The effect of cyclooxygenase‐2 expression on tumor vascularity in advanced stage ovarian serous carcinoma

Ali-Fehmi, Rouba; Che, Mingxin; Khalifeh, Ibrahim; Malone, John M.; Morris, Robert T.; Lawrence, W. Dwayne; Munkarah, Adnan

doi:10.1002/cncr.11650

Cited by 69 publications

(57 citation statements)

References 21 publications

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“…10 One study investigated the expression of both COX-1 and COX-2 isozymes in normal and malignant ovarian epithelium. 25 COX-1 and COX-2 proteins were present in 69.3% and 70.8%, respectively, of all tumors studied. Notably, COX-2-positive staining seemed significantly higher in the metastatic than in the primary sites.…”

Section: Recently Kurman Et Al Proposed a New Classification Ofmentioning

confidence: 92%

“…Several recent studies have shown that COX-2 is overexpressed in epithelial ovarian and primary peritoneal cancers and that overexpression correlates with worse clinical behavior. [25][26][27][28][29] COX-2 overexpression was noted in 65% to 75% of serous ovarian carcinomas studied. It was associated with increased tumor vascularity.…”

Section: Recently Kurman Et Al Proposed a New Classification Ofmentioning

confidence: 93%

“…25,27,30 Women with COX-2-positive tumors had a lower response to chemotherapy and shorter survival. 25 Gene expression profiling of postchemotherapy patient tissues suggests COX-1 as a potential marker for chemoresistance. COX-1 and COX-2 have been reported to be the potential target for the treatment of epithelial ovarian cancer.…”

Section: Recently Kurman Et Al Proposed a New Classification Ofmentioning

confidence: 99%

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Molecular typing of epithelial ovarian carcinomas using inflammatory markers

Ali-Fehmi

Semaan

Sethi

et al. 2010

Cancer

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BACKGROUND: Ovarian epithelial carcinomas have recently been classified as slow growing type I tumors and rapidly growing highly aggressive type II tumors. The present study sought to molecularly characterize type I and II tumors using known molecular markers. METHODS: Specimens from 213 patients with ovarian carcinoma were categorized as type I or type II, and evaluated by immunohistochemistry for the inflammatory markers glucose transporter protein-1 (Glut-1), inducible nitric oxide synthase (iNOS), cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and nuclear factor kappa B. Statistical analysis was performed to investigate whether these molecular markers could distinguish between type I and type II tumors. Kaplan-Meier survival curves and COX regression analysis were used to determine the prognostic effect of these markers on survival in the 2 types of tumors. RESULTS: Overexpression of COX-1, COX-2, iNOS, and Glut-1 was significantly higher in type II tumors (P < .05). Women with type II tumors had a poorer median survival (60 months) as compared with those with type I tumors (141 months) (P ¼.0001). Multivariate analysis revealed type II tumors, late stage, and age >60 years as significant predictors of poor survival. For type II tumors, median survival of patients with tumors overexpressing COX-2 was 44 compared with 85 months for those with tumors with low COX-2 expression (P ¼.029). Looking at both type I and II tumors, the number of markers simultaneously overexpressed in each tumor was a significant predictor of poor patient survival (P ¼.005). CONCLUSIONS: The present study demonstrates that the new proposed histologic classification of ovarian epithelial carcinomas correlates with a distinct expression of inflammatory pathway proteins. High expression of these markers may explain the different biologic behavior of these 2 tumor types and provide targets for therapy. Cancer 2011;117:301-9.

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Section: Recently Kurman Et Al Proposed a New Classification Ofmentioning

confidence: 92%

Section: Recently Kurman Et Al Proposed a New Classification Ofmentioning

confidence: 93%

Section: Recently Kurman Et Al Proposed a New Classification Ofmentioning

confidence: 99%

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Molecular typing of epithelial ovarian carcinomas using inflammatory markers

Ali-Fehmi

Semaan

Sethi

et al. 2010

Cancer

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“…Low expression was defined as intensity 0, 1, 2 or 3 and o10% cells staining or intensity 0, 1 and o50% cells staining; high expression was defined as intensity 2, 3 and 410% cells staining or intensity 1, 2, 3 and 450% of cells staining. 18 To determine Ki-67 and p53 expression, nuclei from at least 1000 tumor cells were counted from the tumor fields, and the labeling index was calculated as the percentage of labeled nuclei of the total number of tumor cells that were counted. 19 Tumors with a Ki-67 labeling index above 44% (median value) were considered to have high proliferation indices.…”

Section: Assessment Of Antibody Expressionsmentioning

confidence: 99%

Increased expression of hypoxia-inducible factor 1α in type I and type II endometrial carcinomas

et al. 2007

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Hypoxia-inducible factor 1a (HIF-1a) is a nuclear protein that is upregulated in many tumors and triggers biologic events intimately associated with aggressive tumor behavior. The aim of this study was to analyze the expression of HIF-1a, vascular endothelial growth factor (VEGF), Ki-67 and p53 in type I and type II endometrial adenocarcinoma. In total, 149 patients diagnosed with endometrial adenocarcinoma in our institute from 1995 to 2001 were included in this study, of which 108 were type I and 41 were type II endometrial adenocarcinoma. Patient demographics, clinical and pathological data were reviewed. Tissue microarrays were prepared from the paraffin blocks and immunohistochemistry was performed for antibodies against HIF-1a, VEGF, Ki-67 and p53. High expression of HIF-1a, VEGF, Ki-67 and p53 were significantly more frequent in type II than type I endometrial adenocarcinoma (Po0.001). HIF-1a expression was highly correlated with VEGF expression in the tumor cells (P ¼ 0.001). In type I endometrial adenocarcinoma, high expression of HIF-1a showed a significant correlation with higher grade of the tumor, depth of myometrial invasion, adnexal invasion and clinical stage. A similar correlation was not observed in type II endometrial adenocarcinoma. Surgical stage was the only independent prognostic marker for survival. In conclusion, high expression of HIF-1a is more frequent in type II than in type I endometrial adenocarcinoma. In type I endometrial adenocarcinoma, HIF-1a expression correlates with morphologic features of aggressiveness. In type II endometrial adenocarcinoma, there is no correlation between HIF-1a expression and these features. Thus, HIF-1a may play an important role in endometrial adenocarcinoma progression, particularly in type I endometrial adenocarcinoma. Additional investigations of HIF-1a as a biomarker of aggressive potential and as a novel target for therapeutics in endometrial adenocarcinoma are warranted. Hypoxia-inducible factor 1 (HIF-1) is a nuclear protein that activates gene transcription specifically in response to reduced cellular oxygen concentration and therefore acts as a marker for hypoxia. It is a dimeric protein with two subunits, a and b. HIF-1a is the specific hypoxia-regulated subunit. 2 Hypoxia results in stabilization of HIF-1a, facilitating nuclear HIF-1a binding and restoration of oxygen homeostasis by inducing glycolysis and angiogenesis through upregulation of vascular endothelial growth

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“…Aoki et al 54 reported gene expression of cox-2 to be correlated with that of bcl-2 in pleomorphic adenoma and Tatsaguchi et al 55 found both bcl-2 expression and low apoptosis to be closely related to cox-2 expression in gastric cancer cells, and moreover, cox-2 and bcl-2 protein levels to be correlated with each other. On the other hand, Sweeney et al 56 did not observe any correlation between cox-2 and bcl-2 protein in lung or bladder cancer specimens and Ali-Fehmi et al 57 observed no association between cox-2 and bcl-2 levels in ovarian carcinoma. Again, it is difficult to tell whether these discrepancies really indicate differences in the mechanism of cox-2 activity among tumor types or result from technical problems associated with the use of semiquantitative IHC methodology, which can have standardization issues related to using different antibodies, staining and scoring protocols.…”

Section: Discussionmentioning

confidence: 95%

Increasing cyclooxygenase‐2 (cox‐2) gene expression in the progression of Barrett's esophagus to adenocarcinoma correlates with that of Bcl‐2

Shimizu

Vallböhmer

Kuramochi

et al. 2006

Intl Journal of Cancer

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Previous studies from our laboratory and others have suggested that increased expression of cox-2 is important in the genesis of esophageal adenocarcinoma. In vitro studies suggest that cox-2 regulates expression of the anti-apoptotic protein bcl-2, thus possibly accounting for reduced apoptosis in carcinogenesis. The aim of this study was to investigate the relationship of these 2 genes in the development of Barrett's-associated adenocarcinoma. Histologic sections from endoscopic biopsies or esophagectomy specimens were classified as non-dysplastic Barrett's (n 5 30), intraepithelial neoplasia (n 5 12) and adenocarcinoma (n 5 48). The desired tissue was isolated by laser capture microdissection and expression levels of cox-2 and bcl-2 were measured by quantitative real-time PCR (Taqman 1 ). Gene expression levels were compared to samples of the distal esophageal squamous epithelium (n 5 55) and reflux-esophagitis (n 5 25), without Barrett's or cancer. Expression of both bcl-2 and cox-2 were increased in non-dysplastic Barrett's (p 5 0.0077, p 5 0.0037), intraepithelial neoplasia (p 5 0.0053, p 5 0.0220) and adenocarcinoma (p < 0.0001, p < 0.0001) compared to squamous epithelium or reflux-esophagitis. Furthermore, there is a significant correlation between these two genes, especially in carcinoma (p < 0.0001). ' 2006 Wiley-Liss, Inc.Key words: bcl-2; cox-2; carcinogenesis; esophageal adenocarcinoma; Barrett's esophagusThe incidence of esophageal adenocarcinoma is increasing in a dramatic rate and this previously uncommon tumor has recently surpassed squamous cell carcinoma to become the most common esophageal cancer in many Western countries. Adenocarcinoma develops in a multi-step progression starting from a precursor lesion, Barrett's esophagus, a condition in which the normal squamous epithelium of the distal esophagus is replaced with metaplastic specialized intestinal-type epithelium as a sequela of chronic gastroesophageal reflux disease. [1][2][3] We and others have previously shown that the progression from metaplasia to intraepithelial neoplasia (IN) to adenocarcinoma in esophageal cancer is accompanied by increasing expression of cox-2, 4-13 one of the rate-limiting enzymes in the conversion of arachidonic acid to prostaglandins. Cox-2 appears to affect a remarkable variety of processes relevant to tumor development, including stimulation of epithelial cell proliferation, 14,15 apoptosis, 16 angiogenesis, 17,18 cell invasiveness, 19 immune suppression 20 and production of mutagens. 21 There is particularly good evidence that cox-2 promotes anti-apoptotic signaling and that this plays an important role in carcinogenesis, even though questions remain regarding the specific molecular mechanism of the effect. Early studies suggested that the effects of cox-2 on apoptosis were mediated through the induction of the anti-apoptotic molecule bcl-2. Tsujii and Dubois 22 showed that forced expression of cox-2 in cox-2-negative cells caused elevated levels of bcl-2, an effect that was reversed by a cox-2 inhibito...

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The effect of cyclooxygenase‐2 expression on tumor vascularity in advanced stage ovarian serous carcinoma

Cited by 69 publications

References 21 publications

Molecular typing of epithelial ovarian carcinomas using inflammatory markers

Molecular typing of epithelial ovarian carcinomas using inflammatory markers

Increased expression of hypoxia-inducible factor 1α in type I and type II endometrial carcinomas

Increasing cyclooxygenase‐2 (cox‐2) gene expression in the progression of Barrett's esophagus to adenocarcinoma correlates with that of Bcl‐2

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