Claudin upregulation in ovarian carcinoma effusions is associated with poor survival.
ABSTRACT Claudins are tight junction proteins that are highly expressed in ovarian carcinoma (OC). The objective of this study was to analyze the anatomic site-related expression and clinical role of claudins in OC. Effusions (n = 218), corresponding primary tumors (n = 81), and solid metastases (n = 164) (total = 463 tumors) were immunostained for claudin-1, claudin-3, claudin-4, and claudin-7. Results were analyzed for association with anatomic site, clinicopathologic parameters, and survival. All 4 claudins were expressed in >85% of tumors at all anatomic sites. However, staining extent of all except claudin-4 was significantly higher in effusions compared with both primary carcinomas and solid metastases (P < .001). In univariate survival analysis of the entire cohort, higher claudin-3 (P = .038) and claudin-7 (P = .035) expression in effusions correlated with shorter overall survival (OS), with similar results for claudin-7 in analysis of progression-free survival (P = .026). In separate analysis for patients with prechemotherapy effusions, higher claudin-7 expression correlated with shorter OS (P = .045). For patients with postchemotherapy effusions, higher claudin-1 (P = .018) and claudin-3 (P = .009) expression correlated with shorter OS. In multivariate survival analysis of the entire cohort, claudin-7 expression was an independent predictor of poor progression-free survival (P = .017). Claudin-3 independently predicted poor OS for patients with postchemotherapy effusions (P = .012). With the exception of claudin-4, claudins are upregulated in OC effusions compared with solid tumors, in agreement with our previous data for cadherins and integrins in this cancer type, suggesting a prosurvival role for these surface molecules. Claudin-3 and claudin-7 expression in effusions independently predicts poor survival in OC.
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ABSTRACT: Background:Several markers have been used to make a distinction between metastatic adenocarcinoma and reactive mesothelial cells in the body cavity effusions. This study aimed to evaluate the diagnostic value of claudin-4 marker in making such a distinction.Materials and Methods:In this cross-sectional study, a total of 92 pleural/peritoneol effusions have been studied, including 47 cases of definite metastatic carcinoma and 45 cases of reactive mesothelium, and definitely negative for malignancy. Specimens were collected from patients; cell block samples were derived and used for immunohistochemical staining. The antibody used for immunohistochemical labeling was monoclonal anti-claudin-4. In the evaluation, membrane-bound reactivity was considered as significant and positive cases were defined when at least more than 10% of tumor cells were distinctly labeled.Results:Claudin-4 protein was positive in 40 specimens of metastatic carcinoma, while none of the cases of reactive mesothelium stained with the marker. This was not detected in the mesothelial cells, though. Positive staining for claudin-4 was significantly more frequent in metastatic carcinoma than in the reactive mesothelium (P > 0.0001). The sensitivity and specificity of claudin-4 to distinguish reactive mesothelium from metastatic carcinoma were 85% (95% confidence interval [CI], 71.1-93.8%) and 100% (95% CI, 91.1-100%), respectively. Furthermore, negative likelihood ratio was 0.15 (95% CI, 0.08-0.29).Conclusion:The results of this study demonstrated that claudin-4 is less frequently expressed in reactive mesothelium. Thus, this claudin may be helpful in differentiating metastatic carcinoma from reactive mesothelial cells in pleural and peritoneal fluid cytology specimen.08/2014; 3:161. DOI:10.4103/2277-9175.138888
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ABSTRACT: Seventy percent of ovarian cancer patients die due to consecutive episodes of recurrences resulting from the re-growth of ovarian tumor cells resistant to conventional chemotherapies. In an effort to identify chemoresistance mechanisms, we compared the expression of genes in tumor cells isolated from the ascites of advanced-stage serous ovarian cancer patients prior to (chemonaive, CN) and after chemotherapy treatments (chemoresistant/recurrent, CR). A novel, recently published method was used for the isolation of tumor cells from the ascites of CN and CR patients. Illumina HT-12 platform was used to assess the differential expression of genes (DEGs) between the isolated tumor cells from the ascites of CN and CR patients. The identification of DEGs was achieved by comparing the genetic signatures of CN versus CR samples by a mean expression ratio (fold change) of 2 and P < 0.05. Validation of selected genes was performed by quantitative Real Time Polymerase Chain Reaction (qRT-PCR). The dominant canonical pathways in the CR versus CN tumor cells were determined by Ingenuity Pathway Analysis. Gene expression analysis revealed differential expression of 414 genes, with 179 genes up regulated and 235 down regulated in the CR group. There were significant differences in gene expressions encoding for proteins involved with cancer stem cells, cell-cell adhesion, embryonic development, tumor suppression, immune surveillance, retinoic acid and energy metabolism in tumor cells isolated from CR compared to CN patients. Pathway analysis revealed that changes in cell cycle pathways, prominently those involved with mitosis and polo-like kinase (PLK1), G2/M DNA damage and proteins linked with cell cycle checkpoint regulation associated with chemoresistance. This preliminary molecular profiling, on a small number of patient samples, suggests an important discrimination of genes in the isolated tumor cells derived from the ascites of CN and CR patients. This type of study on a larger cohort of samples may have important clinical implications for the development of therapeutic strategies to overcome chemoresistance and associated recurrences in ovarian cancer patients.
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ABSTRACT: Ovarian cancers highly overexpress folate receptor α (FRα) and claudin3 (CLDN3), both of which are associated with tumor progression and poor prognosis of patients. Downregulation of FRα and CLDN3 in ovarian cancer may suppress tumor growth and promote benign differentiation of tumor. In this study, F-P-LP/CLDN3, a FRα targeted liposome loading with short hairpin RNA (shRNA) targeting CLDN3 was prepared and the pharmaceutical properties were characterized. Then, antitumor effect of F-P-LP/CLDN3 was studied in vivo model of advanced ovarian cancer. Compared with Control, F-P-LP/CLDN3 promoted benign differentiation of tumor and achieved about 90% tumor growth inhibition. In the meantime, malignant ascites production was completely inhibited, and tumor nodule number and tumor weight were significantly reduced (p<0.001). FRα and CLDN3 were downregulated together in tumor tissues treated by F-P-LP/CLDN3. The antitumor mechanisms were achieved by promoting tumor cell apoptosis, inhibiting tumor cell proliferation and reducing microvessel density. Finally, safety evaluation indicated that F-P-LP/CLDN3 was a safe formulation in intraperitoneally administered cancer therapy. We come to a conclusion that F-P-LP/CLDN3 is a potential targeting formulation for ovarian cancer gene therapy.Journal of Controlled Release 10/2013; 172(3). DOI:10.1016/j.jconrel.2013.10.015 · 7.26 Impact Factor