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BACKGROUND The granulin-epithelin precursor (GEP) was preferentially expressed in invasive ovarian tumor epithelium specimens compared with specimens of borderline ovarian tumors. The objective of the current study was to evaluate the anatomic site-related and cellular expression of GEP and its association with clinicopathologic parameters and survival in patients with advanced-stage ovarian carcinoma. METHODS Effusions (n = 190), corresponding primary tumor specimens (n = 64), and specimens of metastatic lesions (n = 125) were analyzed using immunohistochemistry with a specific polyclonal antipeptide antibody. In addition, 36 effusions were analyzed using immunoblotting. RESULTS GEP was detected in tumor cells in 171 of 190 (90%) effusions and demonstrated both focal membrane and cytoplasmic localization. Mesothelial cells were often GEP positive (81%). GEP was found in carcinoma cells in 180 of 189 (95%) tumor biopsy specimens, with stromal and endothelial cell expression in 93 of 180 (52%) and 124 of 185 (67%) specimens, respectively. Lower GEP expression in stromal cells was observed in metastases sampled during or after chemotherapy (P = 0.034). The presence of GEP-positive stromal cells in untreated primary tumor specimens correlated with worse overall survival (P = 0.014). Significantly more frequent GEP expression was observed in tumor cells of both primary (P = 0.002) and metastatic (P < 0.001) tissue specimens compared with malignant effusions. CONCLUSIONS GEP expression was observed in primary and metastatic epithelial ovarian carcinoma specimens, with down-regulated expression in tumor cells of malignant effusions. The poor outcome associated with stromal GEP expression suggests a prognostic role for this growth factor in ovarian carcinoma. Cancer 2004. Published 2004 American Cancer Society.

BACKGROUND. Death receptors mediate both apoptosis and survival in cancer cells. The authors analyzed death receptor expression in metastatic ovarian carcinoma. METHODS. Viable tumor cells in ovarian carcinoma effusions (n = 95) were analyzed for DR4, DR5, Fas, TNFR1, and TNFR2 expression using flow cytometry. Results were analyzed for association with clinicopathologic parameters, chemotherapy response, and survival. RESULTS. DR4, DR5, and Fas were expressed by the majority of specimens, with less frequent expression of TNFR1 and TNFR2. DR4 (P = .005) and TNFR2 (P = .041) expression was higher in FIGO stage IV compared with stage III tumors. Effusions from patients who responded poorly to chemotherapy administered at disease recurrence had significantly higher DR4 (P = .006), DR5 (P = .01), and Fas (P = .001) expression. In univariate survival analysis, higher DR4 expression in viable cells correlated with poor overall (P = .0352) and progression-free (P = .0411) survival. DR4 expression was found to be an independent predictor of overall (P = .008) and progression-free (P = .003) survival. CONCLUSIONS. The authors have presented the first evidence of death receptor coexpression in ovarian carcinoma effusions. The association of death receptor expression in effusions with advanced stage, poor response to chemotherapy, and shorter survival suggests that these molecules are linked to an aggressive clinical course in metastatic ovarian carcinoma. Cancer 2008. © 2007 American Cancer Society.

BACKGROUND. The authors recently reported on the role of cyclin E in differentiating ovarian/primary peritoneal carcinoma from malignant peritoneal mesothelioma using gene expression arrays. In the current study, they analyzed the expression of low-molecular weight (LMW) forms of cyclin E in ovarian carcinoma, malignant mesothelioma, and benign reactive effusions. METHODS. Cyclin E protein expression was analyzed in 98 effusions (72 ovarian carcinomas, 14 malignant mesotheliomas, and 12 reactive specimens) using immunoblotting. Sixty-two ovarian carcinoma effusions were studied further for cyclin E expression using immunohistochemistry. The correlations between cyclin E expression in ovarian carcinoma and clinical parameters, including chemotherapy response, were analyzed. RESULTS. LMW forms of cyclin E were identified in 54 of 72 ovarian carcinoma effusions (75%) compared with 1 of 14 malignant mesothelioma effusions (7%) and 1 of 12 reactive effusions (8%) (P < .001). Their presence in ovarian carcinoma was associated with a higher percentage of cyclin E-positive cells (P = .001) and increased staining intensity (P < .001) using immunohistochemistry. The presence of LMW forms of cyclin E was correlated with shorter overall survival (P = .021) and progression-free survival (P = .020). The presence of a higher percentage of cyclin E-positive cells using immunohistochemistry was correlated with shorter progression-free survival (P = .026). No association with chemotherapy response was observed. CONCLUSIONS. LMW forms of cyclin E differentiated ovarian carcinoma from benign and malignant mesothelial cells and were associated with increased protein expression using immunohistochemistry. The expression of LMW cyclin E forms was not associated with chemotherapy response, although it may be a marker of aggressive disease in patients with metastatic ovarian carcinoma. Cancer 2007. © 2007 American Cancer Society.

Inhibitor of apoptosis proteins (IAPs) mediate cancer cell survival and chemoresistance. The expression of XIAP, Survivin, and Livin in ovarian carcinoma was analyzed.Effusions (106) were analyzed for XIAP, Survivin, and Livin expression using immunoblotting. Effusions (220), corresponding primary tumors (60), and solid metastases (103) were further immunohistochemically analyzed for XIAP and Survivin expression. The results were analyzed for association with anatomic site, clinicopathologic parameters, and survival.Immunoblotting showed frequent expression of XIAP and Survivin, and no expression of Livin. Immunohistochemistry showed cytoplasmic XIAP expression in 208 of 220 (94%) effusions, 50 of 60 (83%) primary tumors, and 87 of 103 (84%) solid metastases, with a significantly higher staining extent in effusions (P.001). Cytoplasmic Survivin was found in 194 of 220 (88%) effusions, 55 of 60 (92%) primary tumors, and 102 of 103 (99%) solid metastases, with a significantly higher cytoplasmic staining extent in solid metastases (P = .018 and P = .006 compared with primary tumors and effusions, respectively). Nuclear Survivin was expressed in 159 of 220 (72%) effusions, 54 of 60 (90%) primary carcinomas, and 96 of 103 (93%) solid metastases (P.05). For patients with prechemotherapy effusions, higher nuclear Survivin expression correlated with better progression-free (P = .0003) and overall (P = .002) survival in univariate survival analysis. Nuclear Survivin expression was found to be an independent predictor of progression-free survival (P = .004).XIAP and Survivin, but not Livin, are frequently expressed in ovarian carcinoma. XIAP and cytoplasmic Survivin are up-regulated in effusions and solid metastases, respectively, possibly mediating survival at these sites. Nuclear Survivin expression predicts better outcome in prechemotherapy patients.

The granulin-epithelin precursor (GEP) was preferentially expressed in invasive ovarian tumor epithelium specimens compared with specimens of borderline ovarian tumors. The objective of the current study was to evaluate the anatomic site-related and cellular expression of GEP and its association with clinicopathologic parameters and survival in patients with advanced-stage ovarian carcinoma.Effusions (n = 190), corresponding primary tumor specimens (n = 64), and specimens of metastatic lesions (n = 125) were analyzed using immunohistochemistry with a specific polyclonal antipeptide antibody. In addition, 36 effusions were analyzed using immunoblotting.GEP was detected in tumor cells in 171 of 190 (90%) effusions and demonstrated both focal membrane and cytoplasmic localization. Mesothelial cells were often GEP positive (81%). GEP was found in carcinoma cells in 180 of 189 (95%) tumor biopsy specimens, with stromal and endothelial cell expression in 93 of 180 (52%) and 124 of 185 (67%) specimens, respectively. Lower GEP expression in stromal cells was observed in metastases sampled during or after chemotherapy (P = 0.034). The presence of GEP-positive stromal cells in untreated primary tumor specimens correlated with worse overall survival (P = 0.014). Significantly more frequent GEP expression was observed in tumor cells of both primary (P = 0.002) and metastatic (P0.001) tissue specimens compared with malignant effusions.GEP expression was observed in primary and metastatic epithelial ovarian carcinoma specimens, with down-regulated expression in tumor cells of malignant effusions. The poor outcome associated with stromal GEP expression suggests a prognostic role for this growth factor in ovarian carcinoma.