort in linking Dysadherin expression with ß-catenin, which plays a pivotal role in the regulation of E-cadherin, nevertheless, we did not identify any correlation between Dysadherin and ß-catenin expression in prostatic normal/benign and malignant tissue.
The interplay between Dysadherin, E-cadherin, and β-catenin is particularly intriguing in the context of Wnt signaling, a pathway known to be dysregulated in prostate cancer. β-catenin serves as a central mediator of Wnt signaling and a critical component of cell adhesion complexes. While our study did not find a direct correlation between Dysadherin and β-catenin expression, it is plausible that Dysadherin influences β-catenin indirectly through other signaling intermediates. For example, Dysadherin’s role in modulating CCL2 production, may impact the tumor microenvironment and alter β-catenin activity.
Similar to previous findings on E-cadherin expression in prostatic adenocarcinoma [35–37], in our study patients with a high expression of E-cadherin in prostatic adenocarcinoma had significantly better survival time to recurrence (log rank test, P = 0.028) compared to the negative and weak expression group (Figure 3). Whereas a noteworthy aspect of our findings is the lack of significant survival differences associated with Dysadherin expression. Larger, multicenter studies with extended follow-up periods are necessary to validate Dysadherin’s prognostic value. Targeting Dysadherin may hold promise for inhibiting metastasis and improving treatment outcomes, particularly in high-risk prostate cancer patients. The role of Dysadherin in immune modulation also deserves attention. When acknowledging the limitations of our study, we recognize that the relatively small sample size from a single center restricts the broader applicability of our findings regarding Dysadherin expression in prostatic tissue. Although the observed correlations between Dysadherin expression and key clinicopathological parameters appear consistent, this limited sample size restricts the statistical power and generalizability of our findings. Additional multicenter studies with larger cohorts and more diverse patient populations are essential to validate these preliminary results and to determine whether Dysadherin and its potential interactions with E-cadherin and β-catenin consistently hold prognostic significance in prostatic adenocarcinoma. Furthermore, future prospective research could more definitively clarify whether Dysadherin may serve as a robust biomarker or a potental therapeutic target.
Nevertheless, its important to highlight that this study represents the inaugural effort to assess and establish correlations between Dysadherin expression and clinicopathological features of prostatic adenocarcinoma. While the results provide valuable insights, they also emphasize the necessity for further investigation to elucidate Dysadherin’s role in the context of prostate cancer biology.
Prostate cancer research continues to evolve, with growing emphasis on understanding the molecular mechanisms driving tumor progression and metastasis. Dysadherin, along with E-cadherin and β-catenin, represents a focus area due to its potential involvement in cell adhesion, migration, and interaction with inflammatory pathways. This includes exploring Dysadherin’s role in different stages of prostatic adenocarcinoma. Investigating how Dysadherin interacts with hormonal and metabolic pathways is another field that should be explored that can potentially uncover new understanding on prostatic adenocarcinoma progression.
In breast and lung cancers, Dysadherin-driven secretion of CCL2 facilitates the recruitment of tumor-associated macrophages (TAMs), which support immune evasion and angiogenesis [4,11]. While TAM infiltration is also observed in prostate cancer, the specific contribution of Dysadherin to this process has not been investigated. Prostate cancer is characterized by an immunosuppressive microenvironment, therefore Dysadherin’s ability to regulate chemokine production and recruit immune cells may contribute to immune evasion. Understanding how Dysadherin influences the immune landscape in prostate cancer could reveal novel strategies for immunotherapy.
Additionally, the interaction between Dysadherin and ECM is well-documented in gastric and colorectal cancers, where Dysadherin upregulates MMPs to degrade ECM components [8,11]. Whereas, in prostate cancer, ECM remodeling is a hallmark of disease progression, yet Dysadherin’s involvement in this process remains unclear. Future studies should investigate whether Dysadherin contributes to ECM dynamics in prostate cancer, potentially through MMP regulation or other mechanisms.
5. Conclusion
Dysadherin emerges as a promising prognostic marker for prostatic adenocarcinoma. The presence of Dysadherin expression within the nuclei of prostatic acinar cells prompts the exploration of alternative roles and potential mechanisms of Dysadherin nuclear localization in prostate epithelial cells. We reveal no significant correlation between Dysadherin and the expression of E-cadherin and ß-catenin in prostatic tissue, which underscores the possibility of other roles for Dysadherin beyond its initially reported function as an anti-cell-cell adhesion molecule that downregulates E-cadherin.
We report that E-cadherin is inversely correlated with the survival time to recurrence. Our results underscore the potential of E-cadherin and ß-catenin as prognostic markers and potential therapeutic targets in prostate adenocarcinoma.
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki, and approved by Ethics Committee of School of Medicine, University of Zagreb.(No. 8.1-19/193-2 on 3 June 2015).
Patient consent for publication
Informed consent was obtained from all subjects involved in the study.
Conflicting interests
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Availability of data and material
All original materials and data are available upon request.
References
Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.
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Data Availability Statement
All original materials and data are available upon request.