Epithelial Syndecan-1 Expression Research Articles

Stromal and epithelial syndecan-1 expression in benign and malignant salivary gland tumors: which is more reflective of behavior?

IntroductionSalivary gland tumors are a diverse group of lesions, with various origins and extremely different behaviors, leading to a variety of outcomes for patients. Therefore, the need to discover novel markers with the ability to predict the behavior of benign and malignant salivary gland neoplasms is crucial. Syndecan-1 is a cell-surface protein with significant roles in various aspects of tumor function. Its expression in salivary gland neoplasms, especially their stromal component, has not been investigated. ObjectivesWe aimed to assess the immunopositivity of syndecan-1 in epithelial and stromal components of salivary gland neoplasms and to compare it between benign and malignant subtypes in addition to evaluating its correlation with clinicopathologic parameters. Methods133 salivary gland tumors were immunohistochemically stained with syndecan-1 and the intensity and percentage of this protein was determined, compared between the tumors and correlated with clinicopathologic factors. ResultsStatistical analysis of lesions with a sufficient sample size showed significant differences in percentage and intensity between both epithelial and stromal components of all tumors (p<0.05). Pairwise-comparisons demonstrated significantly higher staining-percentage of epithelial cells (p=0.02) in Warthin’s tumor compared to pleomorphic adenoma and adenoid cystic carcinoma. Similarly, significantly higher staining intensities and/or percentages was observed in mucoepidermoid carcinoma and adenoid cystic carcinoma compared to pleomorphic adenoma and Warthin’s tumor (p<0.05). Of the clinicopathologic factors, there was only a significant negative correlation between stromal percentage of mucoepidermoid carcinoma and age and a significant difference between stromal intensity+percentage of adenoid cystic carcinoma and gender (p<0.05). ConclusionsAccording to our findings we postulate that stromal syndecan-1 correlates with the behavior of salivary gland tumors, with malignant neoplasms demonstrating a higher expression, indicating a role for syndecan-1 in invasion and metastasis.

Epithelial and stromal syndecan‐1 and ‐2 are distinctly expressed in oral‐ and cutaneous squamous cell carcinomas

Oral squamous cell carcinoma (OSCC) and cutaneous squamous cell carcinoma (CSCC) are epithelial neoplasms of which OSCC has worse survival and higher risk of metastasis than CSCC. The aim of this study was to explore the differences of immunoexpressions between syndecan-1 and -2 in OSCC and head and neck CSCC. A total of 35 patients diagnosed with OSCC and 25 with CSCC, presented T1 and T2 tumors and treated at Helsinki University Central Hospital between years 2001 and 2009, were selected into this study. The levels and locations of syndecan-1 and -2 immunostainings were analyzed using formalin-fixed and paraffin-embedded tissue samples of OSCC and CSCC cases together with clinical data. Cell membrane epithelial syndecan-1 expression decreased significantly compared to normal tissue in both cancer types. Cell membrane syndecan-1 expression in the invasive front had negative correlation with invasion depth of both tumors (OSCC, r = -0.339, P = 0.025; CSCC, r = -0.469, P = 0.004). In cancers over 4-mm invasion depth, the number of stromal syndecan-1-positive collagen fibers and inflammatory cells were higher in OSCC than in CSCC. Syndecan-2 expression in non-malignant stroma was higher in CSCC than in OSCC tumors. In addition, unlike syndecan-1, syndecan-2 was more often and more intensively expressed in the tumor inflammatory cells in CSCC than in OSCC. Our results suggest that variable stromal expression of syndecan-1 and -2 in OSCC compared to CSCC may at least partially explain the differences in their clinical behavior.

The Prognostic Value of Syndecan-1 in Ovarian Cancer Patients with Long-Term Follow up

IntroductionSyndecan-1 plays a role in the cell regulation through cell-extracellular matrix adhesion, cell-cell adhesion, migration, and morphogenesis. It functions as a co-receptor for several growth factors, modulating the affinity of the growth-factor receptor interactions. Syndecan-1 has been investigated as a prognostic factor for several malignant cancer types, but its role still seems unclear. The purpose of the present study was to investigate the possible role of syndecan-1 as a prognostic factor in ovarian cancer. MethodsThe expression of syndecan-1 was examined in ovarian cancer specimens from 164 patients who were enrolled in a Danish protocol after primary surgery in the period from 1991 to 1994. Immunohistochemistry and tissue microarrays (TMAs) were used for the detection of syndecan-1 in both tumor epithelial and stromal cells. ResultsThe median duration of follow-up for those still alive was 18 years. Positive tumor epithelial syndecan-1 staining was found in 18% of the patients, whereas positive stromal syndecan-1 immunoreactivity was seen in 50% of the patients. Positive expression of syndecan-1 in epithelial cells was observed less frequently in serous adenocarcinoma, whereas positive stromal expression was found more frequently in poorly differentiated tumors. Positive epithelial syndecan-1 expression was associated with unfavorable overall survival (OS) in univariate analysis (P = 0.02), which, however, was not confirmed in multivariate analysis, although there was a tendency (P = 0.12) and a hazard ratio of 1.52. ConclusionSyndecan-1 is present in a subset of ovarian carcinomas and may be an indicator of survival, but further investigations are required.

Clinical significance of syndecan-1 and versican expression in human epithelial ovarian cancer

Proteoglycans are ubiquitous components of the extracellular matrix and cell surface, and may mediate tumor progression and metastasis. The aim of this study was to evaluate the expression of syndecan-1 and versican in epithelial ovarian cancer. We immunohistochemically evaluated the expression of syndecan-1 and versican in 111 patients with epithelial ovarian cancer, and analyzed the correlation of this expression with various observed clinicopathological features, including patient outcome. There is a significant correlation between primary and metastatic sites with respect to syndecan-1 and versican expression. Epithelial syndecan-1 expression was significantly lower in patients with advanced disease. Epithelial versican expression was significantly higher in patients with early disease, especially in clear cell adenocarcinoma patients. Stromal syndecan-1 and versican expression was significantly higher in patients with advanced disease. Multivariate analysis showed that negative epithelial syndecan-1 expression was an independent prognostic factor for progression-free survival. Stromal syndecan-1 and versican co-expression was of borderline significance for progression-free and overall survival. Loss of epithelial syndecan-1 expression and induction of stromal syndecan-1 and versican expression may be associated with tumor progression in epithelial ovarian cancer. Syndecan-1 and versican expression status can serve as an indicator of prognosis in patients with epithelial ovarian cancer.

Reduction of syndecan‐1 expression during lip carcinogenesis

Actinic cheilitis (AC) is an oral pre-cancerous lesion that sometimes develops into lip squamous cell carcinoma (SCC). Syndecan-1, a transmembrane heparan sulfate proteoglycan, modulates cell-proliferation, adhesion, migration and angiogenesis. Malignant epithelial cells often down-regulate their own syndecan-1 production, and are capable of inducing aberrant syndecan-1 expression in stromal cells. The aim of this study was to evaluate the variations in syndecan-1 expression during lip carcinogenesis, in normal lip (NL), AC and well-differentiated lip SCC. Biopsies of NL vermillion (n = 19), AC (n = 23) and lip SCC (n = 24) were stained immunohistochemically for syndecan-1. Syndecan-1 expression was significantly reduced in AC and lip SCC as compared to NL (P < 0.05), with a significant reduction in lip SCC as compared to AC (P < 0.0001). In lip SCC lesions, syndecan-1 expression at the epithelium overlying the tumor was increased when compared to the tumor itself (P < 0.03), but was significantly reduced as compared to AC and NL (P < 0.001). The results showed that epithelial syndecan-1 expression is reduced as lip carcinogenesis progresses (NL>AC>lip SCC), suggesting that syndecan-1 could be a useful marker of malignant transformation in the lip.

Syndecan-1 Expression in Gallbladder Cancer and Its Prognostic Significance

Aim: To determine whether the immunohistochemical detection of syndecan-1 could provide useful information as a novel therapeutic or prognostic factor in primary gallbladder (GB) cancer. Materials and Methods: Forty-three GB cancer tissues were evaluated by immunohistochemistry for syndecan-1 expression. The relationship between syndecan-1 expression and clinicopathological characteristics, and the univariate survival analysis for the influence of the syndecan-1 expression on the overall survival were analysed. Results: Epithelial syndecan-1 immunoreactivity was observed in 25 (58.1%) of the 43 GB cancer cases. The tumors with a positive syndecan-1 expression more frequently showed lymph node metastasis (p = 0.037). Although there was no statistically significant association, the tumors with a positive syndecan-1 expression tended to show a deeper invasion depth (p = 0.087) and more frequent lymphovascular invasion (p = 0.064). The Kaplan-Meier survival curves demonstrated that patients with positive syndecan-1 expression had a significantly shorter survival time than those patients with negative syndecan-1 expression (p = 0.05). Conclusions: A subset of GB cancers revealed an epithelial overexpression of syndecan-1, which was associated with a progressive pathological feature and an aggressive clinical course. Therefore, epithelial syndecan-1 expression may be a predictor for a poor prognosis in patients with GB cancer.

Prognostic impact of syndecan-1 expression in invasive ductal breast carcinomas

Carcinoma cells lack syndecan-1 expression when they are transiting from an epithelial to a less-differentiated mesenchymal phenotype (epithelial–mesenchymal transition, EMT). Furthermore, a shift of syndecan-1 expression from malignant epithelial cells to reactive stromal cells has also been observed during progression of many carcinomas. Finally, epithelial and/or stromal syndecan-1 expression is of prognostic value in many carcinomas. Because recent results are contradictory in breast carcinomas, we have re-evaluated the prognostic significance of syndecan-1 expression in a cohort of 80 patients with invasive ductal breast carcinomas. The tumours from 80 patients diagnosed with invasive ductal breast carcinomas were used to construct a tissue microarray, which was stained with syndecan-1 by immunohistochemistry. We correlated syndecan-1 expression with clinicopathologic parameters and relapse-free survival (RFS). Exclusive epithelial expression of syndecan-1 is observed in 61.25% of the patients, whereas exclusive stromal expression is observed in 30% of the patients. Only 8.75% of the patients had both stromal and epithelial expressions of syndecan-1. A significant correlation was found between the loss of syndecan-1 epithelial expression and the syndecan-1 stromal expression with high grade of malignancy (P=0.011). The loss of syndecan-1 epithelial expression is correlated with RFS (P=0.001). Using multivariate Cox analysis, loss of epithelial syndecan-1 expression was the only prognostic indicator (P<0.001). We concluded that the loss of syndecan-1 epithelial expression was of strong prognostic value in breast carcinomas.

Epithelial Syndecan-1 Expression Is Associated with Stage and Grade in Colorectal Cancer

Objectives: Loss of epithelial heparan sulfate proteoglycan syndecan-1 has been associated with a more aggressive behavior in various cancer forms, but the prognostic significance of syndecan-1 expression in colorectal cancer is unclear. The aim of this study was to evaluate the prognostic value of immunohistochemical syndecan-1 expression in a series of 237 patients with colorectal cancer. Methods: Paraffin-embedded formalin-fixed specimens were stained with a syndecan-1-specific monoclonal antibody, and both the epithelial and stromal expression were analyzed. Results: Epithelial expression of syndecan-1 was seen in 222 tumors (94%), and it was associated with low stage of disease (p = 0.002) and low histological differentiation grade (p = 0.048). The cumulative 5-year survival of patients with weak and strong syndecan-1 expression was 49 and 54 %, respectively (p = 0.234). Syndecan-1 stromal immunoreactivity was observed in 138 tumors (58%), but lacked prognostic significance. Staining pattern and distribution can be viewed from digitized representative microscope slides (virtual slides) at http://www.webmicroscope.net/supplements/syndecan. Conclusions: The results are in line with previous reports in that low epithelial syndecan-1 expression was associated with a higher histological grade and a more advanced clinical stage of the patients. This study shows that syndecan-1 is expressed also in stromal tissue of colorectal cancer, but it does not support the proposed role of stromal syndecan-1 expression as a marker of poor clinical outcome.

Prognostic significance of syndecan-1 expression in human endometrial cancer

Background:: Syndecan-1 binds to various extracellular matrix components via its heparan sulfate glycosaminoglycans. The aim of this study was to investigate syndecan-1 expression in endometrial cancers.Patients and methods:: We investigated the expression of the syndecan-1 core protein by immunohistochemistry in 109 endometrial cancers, and analyzed correlation with various clinicopathological features, including patient outcome.Results:: Epithelial syndecan-1 expression was significantly lower in advanced stage, high grade, deep myometrial invasion, cervical involvement, lymph node metastasis, lymph vascular space involvement and positive peritoneal cytology. Stromal syndecan-1 expression was significantly higher in high-grade tumors. The disease-free and overall survival rates of patients exhibiting both low epithelial and high stromal syndecan-1 expression was poor. Multivariate analysis showed that high stromal syndecan-1 expression was an independent prognostic factor for both disease-free and overall survival. Low epithelial syndecan-1 expression was a prognostic factor only in the univariate analysis.Conclusions:: Loss of epithelial syndecan-1 and induction of stromal syndecan-1 expression may be associated with tumor progression. Stromal syndecan-1 expression can serve as an indicator of poor prognosis in patients with endometrial cancer.

Syndecan-1 Expression – A Novel Prognostic Marker in Pancreatic Cancer

Objective: Syndecan-1 is a transmembrane receptor that participates in cell-cell and cell-matrix interactions, cell proliferation and cell migration. Expression of syndecan-1 is downregulated in many cancers, but in pancreatic ductal adenocarcinoma it is upregulated. Method: We studied the immunohistochemical expression of syndecan-1 in 144 pancreatic adenocarcinomas and evaluated the prognostic value of syndecan-1 expression. Formalin-fixed, paraffin-embedded specimens were stained with mouse monoclonal antibody B-B4 against human syndecan-1. The epithelial and stromal staining was separately evaluated and compared with patient survival, clinical stage and histological grade. Result: Epithelial immunoreactivity was observed in most of the pancreatic carcinoma samples: in 70 (49%) of the samples the epithelial staining was weak, in 48 (33%) moderate, in 18 (12%)strong and in only 8 (6%) of the samples the epithelial staining was negative. Stromal staining was weak in 24 (17%), moderate in 31 (22%), strong in 11 (8%) and negative in 78 (54%) of the pancreatic carcinoma samples. Lack of stromal expression predicted a better prognosis (p = 0.002; HR 1.7) and it was independent of stage (p = 0.01; HR = 1.5) and grade (p = 0.0004; HR 2.1) in multivariate analysis. Epithelial expression predicted better prognosis for patients that underwent surgery for cure (n = 94, p = 0.03). Conclusion: Stromal syndecan-1 expression is an independent prognostic marker in pancreatic cancer, whereas epithelial syndecan-1 expression predicts better prognosis only in resectable disease.

Prognostic Value of Syndecan-1 Expression in Breast Cancer

Objective: Syndecan-1 is a cell surface heparan sulphate proteoglycan which participates in cell proliferation, cell migration and cell-matrix interactions. Epithelial syndecan-1 expression is reduced in several malignant tumours, but in breast and pancreatic cancer, increased expression has also been described. Loss of epithelial syndecan-1 has been associated with poor prognosis in some forms of cancer, but previous findings in breast cancer have been contradictory. The objective of this study was to evaluate the prognostic value of the immunohistochemical expression of syndecan-1 in a series of 200 patients with invasive breast cancer with a median follow-up of 17 years. Methods: Formalin-fixed paraffin-embedded specimens were stained using a monoclonal antibody against syndecan-1. Results: Syndecan-1 was expressed in the epithelium in 61% and in the stroma in 67% of the tumours. Epithelial syndecan-1 expression was associated with negative oestrogen receptor (ER) status (p < 0.01), and stromal syndecan-1 expression with positive ER status (p = 0.02). The breast cancer-specific 10-year overall survival for patients with epithelial syndecan-1 expression was 65%, compared with 82% for those with loss of epithelial expression (p = 0.02). Ten-year survival was 66% for those expressing stromal syndecan-1 and 83% for those lacking stromal expression (p = 0.15). Patients with both epithelial and stromal expression had a 10-year survival of only 56%, compared to 78% in patients with other expression pattern combinations (p < 0.002). In Cox multivariate analysis, only axillary involvement and tumour size were significant predictors of breast cancer-specific survival. Conclusion: Concomitant expression of syndecan-1 in both epithelium and stroma may be a predictor of unfavourable prognosis in breast cancer, and in contrast with previous studies, loss of epithelial syndecan-1 was associated with a more favourable prognosis.

Syndecan-1 expression in thyroid carcinoma: stromal expression followed by epithelial expression is significantly correlated with dedifferentiation.

To investigate the expression of syndecan-1 in thyroid neoplasia. Syndecan-1 is a proteoglycan regulating cell adhesion. Previous studies have demonstrated that decreased expression of syndecan-1 is linked to malignant progression. Syndecan-1 expression in thyroid neoplasia was studied immunohistochemically. Syndecan-1 was expressed in stromal cells as well as neoplastic epithelial cells. Stromal syndecan-1 expression was observed more frequently in papillary carcinomas larger than 10 mm in size than in microcarcinomas and in widely invasive than in minimally invasive follicular carcinomas. Furthermore, poorly differentiated carcinomas showed this phenomenon more than well-differentiated carcinomas, but the expression in undifferentiated carcinomas was similar to that of poorly differentiated carcinomas. Epithelial syndecan-1 expression was more frequently observed in anaplastic (undifferentiated) carcinomas than in papillary and follicular carcinomas. No significant difference in epithelial expression was found between well and poorly differentiated carcinomas, but undifferentiated carcinomas expressed epithelial syndecan-1 more frequently than did poorly differentiated carcinomas. These results are in contrast to those previously reported for carcinomas at other sites. It is suggested that the role of syndecan-1 in thyroid carcinomas might be unique. Stromal syndecan-1 expression followed by its epithelial expression is significantly related to progression, including dedifferentiation of thyroid carcinoma.

Regulation of epithelial syndecan-1 expression by inflammatory cytokines.

Syndecan-1 is expressed on the basolateral surface of columnar epithelium and contributes to wound repair by facilitating increased growth factor binding. Inflammatory bowel disease (IBD) is associated with reduced syndecan-1 expression in areas of inflamed mucosa that is likely to impair mucosal healing. Reduced syndecan-1 expression in IBD may be related to the presence of increased inflammatory cytokines. To test this hypothesis, monolayers of HT29 and T84 colonic epithelial cells were stimulated with tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta or IL-6. Stimulation of HT29 cells with TNF-alpha and IL-1beta resulted in reversible down-regulation of syndecan-1 at both protein and mRNA levels but little effect was observed with IL-6. Loss of syndecan-1 expression was caused by shedding of the ectodomain as revealed by increased levels of soluble syndecan-1 measured in the conditioned medium of stimulated cells. No increase in cytoplasmic staining accompanied the loss of cell surface syndecan-1 expression. TNF-alpha and IL-1beta are capable of down-regulating syndecan-1 expression and may account in part for the reduced expression of syndecan-1 seen in IBD.

Epithelial and stromal syndecan-1 expression as predictor of outcome in patients with gastric cancer.

The prognostic value of the immunohistochemical expression of epithelial and stromal syndecan-1 was evaluated in 296 patients with gastric carcinoma. Formalin-fixed, paraffin-embedded specimens of gastric adenocarcinomas were stained with mouse monoclonal antibody B-B4 against human syndecan-1. Loss of immunoreactivity (syndecan-1 immunoreactivity correlated with a higher stage of disease (stages II-IV), tumour location in the upper third of the stomach, nodal metastases (N1 or N2), positive stromal syndecan-1 staining, deep tumour penetration (to subserosa or deeper = T2-T4), larger tumour size (> or = 5 cm) and intestinal type of cancer. No correlation between epithelial syndecan-1 immunoreactivity and age, gender, distant metastases, grade of differentiation or Borrmann classification was observed. Positive stromal syndecan-1 immunoreactivity correlated with decreased epithelial syndecan-1 expression, intestinal type of cancer and Borrmann type I. Patients with low epithelial syndecan-1 expression in cancer cells had worse overall survival than patients with strong epithelial syndecan-1 staining (p = 0.0012). Stromal syndecan-1-positive patients had a worse outcome than patients with syndecan-1-negative stroma (p = 0.0193). In Cox multivariate analysis, stromal syndecan-1 immunoreactivity was a prognostic factor independent of TNM stage, surgery for cure and tumour size. Thus, the immunohistochemical expression of syndecan-1 might be a predictor of outcome in patients with gastric adenocarcinoma.

Suppression of epithelial syndecan-1 expression by tumour necrosis factor-a

Background: Syndecan-I, a transmembrane heparan sulphate proteoglycan, is expressed on the basolateral surface of columnar epithelium where it functions as a cell-cell, cell-matrix adhesion molecule. Syndecan-I binds to a variety of matrix and heparin-binding growth factor molecules and is thought to play an important role during wound repair, where its expression is usually upregulated, by facilitating increased growth factor binding. In inflammatory bowel disease (ffiD) syndecan-l expression is reduced in areas of ulcerated mucosa, particularly in reparative epithelium. The mechanism causing reduced syndecan-l expression in ffiD is unknown. Aim: To investigate the regulatory effect of the pro-inflammatory cytokine tumour necrosis factor-a (TNF-a) on syndecan-I expression in the HT29 colonic epithelial cell line. Methods: Confluent monolayers of HT29 cells were stimulated with TNF-a (0.625, 0.125, 2.5, 5.0, 10, 25, 50 ng/ml) for 24 hours. Flow cytometry (FACS) and immunofluorescent microscopy using indirect immunostaining procedures were used to analyze syndecan-l protein expression. The mean fluorescent intensity (MFI) of syndecan-I staining in viable antibody labeled treated cells was compared with that of untreated control cells. All experiments were performed in triplicate. Modulation of syndecan-I expression at the RNA level was determined using RT-PCR. Results: Stimulation of HT29 monolayers with TNF-a resulted in down-regulation of syndecan-I at both the protein and RNA levels as revealed by FACS analysis and RT-PCR. Reduction of MFI ranged from 10% at 0.625 ng/ml to 64% at 50 ng/ml. Time course studies revealed that cells treated with 5 ng/ml TNF-a had a 2% reduction in MFI at 3-5 hours and a maximum reduction (-35%) at 13 hours. Immunofluorescence microscopy revealed a visible progressive reduction in membrane staining with increasing concentrations of TNF-a. No increase in cytoplasmic staining was observed at any concentration of TNF-a. Conclusions: Reduced syndecan-l expression is likely to impair mucosal healing due to diminished anti-ulcerogenic growth factor binding. These data show that TNF-a, a pro-inflammatory cytokine thought to have an etiological role in Crohn's disease, has a strong effect on the downregulation of syndecan-l expression. Such an effect may account for the apparently unique reduction of syndecan-I expression in ffiD.