Kleinberg L, Holth A, Trope CG, Reich R, Davidson BClaudin upregulation in ovarian carcinoma effusions is associated with poor survival. Hum Pathol 39: 747-757

Pathology Clinic, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, N-0310 Oslo, Norway.
Human Pathlogy (Impact Factor: 2.77). 06/2008; 39(5):747-57. DOI: 10.1016/j.humpath.2007.10.002
Source: PubMed


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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    • "The expression of claudins 1, 2, 3, 4, 5, and 7 were analyzed in 35 reactive mesothelium and 24 metastatic adenocarcinomas of different origins by Soini et al.[19] Authors in this study reported that reactive mesothelium have a lower expression of claudins 1, 3, 4, 5, and 7 than adenocarcinomas, and their expression could thus be used as an adjunct in the differential diagnosis between the two. In another study, Kleinberg et al.[20] analyzed the diagnostic role of claudins in effusion cytology in 325 effusions, including 218 ovarian, 49 breast, 15 cervical or endometrial, 10 gastrointestinal, and 8 lung adenocarcinomas and 25 malignant mesotheliomas, and suggested that claudins can be included in a panel of diagnostic markers for the differential diagnosis of effusion samples, whereas the expression of claudin-3 or claudin-7 is specific for adenocarcinoma and rules out the diagnosis of cells as mesothelial. They also recommended that the absence of claudin-1 expression essentially excludes ovarian carcinoma as the possible origin in metastatic adenocarcinoma. "
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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.
    Full-text · Article · Aug 2014
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    • "[14, 71, 72, 314–316] CLDNs Large family of integral membrane proteins essential for tight junction formation and function; CLDN3 and CLDN4 expression levels are upregulated in EOCs of all subtypes and correlate with MMP-2 activity; CLDNs may promote ovarian cancer invasion and metastasis; CLDN upregulation in ovarian carcinoma effusions is associated with poor survival; cells that overexpress CLDN4 exhibit low DNA methylation and high histone H3 acetylation of the critical CLDN4 promoter region, while the converse is true for cells that do not overexpress it; CLDN4-expressing EOC cells secrete proangiogenic factors (e.g., IL-8) and downregulate genes of the angiostatic IFN pathway; CLDN5 overexpression is associated with aggressive behavior in serous ovarian adenocarcinoma; CLDNs are, therefore, suitable biomarkers for different types of ovarian cancer and promising molecular targets for ovarian cancer therapy. [317] [318] [319] [320] [321] [322] [323] [324] [325] [326] APOA1 "
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    ABSTRACT: The hallmarks of ovarian cancer encompass the development of resistance, disease recurrence and poor prognosis. Ovarian cancer cells express gene signatures which pose significant challenges for cancer drug development, therapeutics, prevention and management. Despite enhancements in contemporary tumor debulking surgery, tentative combination regimens and abdominal radiation which can achieve beneficial response rates, the majority of ovarian cancer patients not only experience adverse effects, but also eventually relapse. Therefore, additional therapeutic possibilities need to be explored to minimize adverse events and prolong progression-free and overall response rates in ovarian cancer patients. Currently, a revival in cancer drug discovery is devoted to identifying diagnostic and prognostic ovarian cancer biomarkers. However, the sensitivity and reliability of such biomarkers may be complicated by mutations in the BRCA1 or BRCA2 genes, diverse genetic risk factors, unidentified initiation and progression elements, molecular tumor heterogeneity and disease staging. There is thus a dire need to expand existing ovarian cancer therapies with broad-spectrum and individualized molecular targeted approaches. The aim of this review is to profile recent developments in our understanding of the interrelationships among selected ovarian tumor biomarkers, heterogeneous expression signatures and related molecular signal transduction pathways, and their translation into more efficacious targeted treatment rationales.
    Full-text · Article · Feb 2012 · Journal of Oncology
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    • "In ovarian carcinoma high claudin 3 and 7 expression in cells of the effusion fluid predicted a poor survival [58]. "
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    ABSTRACT: Tight junctions are structures located in the apicobasal region of the cell membranes. They regulate paracellular solute and electrical permeability of cell layers. Additionally, they influence cellular polarity, form a paracellular fence to molecules and pathogens and divide the cell membranes to apical and lateral compartments. Tight junctions adhere to the corresponding ones of neighbouring cells and by this way also mediate attachment of the cells to one other. Molecules forming the membranous part of tight junctions include occludin, claudins, tricellulin and junctional adhesion molecules. These molecules are attached to scaffolding proteins such as ZO-1, ZO-2 and ZO-3 through which signals are mediated to the cell interior. Expression of tight junction proteins, such as claudins, may be up- or downregulated in cancer and they are involved in EMT thus influencing tumor spread. Like in tumors of other sites, lung tumors show changes in the expression in tight junction proteins. In this review the significance of tight junctions and its proteins in lung cancer is discussed with a focus on the proteins forming the membranous part of these structures.
    Full-text · Article · Jan 2012 · International journal of clinical and experimental pathology
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