Epithelial ovarian cancer: the molecular genetics of epithelial ovarian cancer.

PubMed

Krzystyniak, J; Ceppi, L; Dizon, D S; Birrer, M J

2016-04-01

Epithelial ovarian cancer (EOC) remains one of the leading causes of cancer-related deaths among women worldwide, despite gains in diagnostics and treatments made over the last three decades. Existing markers of ovarian cancer possess very limited clinical relevance highlighting the emerging need for identification of novel prognostic biomarkers as well as better predictive factors that might allow the stratification of patients who could benefit from a more targeted approach. A summary of molecular genetics of EOC. Large-scale high-throughput genomic technologies appear to be powerful tools for investigations into the genetic abnormalities in ovarian tumors, including studies on dysregulated genes and aberrantly activated signaling pathways. Such technologies can complement well-established clinical histopathology analysis and tumor grading and will hope to result in better, more tailored treatments in the future. Genomic signatures obtained by gene expression profiling of EOC may be able to predict survival outcomes and other important clinical outcomes, such as the success of surgical treatment. Finally, genomic analyses may allow for the identification of novel predictive biomarkers for purposes of treatment planning. These data combined suggest a pathway to progress in the treatment of advanced ovarian cancer and the promise of fulfilling the objective of providing personalized medicine to women with ovarian cancer. The understanding of basic molecular events in the tumorigenesis and chemoresistance of EOC together with discovery of potential biomarkers may be greatly enhanced through large-scale genomic studies. In order to maximize the impact of these technologies, however, extensive validation studies are required. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Cigarette smoking and the risk of epithelial ovarian cancer.

PubMed

Franks, A L; Lee, N C; Kendrick, J S; Rubin, G L; Layde, P M

1987-07-01

Cigarette smoking may affect each of the currently proposed mechanisms of ovarian carcinogenesis. Whether cigarette smoking has any effect on the development of ovarian cancer has not been adequately evaluated. To study this issue, the authors examined data from the Cancer and Steroid Hormone Study, a multicenter, case-control study of gynecologic cancers conducted between December 1, 1980, and December 31, 1982, in eight geographic areas of the United States. This analysis utilized data on 494 women with newly diagnosed epithelial ovarian cancer and 4,238 population-based control women 20-54 years of age. There was no association of epithelial ovarian cancer with dose of cigarette smoking, age smoking started, time since smoking started, or time since smoking last occurred. Simultaneous adjustment for age, parity, history of oral contraceptive use, and other potentially confounding factors did not alter these results.

Sirolimus and Vaccine Therapy in Treating Patients With Stage II-IV Ovarian Epithelial, Fallopian Tube, or Primary Peritoneal Cavity Cancer

ClinicalTrials.gov

2018-03-28

Recurrent Fallopian Tube Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Primary Peritoneal Cavity Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Epithelial Cancer; Stage IIA Primary Peritoneal Cavity Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Epithelial Cancer; Stage IIB Primary Peritoneal Cavity Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Epithelial Cancer; Stage IIC Primary Peritoneal Cavity Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIA Primary Peritoneal Cavity Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Epithelial Cancer; Stage IIIB Primary Peritoneal Cavity Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Epithelial Cancer; Stage IIIC Primary Peritoneal Cavity Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Primary Peritoneal Cavity Cancer

Prolactin Alters the Mammary Epithelial Hierarchy, Increasing Progenitors and Facilitating Ovarian Steroid Action.

PubMed

O'Leary, Kathleen A; Shea, Michael P; Salituro, Stephanie; Blohm, Courtney E; Schuler, Linda A

2017-10-10

Hormones drive mammary development and function and play critical roles in breast cancer. Epidemiologic studies link prolactin (PRL) to increased risk for aggressive cancers that express estrogen receptor α (ERα). However, in contrast to ovarian steroids, PRL actions on the mammary gland outside of pregnancy are poorly understood. We employed the transgenic NRL-PRL model to examine the effects of PRL alone and with defined estrogen/progesterone exposure on stem/progenitor activity and regulatory networks that drive epithelial differentiation. PRL increased progenitors and modulated transcriptional programs, even without ovarian steroids, and with steroids further raised stem cell activity associated with elevated canonical Wnt signaling. However, despite facilitating some steroid actions, PRL opposed steroid-driven luminal maturation and increased CD61 + luminal cells. Our findings demonstrate that PRL can powerfully influence the epithelial hierarchy alone and temper the actions of ovarian steroids, which may underlie its role in the development of breast cancer. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Risk of Epithelial Ovarian Cancer in Relation to Benign Ovarian Conditions and Ovarian Surgery

PubMed Central

Rossing, Mary Anne; Cushing-Haugen, Kara L.; Wicklund, Kristine G.; Doherty, Jennifer A.; Weiss, Noel S.

2009-01-01

Objective Some forms of ovarian neoplasms may be preventable through the removal of precursor lesions. We assessed risk associated with a prior diagnosis of, and ovarian surgery following, ovarian cysts and endometriosis, with a focus on characterizing risk among tumor subgroups. Methods Information was collected during in-person interviews with 812 women with ovarian cancer diagnosed in western Washington State from 2002–2005 and 1,313 population-based controls. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results The risk of a borderline mucinous ovarian tumor associated with a history of an ovarian cyst was increased (OR=1.7, 95% CI 1.0–2.8) but did not vary notably according to receipt of subsequent ovarian surgery. While risk of invasive epithelial ovarian cancer was slightly increased among women with a cyst who had no subsequent ovarian surgery, it was reduced when a cyst diagnosis was followed by surgery (OR= 0.6, 95% CI 0.4–0.9). This reduction in risk was most evident for serous invasive tumors. Women with a history of endometriosis had a three-fold increased risk of endometrioid and clear cell invasive tumors, with a lesser risk increase among women who underwent subsequent ovarian surgery. Conclusions Our results suggest differences in the relation of ovarian cysts and endometriosis with risk of specific subtypes of ovarian cancer, as well as the possibility that ovarian surgery in women with these conditions may lower the risk of invasive disease. PMID:18704718

Nesfatin-1 inhibits ovarian epithelial carcinoma cell proliferation in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Yang; Pang, Xiaoyan; Dong, Mei

Highlights: •Nesfatin-1 inhibits the proliferation and growth of HO-8910 cells by G1 phase arrest. •Nesfatin-1 enhances HO-8910 cell apoptosis. •Nesfatin-1 inhibits HO-8910 cell proliferation via mTOR and RhoA/ROCK signaling pathway. •The first report of nesfatin-1-mediated proliferation in ovarian epithelial carcinoma. -- Abstract: Nesfatin-1, an 82-amino-acid peptide derived from a 396-amino-acid precursor protein nucleobindin 2 (NUCB2), was originally identified in hypothalamic nuclei involved in the regulation of food intake. It was recently reported that nesfatin-1 is a novel depot specific adipokine preferentially produced by subcutaneous tissue, with obesity- and food deprivation-regulated expression. Although a relation between ovarian cancer mortality and obesitymore » has been previously established, a role of nesfatin-1 in ovarian epithelial carcinoma remains unknown. The aim of the present study is to examine the effect of nesfatin-1 on ovary carcinoma cells proliferation. We found that nesfatin-1 inhibits the proliferation and growth of HO-8910 cells by G1 phase arrest, this inhibition could be abolished by nesfatin-1 neutralizing antibody. Nesfatin-1 enhances HO-8910 cell apoptosis, activation of mammalian target of rapamycin (mTOR) and RhoA/ROCK signaling pathway block the effects of nesfatin-1-induced apoptosis, therefore reverses the inhibition of HO-8910 cell proliferation by nesfatin-1. In conclusion, the present study demonstrated that nesfatin-1 can inhibit the proliferation in human ovarian epithelial carcinoma cell line HO-8910 cells through inducing apoptosis via mTOR and RhoA/ROCK signaling pathway. This study provides a novel regulatory signaling pathway of nesfatin-1-regulated ovarian epithelial carcinoma growth and may contribute to ovarian cancer prevention and therapy, especially in obese patients.« less

Complex Determinants of Epithelial: Mesenchymal Phenotypic Plasticity in Ovarian Cancer

PubMed Central

Klymenko, Yuliya; Kim, Oleg; Stack, M. Sharon

2017-01-01

Unlike most epithelial malignancies which metastasize hematogenously, metastasis of epithelial ovarian cancer (EOC) occurs primarily via transcoelomic dissemination, characterized by exfoliation of cells from the primary tumor, avoidance of detachment-induced cell death (anoikis), movement throughout the peritoneal cavity as individual cells and multi-cellular aggregates (MCAs), adhesion to and disruption of the mesothelial lining of the peritoneum, and submesothelial matrix anchoring and proliferation to generate widely disseminated metastases. This exceptional microenvironment is highly permissive for phenotypic plasticity, enabling mesenchymal-to-epithelial (MET) and epithelial-to-mesenchymal (EMT) transitions. In this review, we summarize current knowledge on EOC heterogeneity in an EMT context, outline major regulators of EMT in ovarian cancer, address controversies in EMT and EOC chemoresistance, and highlight computational modeling approaches toward understanding EMT/MET in EOC. PMID:28792442

Origins based clinical and molecular complexities of epithelial ovarian cancer.

PubMed

Muinao, Thingreila; Pal, Mintu; Boruah, Hari Prasanna Deka

2018-06-08

Ovarian cancer is the most lethal of all common gynaecological malignancies in women worldwide. Ovarian cancer comprises of >15 distinct tumor types and subtypes characterized by histopathological features, environmental and genetic risk factors, precursor lesions and molecular events during oncogenesis. Recent studies on gene signatures profiling of different subtypes of ovarian cancer have revealed significant genetic heterogeneity between and within each ovarian cancer histological subtype. Thus, an immense interest have shown towards a more personalized medicine for understanding the clinical and molecular complexities of four major types of epithelial ovarian cancer (serous, endometrioid, clear cell, and mucinous). As such, further in depth studies are needed for identification of molecular signalling network complexities associated with effective prognostication and targeted therapies to prevent or treat metastasis. Therefore, understanding the metastatic potential of primary ovarian cancer and therapeutic interventions against lethal ovarian cancer for the development of personalized therapies is very much indispensable. Consequently, in this review we have updated the key dysregulated genes of four major subtypes of epithelial carcinomas. We have also highlighted the recent advances and current challenges in unravelling the complexities of the origin of tumor as well as genetic heterogeneity of ovarian cancer. Copyright © 2017. Published by Elsevier B.V.

Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment.

PubMed

Rojas, Veronica; Hirshfield, Kim M; Ganesan, Shridar; Rodriguez-Rodriguez, Lorna

2016-12-15

Epithelial ovarian cancer is a highly heterogeneous disease characterized by multiple histological subtypes. Molecular diversity has been shown to occur within specific histological subtypes of epithelial ovarian cancer, between different tumors of an individual patient, as well as within individual tumors. Recent advances in the molecular characterization of epithelial ovarian cancer tumors have provided the basis for a simplified classification scheme in which these cancers are classified as either type I or type II tumors, and these two categories have implications regarding disease pathogenesis and prognosis. Molecular analyses, primarily based on next-generation sequencing, otherwise known as high-throughput sequencing, are allowing for further refinement of ovarian cancer classification, facilitating the elucidation of the site(s) of precursor lesions of high-grade serous ovarian cancer, and providing insight into the processes of clonal selection and evolution that may be associated with development of chemoresistance. Potential therapeutic targets have been identified from recent molecular profiling studies of these tumors, and the effectiveness and safety of a number of specific targeted therapies have been evaluated or are currently being studied for the treatment of women with this disease.

Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment

PubMed Central

Rojas, Veronica; Hirshfield, Kim M.; Ganesan, Shridar; Rodriguez-Rodriguez, Lorna

2016-01-01

Epithelial ovarian cancer is a highly heterogeneous disease characterized by multiple histological subtypes. Molecular diversity has been shown to occur within specific histological subtypes of epithelial ovarian cancer, between different tumors of an individual patient, as well as within individual tumors. Recent advances in the molecular characterization of epithelial ovarian cancer tumors have provided the basis for a simplified classification scheme in which these cancers are classified as either type I or type II tumors, and these two categories have implications regarding disease pathogenesis and prognosis. Molecular analyses, primarily based on next-generation sequencing, otherwise known as high-throughput sequencing, are allowing for further refinement of ovarian cancer classification, facilitating the elucidation of the site(s) of precursor lesions of high-grade serous ovarian cancer, and providing insight into the processes of clonal selection and evolution that may be associated with development of chemoresistance. Potential therapeutic targets have been identified from recent molecular profiling studies of these tumors, and the effectiveness and safety of a number of specific targeted therapies have been evaluated or are currently being studied for the treatment of women with this disease. PMID:27983698

DNA methylation profiles of ovarian epithelial carcinoma tumors and cell lines.

PubMed

Houshdaran, Sahar; Hawley, Sarah; Palmer, Chana; Campan, Mihaela; Olsen, Mari N; Ventura, Aviva P; Knudsen, Beatrice S; Drescher, Charles W; Urban, Nicole D; Brown, Patrick O; Laird, Peter W

2010-02-22

Epithelial ovarian carcinoma is a significant cause of cancer mortality in women worldwide and in the United States. Epithelial ovarian cancer comprises several histological subtypes, each with distinct clinical and molecular characteristics. The natural history of this heterogeneous disease, including the cell types of origin, is poorly understood. This study applied recently developed methods for high-throughput DNA methylation profiling to characterize ovarian cancer cell lines and tumors, including representatives of three major histologies. We obtained DNA methylation profiles of 1,505 CpG sites (808 genes) in 27 primary epithelial ovarian tumors and 15 ovarian cancer cell lines. We found that the DNA methylation profiles of ovarian cancer cell lines were markedly different from those of primary ovarian tumors. Aggregate DNA methylation levels of the assayed CpG sites tended to be higher in ovarian cancer cell lines relative to ovarian tumors. Within the primary tumors, those of the same histological type were more alike in their methylation profiles than those of different subtypes. Supervised analyses identified 90 CpG sites (68 genes) that exhibited 'subtype-specific' DNA methylation patterns (FDR<1%) among the tumors. In ovarian cancer cell lines, we estimated that for at least 27% of analyzed autosomal CpG sites, increases in methylation were accompanied by decreases in transcription of the associated gene. The significant difference in DNA methylation profiles between ovarian cancer cell lines and tumors underscores the need to be cautious in using cell lines as tumor models for molecular studies of ovarian cancer and other cancers. Similarly, the distinct methylation profiles of the different histological types of ovarian tumors reinforces the need to treat the different histologies of ovarian cancer as different diseases, both clinically and in biomarker studies. These data provide a useful resource for future studies, including those of potential

Effect of estradiol on the expression of angiogenic factors in epithelial ovarian cancer.

PubMed

Valladares, Macarena; Plaza-Parrochia, Francisca; Lépez, Macarena; López, Daniela; Gabler, Fernando; Gayan, Patricio; Selman, Alberto; Vega, Margarita; Romero, Carmen

2017-11-01

Ovarian cancer presents a high angiogenesis (formation of new blood vessels) regulated by pro-angiogenic factors, mainly vascular endothelial growth factor (VEGF) and nerve growth factor (NGF). An association between endogenous levels of estrogen and increased risk of developing ovarian cancer has been reported. Estrogen action is mediated by the binding to its specific receptors (ERα and ERβ), altered ERα/ERβ ratio may constitute a marker of ovarian carcinogenesis progression. To determine the effect of estradiol through ERα on the expression of NGF and VEGF in epithelial ovarian cancer (EOC). Levels of phosphorylated estrogen receptor alpha (pERα) were evaluated in well, moderate and poorly differentiated EOC samples (EOC-I, EOC-II, EOC-III). Additionally, ovarian cancer explants were stimulated with NGF (0, 10 and 100 ng/ml) and ERα, ERβ and pERα levels were detected. Finally, human ovarian surface epithelial (HOSE) and epithelial ovarian cancer (A2780) cell lines were stimulated with estradiol, where NGF and VEGF protein levels were evaluated. In tissues, ERs were detected being pERα levels significantly increased in EOC-III samples compared with EOC-I (p<0.05). Additionally, ovarian explants treated with NGF increased pERα levels meanwhile total ERα and ERβ levels did not change. Cell lines stimulated with estradiol revealed an increase of NGF and VEGF protein levels (p<0.05). Estradiol has a positive effect on pro-angiogenic factors such as NGF and VEGF expression in EOC, probably through the activation of ERα; generating a positive loop induced by NGF increasing pERα levels in epithelial ovarian cells.

Inhibition of epithelial ovarian cancer by Minnelide, a water-soluble pro-drug.

PubMed

Rivard, Colleen; Geller, Melissa; Schnettler, Erica; Saluja, Manju; Vogel, Rachel Isaksson; Saluja, Ashok; Ramakrishnan, Sundaram

2014-11-01

Minnelide is a water-soluble pro-drug of triptolide, a natural product. The goal of this study was to evaluate the effectiveness of Minnelide on ovarian cancer growth in vitro and in vivo. The effect of Minnelide on ovarian cancer cell proliferation was determined by real time electrical impedance measurements. Multiple mouse models with C200 and A2780 epithelial ovarian cancer cell lines were used to assess the efficacy of Minnelide in inhibiting ovarian cancer growth. Minnelide decreased cell viability of both platinum sensitive and resistant epithelial ovarian cancer cells in vitro. Minnelide with carboplatin showed additive effects in vitro. Minnelide monotherapy increased the survival of mice bearing established ovarian tumors. Minnelide, in combination with carboplatin and paclitaxel, improved overall survival of mice. Minnelide is a promising pro-drug for the treatment of ovarian cancer, especially when combined with standard chemotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.

Polyglutamate Paclitaxel and Carboplatin in Treating Patients With Ovarian Epithelial, Peritoneal, or Fallopian Tube Cancer

ClinicalTrials.gov

2015-05-07

Fallopian Tube Carcinoma; Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Primary Peritoneal Carcinoma; Stage III Ovarian Cancer; Stage IV Ovarian Cancer; Undifferentiated Ovarian Carcinoma

Lack of HPV in Benign and Malignant Epithelial Ovarian Tumors in Iran

PubMed

Farzaneh, Farah; Nadji, Seyed Alireza; Khosravi, Donya; Hosseini, Maryam Sadat; Hashemi Bahremani, Mohammad; Chehrazi, Mohammad; Bagheri, Ghazal; Sigaroodi, Afsaneh; Haghighatian, Zahra

2017-05-01

Background: Ovarian epithelial tumors one of the most common gynecological neoplasms; we here evaluated the presence of HPV in benign and malignant examples. Methods: In this cross-sectional study the records of 105 patients with epithelial ovarian tumors (benign and malignant) referred to Imam Hossein University Hospital from 2012 to 2015 were evaluated along with assessment of the presence of the HPV infection using PCR. Results: Among 105 patients, comprising 26 (24.8%) with malignant and 79 (75.2%) with benign lesions, the factors found to impact on malignancy were age at diagnosis, age at first pregnancy, number of pregnancies and hormonal status. However, malignancies was not related to abortion, late menopause, and early menarche. In none of the ovarian tissues (benign and malignant) was HPV DNA found. Conclusion: In this study HPV DNA could not be found in any epithelial ovarian tumors (benign and malignant) removed from 105 women; more studies with larger sample size are needed for a definite conclusion. Creative Commons Attribution License

Risk factors of epithelial ovarian carcinomas among women with endometriosis: a systematic review.

PubMed

Thomsen, Line H; Schnack, Tine H; Buchardi, Kristina; Hummelshoj, Lone; Missmer, Stacey A; Forman, Axel; Blaakaer, Jan

2017-06-01

The objective of this review was to evaluate the published literature on epidemiologic risk factors for epithelial ovarian cancer among women with a diagnosis of endometriosis. A systematic literature search was conducted in PubMed and Scopus. Studies comparing epidemiologic risk factors of epithelial ovarian cancer among women with endometriosis were included. A quality assessment was conducted using the Newcastle-Ottawa Scale. Eight of 794 articles met the inclusion criteria. A lower risk of epithelial ovarian cancer was observed in women with documented complete surgical excision of endometriotic tissue and suggested among women with unilateral oophorectomy. The use of oral contraceptives (≥10 years) may be associated with a lower risk of epithelial ovarian cancer among women with endometriosis, whereas older age at endometriosis diagnosis (≥45 years, pre- or postmenopausal), nulliparity, hyperestrogenism (endogenous or exogenous), premenopausal status at endometriosis diagnosis, solid compartments as well as larger size of endometrioma (≥9 cm in diameter at endometriosis diagnosis) were all associated with an increased risk of ovarian cancer. A subgroup of women with endometriosis characterized by endometriosis observed through surgery or imaging after the age of 45 years, nulliparity, postmenopausal status at endometriosis diagnosis, larger size of endometrioma (>9 cm) at endometriosis diagnosis, hyperestrogenism (endogenous or exogenous) and/or cysts with solid compartments may have an elevated risk of epithelial ovarian cancer. However, due to the limited number and size of studies in this area we cannot draw definitive conclusions. Further research into a risk factor profile among women with endometriosis is needed before clear recommendations can be made. © 2016 Nordic Federation of Societies of Obstetrics and Gynecology.

Overexpression of Notch3 and pS6 Is Associated with Poor Prognosis in Human Ovarian Epithelial Cancer.

PubMed

Liu, Zhaoxia; Yun, Rongna; Yu, Xiaolin; Hu, Hui; Huang, Genhua; Tan, Buzhen; Chen, Tingtao

2016-01-01

Notch3 and pS6 play important roles in tumor angiogenesis. To assess the expression of Notch3 and pS6 in Chinese ovarian epithelial cancer patients, a ten-year follow-up study was performed in ovarian epithelial cancer tissues from 120 specimens of human ovarian epithelial cancer, 30 specimens from benign ovarian tumors, and 30 samples from healthy ovaries by immunohistochemistry. The results indicate that the expression of Notch3 and pS6 was higher in ovarian epithelial cancer than in normal ovary tissues and in benign ovarian tumor tissues (p < 0.01). In tumor tissues, Notch3 expression and pS6 expression were negatively associated with age (p > 0.05) but positively associated with clinical stage, pathological grading, histologic type, lymph node metastasis, and ascites (p < 0.05 or p < 0.01). A follow-up survey of 64 patients with ovarian epithelial cancer showed that patients with high Notch3 and pS6 expression had a shorter survival time (p < 0.01), in which the clinical stage (p < 0.05) and Notch3 expression (p < 0.01) played important roles. In conclusion, Notch3 and pS6 are significantly related to ovarian epithelial cancer development and prognosis, and their combination represents a potential biomarker and therapeutic target in ovarian tumor angiogenesis.

Vaccine Therapy and IDO1 Inhibitor INCB024360 in Treating Patients With Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Who Are in Remission

ClinicalTrials.gov

2013-12-17

Recurrent Fallopian Tube Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Primary Peritoneal Cavity Cancer; Stage IA Fallopian Tube Cancer; Stage IA Ovarian Epithelial Cancer; Stage IA Primary Peritoneal Cavity Cancer; Stage IB Fallopian Tube Cancer; Stage IB Ovarian Epithelial Cancer; Stage IB Primary Peritoneal Cavity Cancer; Stage IC Fallopian Tube Cancer; Stage IC Ovarian Epithelial Cancer; Stage IC Primary Peritoneal Cavity Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Epithelial Cancer; Stage IIA Primary Peritoneal Cavity Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Epithelial Cancer; Stage IIB Primary Peritoneal Cavity Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Epithelial Cancer; Stage IIC Primary Peritoneal Cavity Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIA Primary Peritoneal Cavity Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Epithelial Cancer; Stage IIIB Primary Peritoneal Cavity Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Epithelial Cancer; Stage IIIC Primary Peritoneal Cavity Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Primary Peritoneal Cavity Cancer

Surgery for advanced epithelial ovarian cancer.

PubMed

Hacker, Neville F; Rao, Archana

2017-05-01

Cytoreductive surgery for patients with advanced epithelial ovarian cancer has been practised since the pioneering work of Tom Griffiths in 1975. Further research has demonstrated the prognostic significance of the extent of metastatic disease pre-operatively, and of complete cytoreduction post-operatively. Patients with advanced epithelial ovarian cancer should be referred to high volume cancer units, and managed by multidisciplinary teams. The role of thoracoscopy and resection of intrathoracic disease is presently investigational. In recent years, there has been increasing use of neoadjuvant chemotherapy and interval cytoreductive surgery in patients with poor performance status, which is usually due to large volume ascites and/or large pleural effusions. Neoadjuvant chemotherapy reduces the post-operative morbidity, but if the tumour responds well to the chemotherapy, the inflammatory response makes the surgery more difficult. Post-operative morbidity is generally tolerable, but increases in older patients, and in those having multiple, aggressive surgical procedures, such as bowel resection or diaphragmatic stripping. Primary cytoreductive surgery should be regarded as the gold standard for most patients until a test is developed which would allow the prediction of platinum resistance pre-operatively. Copyright © 2016. Published by Elsevier Ltd.

Epithelial ovarian cancer and exposure to dietary nitrate and nitrite in the NIH-AARP Diet and Health Study.

PubMed

Aschebrook-Kilfoy, Briseis; Ward, Mary H; Gierach, Gretchen L; Schatzkin, Arthur; Hollenbeck, Albert R; Sinha, Rashmi; Cross, Amanda J

2012-01-01

Ovarian cancer is a leading cause of cancer death among women in the United States and it has the highest mortality rate of all gynecologic cancers. Internationally, there is a five-fold variation in incidence and mortality of ovarian cancer, which suggests a role for environmental factors, including diet. Nitrate and nitrite are found in various food items and they are precursors of N-nitroso compounds, which are known carcinogens in animal models. We evaluated dietary nitrate and nitrite intake and epithelial ovarian cancer in the National Institutes of Health (NIH)-AARP Diet and Health Study, including 151 316 women aged 50-71 years at the time of the baseline questionnaire in 1995-1996. The nitrate and nitrite intake was assessed using a 124-item validated food frequency questionnaire. Through 31 December 2006, 709 incident epithelial ovarian cancer cases with complete dietary information were identified. Using Cox proportional hazards regression to estimate hazard ratios and 95% confidence intervals (CIs), women in the highest intake quintile of dietary nitrate had a 31% increased risk (95% CI: 1.01-1.68) of epithelial ovarian cancer, compared with those in the lowest intake quintile. Although there was no association for total dietary nitrite, those in the highest intake category of animal sources of nitrite had a 34% increased risk (95% CI: 1.05-1.69) of ovarian cancer. There were no clear differences in risk by histologic subtype of ovarian cancer. Our findings suggest that a role of dietary nitrate and nitrite in ovarian cancer risk should be followed in other large cohort studies.

Drugs with potential chemopreventive properties in relation to epithelial ovarian cancer--a nationwide case-control study.

PubMed

Baandrup, Louise

2015-07-01

Ovarian cancer has a poor prognosis because the disease in the majority of patients is diagnosed at an advanced stage as a result of nonspecific symptoms and lack of efficient screening methods. Because of the poor prognosis of ovarian cancer and the challenge of early detection of the disease, identification of protective factors is important. It has been suggested that some commonly used drugs may have a protective effect against cancer, including ovarian cancer; however, the literature on chemopreventive measures for ovarian cancer is sparse and the results are inconclusive. Most previous studies have substantial methodological constraints, including limited study size and self-reporting of drug use, which introduces potential recall bias and misclassification. This PhD thesis includes a nationwide case-control study to evaluate associations between use of drugs with potential chemopreventive properties and risk of epithelial ovarian cancer. The study is nested in the entire Danish female population using data from the following nationwide registries: the Danish Cancer Registry, the Danish Civil Registration System, the Danish Prescription Registry, the Danish National Patient Register, and registries in Statistics Denmark on fertility, education, and income. Information from the included registries is linked by use of the unique personal identification number assigned to all Danish citizens. The cases were all women in Denmark with epithelial ovarian cancer diagnosed during 2000-2009 (Paper 1) and 2000-2011 (Papers 2 and 3), identified in the Cancer Registry. Age-matched female population controls were randomly selected from the Civil Registration System by risk-set sampling. We required that cases and controls have no history of cancer (except non-melanoma skin cancer) and that controls not previously have undergone bilateral oophorectomy or salpingo-oophorectomy. The total study population comprised 3741 epithelial ovarian cancer cases and 50,576 controls in

Evaluation of Ocoxin-Viusid® in Advanced or Metastatic Ovarian Epithelial Cancer

ClinicalTrials.gov

2018-06-08

Carcinoma; Ovarian Neoplasm; Endocrine Gland Neoplasm; Urogenital Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Endocrine System Diseases; Gonadal Disorders; Genital Neoplasm, Female; Neoplasms, Glandular and Epithelial

Treatment of Ovarian Epithelial, Fallopian, & Peritoneal Cancer (PDQ®)—Patient Version

Cancer.gov

Treatment of ovarian epithelial, fallopian tube, and primary peritoneal cancers depend on the stage. Most patients have surgery to remove as much of the tumor as possible. Learn about the different types of surgery, including hysterectomy and bilateral salpingo-oophorectomy, and other ovarian cancer treatment options.

Conditionally immortal ovarian cell lines for investigating the influence of ovarian stroma on the estrogen sensitivity and tumorigenicity of ovarian surface epithelial cells.

PubMed

Jiang, Feng; Saunders, Beatriz O; Haller, Edward; Livingston, Sandra; Nicosia, Santo V; Bai, Wenlong

2003-01-01

The tendency of the ovarian surface epithelium (OSE) to undergo metaplastic and morphogenetic changes during the life cycle, at variance with the adjacent peritoneal mesothelial cells, suggests that its biology may be regulated by underlying ovarian stromal cues. However, little is known about the role that the ovarian stroma plays in the pathobiology of the OSE, largely because of the lack of a suitable in vitro model. Here, we describe the establishment and characterization of conditionally immortalized ovarian stromal and surface epithelial cell lines from H-2K(b)-tsA58 transgenic mice that carry the thermolabile mutant of SV-40 large T antigen under the control of an interferon-gamma (IFN-gamma)-inducible promoter. These cells express functional T antigens, grow continuously under permissive conditions at 33 degrees C in the presence of IFN-gamma, and stop dividing when the activity and expression of the tumor antigen is suppressed by restrictive conditions without IFN-gamma at 39 degrees C. Morphological, immunohistochemical, and ultrastructural analyses show that conditionally immortal OSE cells form cobblestone-like monolayers, express cytokeratin and vimentin, contain several microvilli, and develop tight junctions, whereas stromal cells are spindle-like, express vimentin but not cytokeratin, and contain rare microvilli, thus exhibiting epithelial and stromal phenotypes, respectively. At variance with the reported behavior of rat epithelial cells, conditionally immortal mouse epithelial cells are not spontaneously transformed after continuous culture in vitro. More importantly, conditioned media from stromal cells cultured under permissive conditions increase the specific activity of the endogenous estrogen receptor in BG-1 human ovarian epithelial cancer cells and promote these cells' anchorage-independent growth, suggesting the paracrine influence of a stromal factor. In addition, stromal cells cultured under restrictive conditions retain this growth

A Pilot Study of Circulating MicroRNA-125b as a Diagnostic and Prognostic Biomarker for Epithelial Ovarian Cancer.

PubMed

Zhu, Tao; Gao, Wen; Chen, Xi; Zhang, Ying; Wu, Meijuan; Zhang, Ping; Wang, Shihua

2017-01-01

Early diagnosis of epithelial ovarian cancer is critical for patient survival. The objective of this pilot study is to identify a circulating micro (mi)RNA as a potential biomarker for epithelial ovarian cancer. A total of 135 epithelial ovarian cancer patients and 54 benign ovarian tumor patients were recruited for this study. Using customized TaqMan low density miRNA arrays, we first screened expression levels of 48 miRNAs in sera from 18 epithelial ovarian cancer patients and 16 benign ovarian tumor patients. The most significantly and differentially expressed miRNA was then further examined in all serum samples using real-time polymerase chain reaction. Its expression was further analyzed in relationship with clinicopathological factors and patient survival. Array screening data showed that expression levels of serum miRNA-20a, miRNA-125b, miRNA-126, miRNA-355, and let-7c were significantly different between malignant and benign ovarian tumor patients. Subsequent real-time polymerase chain reaction results showed that serum miRNA-125b levels were significantly higher in epithelial ovarian cancer patients compared to benign controls. Moreover, serum miRNA-125b levels were significantly higher in ovarian cancer patients in early stages I and II, and in patients having no residual tumor following surgery, but were not associated with differentiation and histological types of ovarian cancer. Notably, the higher level of miR-125b was significantly positively correlated with progression-free survival (P = 0.035) and marginally, with overall survival (P = 0.069). miRNA-125b plays an important role in the pathogenesis and progression of epithelial ovarian cancer. Circulating miRNA-125b has the potential to become a novel biomarker for early diagnosis and prognosis prediction of epithelial ovarian cancer.

The role of EMMPRIN expression in ovarian epithelial carcinomas.

PubMed

Zhao, Yang; Chen, Shuo; Gou, Wen-feng; Niu, Zhe-feng; Zhao, Shuang; Xiao, Li-jun; Takano, Yasuo; Zheng, Hua-chuan

2013-09-01

Extracellular matrix metalloproteinase inducer (EMMPRIN) was reported to involve in the invasion and metastasis of malignancies by regulating the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) in stromal and cancer cells. The study aimed to clarify the role of EMMPRIN expression in tumorigenesis and progression of ovarian epithelial carcinomas. EMMPRIN siRNA were transfected into ovarian carcinoma cells with the phenotypes and their related molecules examined. EMMPRIN expression was determined in ovarian normal tissue, benign and borderline tumors, and epithelial carcinomas by real-time PCR, western blot, and immunohistochemistry. EMMPRIN siRNA treatment resulted in a lower growth, G 1 arrest, apoptotic induction, decreased migration, and invasion. The transfectants showed reduced expression of Wnt5a, Akt, p70s6k, Bcl-xL, survivin, VEGF, and MMP-9 than mock and control cells at both mRNA and protein levels. According to real-time PCR and western blot, EMMPRIN mRNA or protein level was higher in ovarian borderline tumor and carcinoma than normal ovary and benign tumors (P<0.05), and positively correlated with dedifferentiation and FIGO staging (P<0.05). Immunohistochemically, EMMPRIN expression was positively correlated with FIGO staging, dedifferentiation, Ki-67 expression, the lower cumulative and relapse-free survival rate (P<0.05). Upregulated expression of EMMPRIN protein and mRNA might be involved in the pathogenesis, differentiation, and progression of ovarian carcinomas, possibly by modulating cellular events, such as proliferation, cell cycle, apoptosis, migration, and invasion.

Cytokeratin 5 positive cells represent a therapy resistant subpopulation in epithelial ovarian cancer

PubMed Central

Corr, Bradley R.; Finlay-Schultz, Jessica; Rosen, Rachel B.; Qamar, Lubna; Post, Miriam D.; Behbakht, Kian; Spillman, Monique A.; Sartorius, Carol A.

2015-01-01

Objective Cytokeratin 5 (CK5) is an epithelial cell marker implicated in stem and progenitor cell activity in glandular reproductive tissues and endocrine and chemotherapy resistance in estrogen receptor (ER)+ breast cancer. The goal of this study was to determine the prevalence of CK5 expression in ovarian cancer and the response of CK5+ cell populations to cisplatin therapy. Materials and Methods CK5 expression was evaluated in two ovarian tissue microarrays, representing 137 neoplasms, and six ovarian cancer cell lines. Cell lines were treated with IC50 cisplatin and the prevalence of CK5+ cells pre- and post-treatment determined. Proliferation of CK5+ vs. CK5− cell populations was determined using bromodeoxyuridine (BrdU) incorporation. Chemotherapy induced apoptosis in CK5+ vs. CK5− cells was measured using immunohistochemical staining for cleaved caspase-3. Results CK5 was expressed in 39.3% (42/107) of epithelial ovarian cancers with a range of 1-80% positive cells. Serous and endometrioid histologic subtypes had the highest percentage of CK5+ specimens. CK5 expression correlated with ER positivity (38/42 CK5+ tumors were also ER+). CK5 was expressed in 5/6 overall and 4/4 ER+ epithelial ovarian cancer cell lines ranging from 2.4-52.7% positive cells. CK5+ compared to CK5− cells were slower proliferating. The prevalence of CK5+ cells increased following 48 hour cisplatin treatment in 4/5 cell lines tested. CK5+ compared to CK5− ovarian cancer cells were more resistant to cisplatin induced apoptosis. Conclusions CK5 is expressed in a significant proportion of epithelial ovarian cancers and represents a slower proliferating, chemoresistant subpopulation that may warrant co-targeting in combination therapy. PMID:26495758

Potential application of curcumin and its analogues in the treatment strategy of patients with primary epithelial ovarian cancer.

PubMed

Terlikowska, Katarzyna M; Witkowska, Anna M; Zujko, Malgorzata E; Dobrzycka, Bozena; Terlikowski, Slawomir J

2014-11-25

Recent findings on the molecular basis of ovarian cancer development and progression create new opportunities to develop anticancer medications that would affect specific metabolic pathways and decrease side systemic toxicity of conventional treatment. Among new possibilities for cancer chemoprevention, much attention is paid to curcumin-A broad-spectrum anticancer polyphenolic derivative extracted from the rhizome of Curcuma longa L. According to ClinicalTrials.gov at present there are no running pilot studies, which could assess possible therapeutic benefits from curcumin supplementation to patients with primary epithelial ovarian cancer. Therefore, the goal of this review was to evaluate potential preclinical properties of curcumin and its new analogues on the basis of in vivo and in vitro ovarian cancer studies. Curcumin and its different formulations have been shown to display multifunctional mechanisms of anticancer activity, not only in platinum-resistant primary epithelial ovarian cancer, but also in multidrug resistant cancer cells/xenografts models. Curcumin administered together with platinum-taxane chemotherapeutics have been reported to demonstrate synergistic effects, sensitize resistant cells to drugs, and decrease their biologically effective doses. An accumulating body of evidence suggests that curcumin, due to its long-term safety and an excellent profile of side effects should be considered as a beneficial support in ovarian cancer treatment strategies, especially in patients with platinum-resistant primary epithelial recurrent ovarian cancer or multidrug resistant disease. Although the prospect of curcumin and its formulations as anticancer agents in ovarian cancer treatment strategy appears to be challenging, and at the same time promising, there is a further need to evaluate its effectiveness in clinical studies.

Epithelial ovarian cancer and exposure to dietary nitrate and nitrite in the NIH-AARP Diet and Health Study

PubMed Central

Aschebrook-Kilfoy, Briseis; Ward, Mary H.; Gierach, Gretchen L.; Schatzkin, Arthur; Hollenbeck, Albert R.; Sinha, Rashmi; Cross, Amanda J.

2012-01-01

Ovarian cancer is a leading cause of cancer death among women in the United States and it has the highest mortality rate of all gynecologic cancers. Internationally, there is a five-fold variation in incidence and mortality of ovarian cancer, which suggests a role for environmental factors, including diet. Nitrate and nitrite are found in various food items and they are precursors of N-nitroso compounds, which are known carcinogens in animal models. We evaluated dietary nitrate and nitrite intake and epithelial ovarian cancer in the National Institutes of Health (NIH)-AARP Diet and Health Study, including 151 316 women aged 50–71 years at the time of the baseline questionnaire in 1995–1996. The nitrate and nitrite intake was assessed using a 124-item validated food frequency questionnaire. Through 31 December 2006, 709 incident epithelial ovarian cancer cases with complete dietary information were identified. Using Cox proportional hazards regression to estimate hazard ratios and 95% confidence intervals (CIs), women in the highest intake quintile of dietary nitrate had a 31% increased risk (95% CI: 1.01–1.68) of epithelial ovarian cancer, compared with those in the lowest intake quintile. Although there was no association for total dietary nitrite, those in the highest intake category of animal sources of nitrite had a 34% increased risk (95% CI: 1.05–1.69) of ovarian cancer. There were no clear differences in risk by histologic subtype of ovarian cancer. Our findings suggest that a role of dietary nitrate and nitrite in ovarian cancer risk should be followed in other large cohort studies. PMID:21934624

Germline Mutations of Inhibins in Early-Onset Ovarian Epithelial Tumors

PubMed Central

Tournier, Isabelle; Marlin, Régine; Walton, Kelly; Charbonnier, Françoise; Coutant, Sophie; Théry, Jean-Christophe; Charbonnier, Camille; Spurrell, Cailyn; Vezain, Myriam; Ippolito, Lorena; Bougeard, Gaëlle; Roman, Horace; Tinat, Julie; Sabourin, Jean-Christophe; Stoppa-Lyonnet, Dominique; Caron, Olivier; Bressac-de Paillerets, Brigitte; Vaur, Dominique; King, Mary-Claire; Harrison, Craig; Frebourg, Thierry

2014-01-01

To identify novel genetic bases of early-onset epithelial ovarian tumors, we used the trio exome sequencing strategy in a patient without familial history of cancer who presented metastatic serous ovarian adenocarcinomas at 21 years of age. We identified a single de novo mutation (c.1157A>G/p.Asn386Ser) within the INHBA gene encoding the βA-subunit of inhibins/activins, which play a key role in ovarian development. In vitro, this mutation alters the ratio of secreted activins and inhibins. In a second patient with early-onset serous borderline papillary cystadenoma, we identified an unreported germline mutation (c.179G>T/p.Arg60Leu) of the INHA gene encoding the α-subunit, the partner of the βA-subunit. This mutation also alters the secreted activin/inhibin ratio, by disrupting both inhibin A and inhibin B biosynthesis. In a cohort of 62 cases, we detected an additional unreported germline mutation of the INHBA gene (c.839G>A/p.Gly280Glu). Our results strongly suggest that inhibin mutations contribute to the genetic determinism of epithelial ovarian tumors. PMID:24302632

[Chemotherapy in epithelial ovarian cancer].

PubMed

Tazi, Y; Pautier, P; Leary, A; Lhomme, C

2013-10-01

Chemotherapy is fundamental in the management of epithelial ovarian carcinomas both for early and advanced stages (rarely surgical treatment alone) and in almost every step of the disease. The reference schema combines carboplatin and paclitaxel intravenously. Intraperitoneal chemotherapy also proved its efficacy after complete surgery for advanced disease and should be reserved to trained teams due to its technical constraints and toxicity issues. Modalities of treatment in relapsed and progressive disease depend mainly on the free interval between this diagnosis and the last dose of platinum. Bevacizumab has proven its effectiveness in prolonging progression-free survival in 1st line setting in association with chemotherapy followed by maintenance and in case of relapse or progression both fore platinum sensitive or resistant disease. Finally, a better understanding of ovarian cancer biology will allow us to consider new molecular-targeted agents guided by the specific characteristics of each patient and each tumor. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

The role of EMMPRIN expression in ovarian epithelial carcinomas

PubMed Central

Zhao, Yang; Chen, Shuo; Gou, Wen-feng; Niu, Zhe-feng; Zhao, Shuang; Xiao, Li-jun; Takano, Yasuo; Zheng, Hua-chuan

2013-01-01

Purpose: Extracellular matrix metalloproteinase inducer (EMMPRIN) was reported to involve in the invasion and metastasis of malignancies by regulating the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) in stromal and cancer cells. The study aimed to clarify the role of EMMPRIN expression in tumorigenesis and progression of ovarian epithelial carcinomas. Methods: EMMPRIN siRNA were transfected into ovarian carcinoma cells with the phenotypes and their related molecules examined. EMMPRIN expression was determined in ovarian normal tissue, benign and borderline tumors, and epithelial carcinomas by real-time PCR, western blot, and immunohistochemisty. Results: EMMPRIN siRNA treatment resulted in a lower growth, G1 arrest, apoptotic induction, decreased migration, and invasion. The transfectants showed reduced expression of Wnt5a, Akt, p70s6k, Bcl-xL, survivin, VEGF, and MMP-9 than mock and control cells at both mRNA and protein levels. According to real-time PCR and western blot, EMMPRIN mRNA or protein level was higher in ovarian borderline tumor and carcinoma than normal ovary and benign tumors (P < 0.05), and positively correlated with dedifferentiation and FIGO staging (P < 0.05). Immuhistochemically, EMMPRIN expression was positively correlated with FIGO staging, dedifferentiation, Ki-67 expression, the lower cumulative and relapse-free survival rate (P < 0.05). Conclusions: Upregulated expression of EMMPRIN protein and mRNA might be involved in the pathogenesis, differentiation, and progression of ovarian carcinomas, possibly by modulating cellular events, such as proliferation, cell cycle, apoptosis, migration, and invasion. PMID:23966157

Epidemiologic and molecular characteristics of borderline and malignant epithelial ovarian tumors

NASA Astrophysics Data System (ADS)

Bastos, Eugenia Maria Chaves De Moraes

Data from the Cancer and Steroid Hormone Study, a multicenter, population-based, case-control study were used to identify risk factors for epithelial ovarian cancer according to tumor behavior, histologic types, as well as p53 expression. Cases were women between 20 to 54 years old diagnosed with epithelial ovarian cancer from 1980 to 1982. Controls were women selected by random digit dialing. Tumor samples were analyzed for p53 overexpression using immunohistochemistry. Case-case and case-control conditional logistic regression models matched on age and diagnosing centers were used to calculate odds ratios (OR's) and 95% confidence intervals (CI's) for borderline, malignant, mucinous, and nonmucinous tumors, and p53 positive and p53 negative cases. The OR's for high number of lifetime ovulatory cycles (376-533 compared with less than 234) were 3.1 (95% CI 1.6-6.1) for malignant and 1.4 (95% CI 0.5-3.7) for borderline cases. The high number of ovulatory cycles was also a strong risk factor among nonmucinous cases. OR's for current and recent ex-smokers compared with never smokers were 2.8 (95% CI 1.7-4.8) for mucinous and 0.9 (95% CI 0.7-1.1) for nonmucinous types. Infertility showed a positive association with borderline ovarian cancer. Family history of ovarian or breast cancer was positively associated with malignant and nonmucinous cases. Parity had an inverse association with malignant ovarian cancer cases. When cases were subdivided by p53 results, the OR for tobacco smoking and p53 positive ovarian cancer was elevated for mucinous (OR = 3.9; 95% CI 0.8-18) at localized stage. Alcohol use showed a positive association with p53 positive malignant cases at advanced stage (OR = 2.0; 95% CI 1.2-3.2) and with p53 positive nonmucinous cases at advanced stage (OR = 2.1; 95% CI 1.2-3.4). A positive association between high number of ovulatory cycles and p53 positive malignant cases was observed in cases with localized stage (OR = 6.6; 95% CI 1.0-45) and advanced

Epithelial Membrane Protein-2 is a Novel Therapeutic Target in Ovarian Cancer

PubMed Central

Fu, Maoyong; Maresh, Erin L.; Soslow, Robert A.; Alavi, Mohammad; Mah, Vei; Zhou, Qin; Iasonos, Alexia; Goodglick, Lee; Gordon, Lynn K.; Braun, Jonathan; Wadehra, Madhuri

2010-01-01

Purpose The tetraspan protein epithelial membrane protein-2 (EMP2) has been shown to regulate the surface display and signaling from select integrin pairs, and it was recently identified as a prognostic biomarker in human endometrial cancer. In this study, we assessed the role of EMP2 in human ovarian cancer. Experimental Design We examined the expression of EMP2 within a population of women with ovarian cancer using tissue microarray assay technology. We evaluated the efficacy of EMP2-directed antibody therapy using a fully human recombinant bivalent antibody fragment (diabody) in vitro and ovarian cancer xenograft models in vivo. Results EMP2 was found to be highly expressed in over 70% of serous and endometrioid ovarian tumors compared to non-malignant ovarian epithelium using a human ovarian cancer tissue microarray. Using anti-EMP2 diabody, we evaluated the in vitro response of 9 human ovarian cancer cell lines with detectable EMP2 expression. Treatment of human ovarian cancer cell lines with anti-EMP2 diabodies induced cell death and retarded cell growth, and these response rates correlated with cellular EMP2 expression. We next assessed the effects of anti-EMP2 diabodies in mice bearing xenografts from the ovarian endometrioid carcinoma cell line OVCAR5. Anti-EMP2 diabodies significantly suppressed tumor growth and induced cell death in OVCAR5 xenografts. Conclusions These findings indicate that EMP2 is expressed in the majority of ovarian tumors and it may be a feasible target in vivo. PMID:20670949

Potential Application of Curcumin and Its Analogues in the Treatment Strategy of Patients with Primary Epithelial Ovarian Cancer

PubMed Central

Terlikowska, Katarzyna M.; Witkowska, Anna M.; Zujko, Malgorzata E.; Dobrzycka, Bozena; Terlikowski, Slawomir J.

2014-01-01

Recent findings on the molecular basis of ovarian cancer development and progression create new opportunities to develop anticancer medications that would affect specific metabolic pathways and decrease side systemic toxicity of conventional treatment. Among new possibilities for cancer chemoprevention, much attention is paid to curcumin—A broad-spectrum anticancer polyphenolic derivative extracted from the rhizome of Curcuma longa L. According to ClinicalTrials.gov at present there are no running pilot studies, which could assess possible therapeutic benefits from curcumin supplementation to patients with primary epithelial ovarian cancer. Therefore, the goal of this review was to evaluate potential preclinical properties of curcumin and its new analogues on the basis of in vivo and in vitro ovarian cancer studies. Curcumin and its different formulations have been shown to display multifunctional mechanisms of anticancer activity, not only in platinum-resistant primary epithelial ovarian cancer, but also in multidrug resistant cancer cells/xenografts models. Curcumin administered together with platinum-taxane chemotherapeutics have been reported to demonstrate synergistic effects, sensitize resistant cells to drugs, and decrease their biologically effective doses. An accumulating body of evidence suggests that curcumin, due to its long-term safety and an excellent profile of side effects should be considered as a beneficial support in ovarian cancer treatment strategies, especially in patients with platinum-resistant primary epithelial recurrent ovarian cancer or multidrug resistant disease. Although the prospect of curcumin and its formulations as anticancer agents in ovarian cancer treatment strategy appears to be challenging, and at the same time promising, there is a further need to evaluate its effectiveness in clinical studies. PMID:25429431

Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube, endometrium, and colon.

PubMed

Marquez, Rebecca T; Baggerly, Keith A; Patterson, Andrea P; Liu, Jinsong; Broaddus, Russell; Frumovitz, Michael; Atkinson, Edward N; Smith, David I; Hartmann, Lynn; Fishman, David; Berchuck, Andrew; Whitaker, Regina; Gershenson, David M; Mills, Gordon B; Bast, Robert C; Lu, Karen H

2005-09-01

Epithelial ovarian cancers are thought to arise from flattened epithelial cells that cover the ovarian surface or that line inclusion cysts. During malignant transformation, different histotypes arise that resemble epithelial cells from normal fallopian tube, endometrium, and intestine. This study compares gene expression in serous, endometrioid, clear cell, and mucinous ovarian cancers with that in the normal tissues that they resemble. Expression of 63,000 probe sets was measured in 50 ovarian cancers, in 5 pools of normal ovarian epithelial brushings, and in mucosal scrapings from 4 normal fallopian tube, 5 endometrium, and 4 colon specimens. Using rank-sum analysis, genes whose expressions best differentiated the ovarian cancer histotypes and normal ovarian epithelium were used to determine whether a correlation based on gene expression existed between ovarian cancer histotypes and the normal tissues they resemble. When compared with normal ovarian epithelial brushings, alterations in serous tumors correlated with those in normal fallopian tube (P = 0.0042) but not in other normal tissues. Similarly, mucinous cancers correlated with those in normal colonic mucosa (P = 0.0003), and both endometrioid and clear cell histotypes correlated with changes in normal endometrium (P = 0.0172 and 0.0002, respectively). Mucinous cancers displayed the greatest number of alterations in gene expression when compared with normal ovarian epithelial cells. Studies at a molecular level show distinct expression profiles of different histologies of ovarian cancer and support the long-held belief that histotypes of ovarian cancers come to resemble normal fallopian tube, endometrial, and colonic epithelium. Several potential molecular markers for mucinous ovarian cancers have been identified.

Characterization of exosomes derived from ovarian cancer cells and normal ovarian epithelial cells by nanoparticle tracking analysis.

PubMed

Zhang, Wei; Peng, Peng; Kuang, Yun; Yang, Jiaxin; Cao, Dongyan; You, Yan; Shen, Keng

2016-03-01

Cellular exosomes are involved in many disease processes and have the potential to be used for diagnosis and treatment. In this study, we compared the characteristics of exosomes derived from human ovarian epithelial cells (HOSEPiC) and three epithelial ovarian cancer cell lines (OVCAR3, IGROV1, and ES-2) to investigate the differences between exosomes originating from normal and malignant cells. Two established colloid-chemical methodologies, electron microscopy (EM) and dynamic light scattering (DLS), and a relatively new method, nanoparticle tracking analysis (NTA), were used to measure the size and size distribution of exosomes. The concentration and epithelial cellular adhesion molecule (EpCAM) expression of exosomes were measured by NTA. Quantum dots were conjugated with anti-EpCAM to label exosomes, and the labeled exosomes were detected by NTA in fluorescent mode. The normal-cell-derived exosomes were significantly larger than those derived from malignant cells, and exosomes were successfully labeled using anti-EpCAM-conjugated quantum dots. Exosomes from different cell lines may vary in size, and exosomes might be considered as potential diagnosis biomarkers. NTA can be considered a useful, efficient, and objective method for the study of different exosomes and their unique properties in ovarian cancer.

Analgesic drug use and risk of epithelial ovarian cancer.

PubMed

Hannibal, Charlotte G; Rossing, Mary Anne; Wicklund, Kristine G; Cushing-Haugen, Kara L

2008-06-15

Analgesic use may reduce ovarian cancer risk, possibly through antiinflammatory or antigonadotropic effects. The authors conducted a population-based, case-control study in Washington State that included 812 women aged 35-74 years who were diagnosed with epithelial ovarian cancer between 2002 and 2005 and 1,313 controls. Use of analgesics, excluding use within the previous year, was assessed via in-person interviews. Logistic regression was used to calculate odds ratios and 95% confidence intervals. Overall, acetaminophen and aspirin were associated with weakly increased risks of ovarian cancer. These associations were stronger after more than 10 years of use (acetaminophen: odds ratio (OR) = 1.8, 95% confidence interval (CI): 1.3, 2.6; aspirin: OR = 1.6, 95% CI: 1.1, 2.2) and were present for indications of headache, menstrual pain, and other pain/injury. Reduced risk was observed among aspirin users who began regular use within the previous 5 years (OR = 0.6, 95% CI: 0.4, 1.0) or used this drug for prevention of heart disease (OR = 0.7, 95% CI: 0.5, 1.0). These results, in the context of prior findings, do not provide compelling evidence of a true increase in risk of ovarian cancer among women who use these drugs. However, they add to the weight of evidence that, in the aggregate, provides little support for the use of analgesic drugs as chemoprevention for this disease.

A6 in Treating Patients With Persistent or Recurrent Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

ClinicalTrials.gov

2015-02-27

Fallopian Tube Carcinoma; Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Primary Peritoneal Carcinoma; Recurrent Ovarian Carcinoma; Undifferentiated Ovarian Carcinoma

Constitutive Proteasomal Degradation of TWIST-1 in Epithelial Ovarian Cancer Stem Cells Impacts Differentiation and Metastatic Potential

PubMed Central

Yin, Gang; Alvero, Ayesha B.; Craveiro, Vinicius; Holmberg, Jennie C.; Fu, Han-Hsuan; Montagna, Michele K.; Yang, Yang; Chefetz-Menaker, Ilana; Nuti, Sudhakar; Rossi, Michael; Silasi, Dan-Arin; Rutherford, Thomas; Mor, Gil

2013-01-01

Epithelial-mesenchymal transition (EMT) is a critical process for embryogenesis but is abnormally activated during cancer metastasis and recurrence. This process enables epithelial cancer cells to acquire mobility and traits associated with stemness. It is unknown whether epithelial stem cells or epithelial cancer stem cells are able to undergo EMT, and what molecular mechanism regulates this process in these specific cell types. We found that Epithelial Ovarian Cancer Stem cells (EOC stem cells) are the source of metastatic progenitor cells through a differentiation process involving EMT and Mesenchymal-Epithelial Transition (MET). We demonstrate both in vivo and in vitro the differentiation of EOC stem cells into mesenchymal spheroid-forming cells (MSFCs) and their capacity to initiate an active carcinomatosis. Furthermore, we demonstrate that human EOC stem cells injected i.p in mice are able to form ovarian tumors, suggesting that the EOC stem cells have the ability to “home” to the ovaries and establish tumors. Most interestingly, we found that TWIST1 is constitutively degraded in EOC stem cells, and that the acquisition of TWIST1 requires additional signals that will trigger the differentiation process. These findings are relevant for understanding the differentiation and metastasis process in EOC stem cells. PMID:22349827

Paclitaxel, Bevacizumab And Adjuvant Intraperitoneal Carboplatin in Treating Patients Who Had Initial Debulking Surgery for Stage II, Stage III, or Stage IV Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube Cancer

ClinicalTrials.gov

2014-06-18

Brenner Tumor; Fallopian Tube Cancer; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Primary Peritoneal Cavity Cancer; Stage II Ovarian Epithelial Cancer; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

Ovarian Epithelial Inclusions With Mucinous Differentiation: A Clinicopathologic Study of 42 Cases.

PubMed

Seidman, Jeffrey D; Krishnan, Jayashree

2017-07-01

Ovarian epithelial inclusions lined by mucinous epithelium are rare and of uncertain origin. Ovaries containing such inclusions were studied in 42 women. The inclusions were divided into 3 groups: serous epithelial lined with typical ciliated morphology but with distinct basophilic cytoplasmic mucin in some or all of the lining cells, those lined by typical mucinous epithelium, and those lined by a combination of typical mucinous epithelium and serous epithelium. The mean patient age was 61.5 years. Pure mucinous inclusions were found in 27 patients, serous-type inclusions with cytoplasmic mucin in 20, and mixed type in 10. All 3 types of inclusions were found in 1 patient. Two types of inclusions were found in 13. Four patients had associated mucinous neoplasms (1 mucinous cystadenoma, 1 atypical proliferative seromucinous tumor, and 2 seromucinous cystadenomas), and 11 patients (26%) had endometriosis. The fallopian tubes in 4 patients (9.5%) also displayed mucinous metaplasia; this was not significantly different from the 3.1% we found in our previously reported series of unselected tubes from the same population. These findings suggest that mucinous inclusions may arise as a direct metaplastic change in serous-type inclusions. Other possible origins of mucinous inclusions in the ovarian cortex include endometriosis and Brenner (transitional cell) nests. Whether such inclusions can be a source of mucinous ovarian neoplasms as are Brenner tumors and mature cystic teratomas is unknown and may warrant further investigation.

Accuracy of ultrasound in prediction of rectosigmoid infiltration in epithelial ovarian cancer.

PubMed

Zikan, M; Fischerova, D; Semeradova, I; Slama, J; Dundr, P; Weinberger, V; Dusek, L; Cibula, D

2017-10-01

To examine prospectively the accuracy of ultrasound in predicting rectosigmoid tumor infiltration in patients with epithelial ovarian cancer. Patients referred for a suspicious pelvic mass between 2012 and 2014 were examined by ultrasound following the standard protocol for assessment of tumor infiltration. Of the 245 patients examined, 191 had proven ovarian cancer and underwent primary surgery and were included in the analysis. Patients with apparently benign or inoperable disease were excluded. Rectosigmoid infiltration was evaluated by histopathology or according to perioperative findings. Clinical, pathological and laboratory parameters were analyzed as factors potentially affecting the sensitivity and specificity of sonography. The sensitivity of ultrasound in detecting rectosigmoid infiltration in patients with ovarian cancer was 86.3%, with specificity of 95.8%, positive predictive value of 92.6%, negative predictive value of 91.9% and overall accuracy of 92.1%. Ultrasound is a highly accurate method for detecting rectosigmoid tumor infiltration in ovarian cancer patients, and thus, can be used for planning adequate management, including patient consultation, surgical team planning, suitable operating time and postoperative care. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Availability of healthcare resources and epithelial ovarian cancer stage of diagnosis and mortality among Blacks and Whites.

PubMed

Sakhuja, Swati; Yun, Huifeng; Pisu, Maria; Akinyemiju, Tomi

2017-08-22

The purpose of this study is to examine whether racial disparities in epithelial ovarian cancer stage at diagnosis and survival may be explained by geographic availability of healthcare resources among Blacks and Whites. Data from the Surveillance, Epidemiology and End Results (SEER) database was used to identify White and Black women ages 40 years and above diagnosed with epithelial ovarian cancer between 2000 and 2010. Data on county-level availability of healthcare resources was obtained from the Area Resource File. Multi-level regression models, overall and stratified by race and age, were used to examine the associations of health care access (HCA) and socioeconomic status (SES) with stage at diagnosis while Cox proportional hazards models were used to examine the association with survival. Among 46,423 women diagnosed with epithelial ovarian cancer, Blacks were more likely to reside in counties with fewer average number of oncology hospitals (p < 0.05) and hospitals with ultrasound (p < 0.001), but higher number of medical doctors (p < 0.0001) and Ob/Gyn (p < 0.001). Black patients had higher odds of late stage diagnosis of epithelial ovarian cancer (OR: 1.13, 95% CI: 1.04-1.25) and higher risk of epithelial ovarian cancer mortality (HR: 1.25, 95% CI: 1.19-1.32) compared with White patients after accounting for differential availability of healthcare resources. Among Black patients, residing in counties with fewer medical doctors was associated with increased odds of late stage diagnosis (OR: 1.86, 95% CI: 1.10-3.13), and the racial disparity in late stage diagnosis and mortality was larger among patients ages <65 years compared with older patients. Racial disparities in availability and utilization of healthcare resources likely contributes to adverse epithelial ovarian cancer outcomes among Black women in the US.

Laparoscopic staging for apparent stage I epithelial ovarian cancer.

PubMed

Melamed, Alexander; Keating, Nancy L; Clemmer, Joel T; Bregar, Amy J; Wright, Jason D; Boruta, David M; Schorge, John O; Del Carmen, Marcela G; Rauh-Hain, J Alejandro

2017-01-01

Whereas advances in minimally invasive surgery have made laparoscopic staging technically feasible in stage I epithelial ovarian cancer, the practice remains controversial because of an absence of randomized trials and lack of high-quality observational studies demonstrating equivalent outcomes. This study seeks to evaluate the association of laparoscopic staging with survival among women with clinical stage I epithelial ovarian cancer. We used the National Cancer Data Base to identify all women who underwent surgical staging for clinical stage I epithelial ovarian cancer diagnosed from 2010 through 2012. The exposure of interest was planned surgical approach (laparoscopy vs laparotomy), and the primary outcome was overall survival. The primary analysis was based on an intention to treat: all women whose procedures were initiated laparoscopically were categorized as having had a planned laparoscopic procedure, regardless of subsequent conversion to laparotomy. We used propensity methods to match patients who underwent planned laparoscopic staging with similar patients who underwent planned laparotomy based on observed characteristics. We compared survival among the matched cohorts using the Kaplan-Meier method and Cox regression. We compared the extent of lymphadenectomy using the Wilcoxon rank-sum test. Among 4798 eligible patients, 1112 (23.2%) underwent procedures that were initiated laparoscopically, of which 190 (17%) were converted to laparotomy. Women who underwent planned laparoscopy were more frequently white, privately insured, from wealthier ZIP codes, received care in community cancer centers, and had smaller tumors that were more frequently of serous and less often of mucinous histology than those who underwent staging via planned laparotomy. After propensity score matching, time to death did not differ between patients undergoing planned laparoscopic vs open staging (hazard ratio, 0.77, 95% confidence interval, 0.54-1.09; P = .13). Planned

Decoding critical long non-coding RNA in ovarian cancer epithelial-to-mesenchymal transition.

PubMed

Mitra, Ramkrishna; Chen, Xi; Greenawalt, Evan J; Maulik, Ujjwal; Jiang, Wei; Zhao, Zhongming; Eischen, Christine M

2017-11-17

Long non-coding RNA (lncRNA) are emerging as contributors to malignancies. Little is understood about the contribution of lncRNA to epithelial-to-mesenchymal transition (EMT), which correlates with metastasis. Ovarian cancer is usually diagnosed after metastasis. Here we report an integrated analysis of >700 ovarian cancer molecular profiles, including genomic data sets, from four patient cohorts identifying lncRNA DNM3OS, MEG3, and MIAT overexpression and their reproducible gene regulation in ovarian cancer EMT. Genome-wide mapping shows 73% of MEG3-regulated EMT-linked pathway genes contain MEG3 binding sites. DNM3OS overexpression, but not MEG3 or MIAT, significantly correlates to worse overall patient survival. DNM3OS knockdown results in altered EMT-linked genes/pathways, mesenchymal-to-epithelial transition, and reduced cell migration and invasion. Proteotranscriptomic characterization further supports the DNM3OS and ovarian cancer EMT connection. TWIST1 overexpression and DNM3OS amplification provides an explanation for increased DNM3OS levels. Therefore, our results elucidate lncRNA that regulate EMT and demonstrate DNM3OS specifically contributes to EMT in ovarian cancer.

Optimal primary surgical treatment for advanced epithelial ovarian cancer.

PubMed

Elattar, Ahmed; Bryant, Andrew; Winter-Roach, Brett A; Hatem, Mohamed; Naik, Raj

2011-08-10

Ovarian cancer is the sixth most common cancer among women. In addition to diagnosis and staging, primary surgery is performed to achieve optimal cytoreduction (surgical efforts aimed at removing the bulk of the tumour) as the amount of residual tumour is one of the most important prognostic factors for survival of women with epithelial ovarian cancer. An optimal outcome of cytoreductive surgery remains a subject of controversy to many practising gynae-oncologists. The Gynaecologic Oncology group (GOG) currently defines 'optimal' as having residual tumour nodules each measuring 1 cm or less in maximum diameter, with complete cytoreduction (microscopic disease) being the ideal surgical outcome. Although the size of residual tumour masses after surgery has been shown to be an important prognostic factor for advanced ovarian cancer, it is unclear whether it is the surgical procedure that is directly responsible for the superior outcome that is associated with less residual disease. To evaluate the effectiveness and safety of optimal primary cytoreductive surgery for women with surgically staged advanced epithelial ovarian cancer (stages III and IV).To assess the impact of various residual tumour sizes, over a range between zero and 2 cm, on overall survival. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 3) and the Cochrane Gynaecological Cancer Review Group Trials Register, MEDLINE and EMBASE (up to August 2010). We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. Retrospective data on residual disease from randomised controlled trials (RCTs) or prospective and retrospective observational studies which included a multivariate analysis of 100 or more adult women with surgically staged advanced epithelial ovarian cancer and who underwent primary cytoreductive surgery followed by adjuvant platinum

Risk factors for benign serous and mucinous epithelial ovarian tumors.

PubMed

Jordan, Susan J; Green, Adèle C; Whiteman, David C; Webb, Penelope M

2007-03-01

To investigate the risk factors for benign serous and mucinous epithelial ovarian tumors. Cases were women newly diagnosed with benign serous ovarian tumors (n=230) or benign mucinous tumors (n=133) between 2002 and 2005. Control women were selected at random from the general population (n=752). All participants completed a comprehensive reproductive and lifestyle questionnaire. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) and to simultaneously adjust for potential confounding factors. Current smoking was associated with a three-fold increase in risk of benign mucinous tumors (OR 3.25, 95% CI 1.97-5.34), and there was a trend of increasing risk with increasing amount smoked (P<.001). Both recent obesity (OR 1.93, 95% CI 1.30-2.88) and obesity at age 20 (OR 4.38, 95% CI 1.88-10.20) were associated with increased risk of benign serous ovarian tumors, and having had a hysterectomy was also related to increased risk of serous (OR 2.75, 95% CI 1.90-3.96), but not mucinous tumors. Ever having had a term pregnancy was inversely associated with both tumor types (combined OR 0.65, 95% CI 0.43-0.97), although greater numbers of pregnancies did not decrease risk further. Use of hormonal contraceptives was unrelated to risk. Our results suggest some differences in risk factors between benign serous and mucinous epithelial ovarian tumors and that risk factors for benign serous tumors differ from those well established for ovarian cancer. The results also suggest that there is potential for prevention of these common conditions through avoidance of smoking and obesity. II.

Cigarette smoking and the risk of invasive epithelial ovarian cancer in a prospective cohort study.

PubMed

Terry, P D; Miller, A B; Jones, J G; Rohan, T E

2003-05-01

Few cohort studies have examined the association between cigarette smoking and ovarian cancer risk, either overall, or by histological subtype. In relation to the latter, it has been suggested that mucinous ovarian tumours may be aetiologically unrelated to the other types of epithelial tumours and that their respective associations with cigarette smoking may differ. We examined the association between smoking and ovarian cancer risk using data from participants in a randomised controlled trial of screening for breast cancer involving 89,835 women aged 40-59 years at recruitment. Cox proportional hazards models were used to estimate rate ratios (RR) and 95% confidence intervals (CI). During an average of 16.5 years of follow-up, we observed 454 incident cases of ovarian cancer (184 serous, 67 endometrioid, 32 mucinous, 171 other or unknown). We found that women who had smoked for several decades had an approximately two-fold increased risk of epithelial ovarian cancer. Relative to never-smokers, women who had smoked for 40 years or more were at the highest risk (RR=2.50, 95% CI=1.37-4.56). The association with non-mucinous tumours was similar to that observed overall. For mucinous tumours, a two-fold increased risk was observed with smoking of shorter duration, although the number of mucinous tumours in our data-set was small. Long-term cigarette smoking may be associated with an increased risk of epithelial ovarian tumours.

The expression of asparaginyl endopeptidase promotes growth potential in epithelial ovarian cancer.

PubMed

Zhu, Qinyi; Tang, Meiling; Wang, Xipeng

2017-04-03

Epithelial ovarian cancer (EOC) is the most common and lethal cancer-related death among females in the world. Asparaginyl endopeptidase (AEP) is a member of C13 family peptidases and expressed in the extracellular matrix and tumor cells. The aim of this article is to explore the function of asparaginyl endopeptidase in epithelial ovarian cancer. The expression of AEP was examined in 20 EOC samples, 3 EOC metastasis samples, 6 fallopian tube metastasis samples, 4 peritoneum metastasis samples and 20 benign ovarian tumor samples by immunohistochemistry. The expression of AEP was also evaluated in serum and ascites of EOC patients by elisa. And we used a lentiviral vector to overexpress AEP in human epithelial ovarian cancer cell lines SKOV3ip and detected the function of AEP-SKOV3ip cells both in vitro and in vivo. The growth of AEP-SKOV3ip cells was observed by MTT, migration and tube formation assays in vitro. Additionally, the subcutaneous mice model was used to identify the tumor growth and metastasis in vivo. Mice tumors were stained for CD31 to determine the microvessel density (MVD). We demonstrated that AEP was highly expressed in the EOC patient tissues and ascites. The AEP transfected SKOV3ip cells could both promote tumor growth in vitro and in vivo. The MVD in AEP-SKOV3ip group was higher than that in NC-SKOV3ip group. Therefore, our results demonstrated that AEP could induce EOC growth and progressionboth in vitro and in vivo.

Ovarian Epithelial, Fallopian, & Peritoneal Cancer Treatment (PDQ®)—Health Professional Version

Cancer.gov

Ovarian epithelial, fallopian tube, and primary peritoneal cancer treatments include surgery, chemotherapy, targeted therapy, and PARP inhibitors. Get detailed information about these cancers, (newly diagnosed or recurrent) and how they are treated in this summary for clinicians.

Belinostat and Carboplatin in Treating Patients With Recurrent or Persistent Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer That Did Not Respond to Carboplatin or Cisplatin

ClinicalTrials.gov

2017-10-18

Brenner Tumor; Fallopian Tube Cancer; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Primary Peritoneal Cavity Cancer; Recurrent Ovarian Epithelial Cancer

Genetically engineered mouse models for epithelial ovarian cancer: are we there yet?

PubMed

Howell, Viive M

2014-03-01

The development of preclinical spontaneous genetically engineered mouse models (GEMMs) requires an understanding of the genetic basis of the human disease. Such robust models have proven invaluable for increasing understanding of human malignancies as well as identifying new biomarkers and testing new therapies for these diseases. While GEMMs have been reported for ovarian cancer, the majority have proven disappointing overall in their recapitulation of paired genetic and histological features especially for serous ovarian epithelial cancer. This review describes GEMMs for ovarian cancer, in particular, high grade serous ovarian cancer and assesses these in light of recent changes in our understanding of the human malignancy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Fertility sparing surgery in early stage epithelial ovarian cancer

PubMed Central

Martinelli, Fabio; Lorusso, Domenica; Haeusler, Edward; Carcangiu, Marialuisa; Raspagliesi, Francesco

2014-01-01

Objective Fertility sparing surgery (FSS) is a strategy often considered in young patients with early epithelial ovarian cancer. We investigated the role and the outcomes of FSS in eEOC patients who underwent comprehensive surgery. Methods From January 2003 to January 2011, 24 patients underwent fertility sparing surgery. Eighteen were one-to-one matched and balanced for stage, histologic type and grading with a group of patients who underwent radical comprehensive staging (n=18). Demographics, surgical procedures, morbidities, pathologic findings, recurrence-rate, pregnancy-rate and correlations with disease-free survival were assessed. Results A total of 36 patients had a complete surgical staging including lymphadenectomy and were therefore analyzed. Seven patients experienced a recurrence: four (22%) in the fertility sparing surgery group and three (16%) in the control group (p=not significant). Sites of recurrence were: residual ovary (two), abdominal wall and peritoneal carcinomatosis in the fertility sparing surgery group; pelvic (two) and abdominal wall in the control group. Recurrences in the fertility sparing surgery group appeared earlier (mean, 10.3 months) than in radical comprehensive staging group (mean, 53.3 months) p<0.001. Disease-free survival were comparable between the two groups (p=0.422). No deaths were reported. All the patients in fertility sparing surgery group recovered a regular period. Thirteen out of 18 (72.2%) attempted to have a pregnancy. Five (38%) achieved a spontaneous pregnancy with a full term delivery. Conclusion Fertility sparing surgery in early epithelial ovarian cancer submitted to a comprehensive surgical staging could be considered safe with oncological results comparable to radical surgery group. PMID:25142621

Transforming growth factor-beta and nitrates in epithelial ovarian cancer.

PubMed

Khalifa, A; Kassim, S K; Ahmed, M I; Fayed, S T

1999-12-01

The role of transforming growth factor-beta (TGF-beta) and nitric oxide (NO) in ovarian neoplasia is still not clear. We studied the expression of TGF-beta by enzyme immunoassay, and nitrates (as a stable end product of NO) in 127 ovarian tissues (36 normal, 37 benign, and 54 malignant). Ploidy status and synthetic phase fraction (SPF) were also assessed by flow cytometry. Mean ranks of TGF-beta, nitrate, and SPF were significant among different groups (X2 = 12.01, P = 0.0025, X2 = 67.42, P = 0.000, X2 = 9.06, P = 0.011 respectively). Nitrate mean ranks were significant among different FIGO stages of the disease (X2 = 17.6, P = 0.000). A significant correlation was shown between TGF-beta, and nitrate levels in all tissues (r = 0.24, P = 0.01), as well as in malignant tissues (r = 0.3, P = 0.026). Cutoff values were determined for both TGF-beta (290 pg/mg protein), and nitrates (310 nmole/mg non protein nitrogenous substances). At these cut-offs, nitrates showed a sensitivity of 93% and 84% specificity for malignant versus normal cases, while TGF-beta had 76% sensitivity, and 82.4% specificity for poor versus good outcome. Patients with epithelial ovarian cancer were followed up for a total of 40 months. Survival analysis showed that patients with TGF-beta above the cut-off had worse prognosis (X2 = 12.69, P = 0.004). The present results suggest that malignant transformation of ovarian tissues is associated with increased TGF-beta and NO production. NO level is related to the development and progression of epithelial ovarian cancer, while high levels of TGF-beta could be of prognostic significance.

Transforming Growth Factor-β and Nitrates in Epithelial Ovarian Cancer

PubMed Central

Khalifa, Ali; Kassim, Samar K.; Ahmed, Maha I.; Fayed, Salah T.

1999-01-01

The role of transforming growth factor-β (TGF-β) and nitric oxide (NO) in ovarian neoplasia is still not clear. We studied the expression of TGF-β by enzyme immunoassay, and nitrates (as a stable end product of NO) in 127 ovarian tissues (36 normal, 37 benign, and 54 malignant). Ploidy status and synthetic phase fraction (SPF) were also assessed by flow cytometry. Mean ranks of TGF-β, nitrate, and SPF were significant among different groups (X2 = 12.01, P = 0.0025, X2 = 67.42, P = 0.000, X2 = 9.06, P = 0.011 respectively). Nitrate mean ranks were significant among different FIGO stages of the disease (X2 = 17.6, P = 0.000). A significant correlation was shown between TGF-â, and nitrate levels in all tissues (r = 0.24, P = 0.01), as well as in malignant tissues (r = 0.3, P = 0.026). Cutoff values were determined for both TGF-β (290 pg/mg protein), and nitrates (310 nmole/mg non protein nitrogenous substances). At these cut-offs, nitrates showed a sensitivity of 93% and 84% specificity for malignant versus normal cases, while TGF-β had 76% sensitivity, and 82.4% specificity for poor versus good outcome. Patients with epithelial ovarian cancer were followed up for a total of 40 months. Survival analysis showed that patients with TGF-β above the cut-off had worse prognosis (X2 = 12.69, P = 0.004). The present results suggest that malignant transformation of ovarian tissues is associated with increased TGF-β and NO production. NO level is related to the development and progression of epithelial ovarian cancer, while high levels of TGF-β could be of prognostic significance. PMID:10689548

M-CSF in a new biomarker panel with HE4 and CA 125 in the diagnostics of epithelial ovarian cancer patients.

PubMed

Będkowska, Grażyna Ewa; Ławicki, Sławomir; Gacuta, Ewa; Pawłowski, Przemysław; Szmitkowski, Maciej

2015-05-03

We investigated plasma levels of M-CSF and conventional tumor markers (HE4 and CA 125) in epithelial ovarian cancer patients as compared to control groups: benign ovarian tumor patients (cysts) and healthy subjects. M-CSF levels were determined by ELISA, HE4 and CA 125 levels - by CMIA method. Our results have demonstrated significant differences in the concentration levels of M-CSF, CA 125 and HE4 between the groups of ovarian cancer patients, cysts patients and the healthy controls. In the groups tested M-CSF demonstrated equal to or higher values than both CA 125 and HE4 in diagnostic sensitivity (SE), positive and negative predictive values (PPV, NPV), and in the area under the ROC curve (AUC), particularly in the group with the serous epithelial sub-type of OC. Moreover, CA 125 showed better results of the aforementioned diagnostic criteria than HE4. The combined use of the parameters studied resulted in a further, significant increase in the value of the diagnostic indicators and in the value of the diagnostic power (AUC), especially in the early stages of ovarian cancer. These findings suggest a high usefulness of M-CSF in diagnosing the serous sub-type of epithelial ovarian cancer and in discriminating between cancer and non-carcinoma lesions, particularly in new diagnostic panels in combination with CA 125 and HE4 for the detection of EOC in the early stages.

Efficacy of neratinib in the treatment of HER2/neu-amplified epithelial ovarian carcinoma in vitro and in vivo.

PubMed

Menderes, Gulden; Bonazzoli, Elena; Bellone, Stefania; Black, Jonathan D; Lopez, Salvatore; Pettinella, Francesca; Masserdotti, Alice; Zammataro, Luca; Litkouhi, Babak; Ratner, Elena; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E; Santin, Alessandro D

2017-05-01

Epithelial ovarian carcinoma is the most lethal of gynecologic malignancies. There is a need to optimize the currently available treatment strategies and to urgently develop novel therapeutic agents against chemotherapy-resistant disease. The objective of our study was to evaluate neratinib's preclinical efficacy in treating HER2-amplified ovarian cancer. Neratinib's efficacy in treating HER2-amplified ovarian cancer was studied in vitro utilizing six primary tumor cell lines with differential HER2/neu expression. Flow cytometry was utilized to assess IC 50 , cell signaling changes, and cell cycle distribution. Neratinib's in vivo efficacy was evaluated in HER2-amplified epithelial ovarian carcinoma xenografts. Three of six (50%) ovarian cancer cell lines were HER2/neu-amplified. Neratinib showed significantly higher efficacy in treating HER2/neu-amplified cell lines when compared to the non-HER2/neu-amplified tumor cell lines (mean ± SEM IC 50 :0.010 μM ± 0.0003 vs. 0.076 μM ± 0.005 p < 0.0001). Neratinib treatment significantly decreased the phosphorylation of the transcription factor S6, leading to arrest of the cell cycle in G0/G1 phase. Neratinib prolonged survival in mice harboring HER2-amplified epithelial ovarian carcinoma xenografts (p = 0.003). Neratinib inhibits proliferation, signaling, cell cycle progression and tumor growth of HER2-amplified epithelial ovarian carcinoma in vitro. Neratinib inhibits xenograft growth and improves overall survival in HER2/neu-amplified ovarian cancer in vivo. Clinical trials are warranted.

Efficacy of neratinib in the treatment of HER2/neu-amplified epithelial ovarian carcinoma in vitro and in vivo

PubMed Central

Menderes, Gulden; Bonazzoli, Elena; Bellone, Stefania; Black, Jonathan D.; Lopez, Salvatore; Pettinella, Francesca; Masserdotti, Alice; Zammataro, Luca; Litkouhi, Babak; Ratner, Elena; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E.

2018-01-01

Epithelial ovarian carcinoma is the most lethal of gynecologic malignancies. There is a need to optimize the currently available treatment strategies and to urgently develop novel therapeutic agents against chemotherapy-resistant disease. The objective of our study was to evaluate neratinib’s preclinical efficacy in treating HER2-amplified ovarian cancer. Neratinib’s efficacy in treating HER2-amplified ovarian cancer was studied in vitro utilizing six primary tumor cell lines with differential HER2/neu expression. Flow cytometry was utilized to assess IC50, cell signaling changes, and cell cycle distribution. Neratinib’s in vivo efficacy was evaluated in HER2-amplified epithelial ovarian carcinoma xenografts. Three of six (50%) ovarian cancer cell lines were HER2/neu-amplified. Neratinib showed significantly higher efficacy in treating HER2/neu-amplified cell lines when compared to the non-HER2/neu-amplified tumor cell lines (mean ± SEM IC50:0.010 μM ± 0.0003 vs. 0.076 μM ± 0.005 p < 0.0001). Neratinib treatment significantly decreased the phosphorylation of the transcription factor S6, leading to arrest of the cell cycle in G0/G1 phase. Neratinib prolonged survival in mice harboring HER2-amplified epithelial ovarian carcinoma xenografts (p = 0.003). Neratinib inhibits proliferation, signaling, cell cycle progression and tumor growth of HER2-amplified epithelial ovarian carcinoma in vitro. Neratinib inhibits xenograft growth and improves overall survival in HER2/neu-amplified ovarian cancer in vivo. Clinical trials are warranted. PMID:28397106

Role of human epididymis protein 4 in chemoresistance and prognosis of epithelial ovarian cancer.

PubMed

Lee, Seungho; Choi, Seowon; Lee, Yookyung; Chung, Donghae; Hong, Suntaek; Park, Nohhyun

2017-01-01

Human epididymis protein 4 (HE4) is a novel biomarker for epithelial ovarian cancer. This study was designed to evaluate the role of HE4 in chemo-response against anti-cancer drugs and prognosis of epithelial ovarian cancer. HE4-depleted cells and HE4-overexpressing cells were generated. The effect of HE4 gene silencing and overexpression was examined using a cell viability assay after exposure to chemotherapeutic agents and the signaling pathway. We studied the expression of HE4 in ovarian cancer tissue and the prognostic significance. Cytoplasmic staining was graded for intensity and percentage of positive cells. The grades were multiplied to determine an H-score. Knockdown of HE4 in OVCAR-3 cells resulted in reduction in cell growth and increased sensitivity to paclitaxel and cisplatin compared to control cells. This effect originated from the decreased activation of cell-growth-related signaling, such as AKT and Erk mediated by epidermal growth factor (EGF), while overexpression of HE4 resulted in enhanced cell growth and suppressed the anti-tumorigenic activity of paclitaxel. Activation of AKT and Erk pathways was enhanced in HE4-overexpressing cells compared to control cells. Based on the results of multivariate analysis, the risk of death was significantly higher in patients with an H-score > 4. HE4 induces chemoresistance against anti-cancer drugs and activates the AKT and Erk pathways to enhance tumor survival. HE4 expression in ovarian cancer tissue is associated with a worse prognosis for epithelial ovarian cancer patients. © 2016 Japan Society of Obstetrics and Gynecology.

Mitochondrial DNA Mutations in Epithelial Ovarian Tumor Progression

DTIC Science & Technology

2007-12-01

of the author( s ) and should not be construed as an official Department of the Army position, policy or decision unless so designated by other...Epithelial Ovarian Tumor Progression 5b. GRANT NUMBER W81XWH-05-1-0054 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR( S ) Felix O. Aikhionbare, Ph.D. 5d...PROJECT NUMBER 5e. TASK NUMBER E-Mail: faikhionbare@msm.edu 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME( S ) AND ADDRESS(ES) 8

Morphologic, Immunophenotypic, and Molecular Features of Epithelial Ovarian Cancer.

PubMed

Ramalingam, Preetha

2016-02-01

Epithelial ovarian cancer comprises a heterogeneous group of tumors. The four most common subtypes are serous, endometrioid, clear cell, and mucinous carcinoma. Less common are transitional cell tumors, including transitional cell carcinoma and malignant Brenner tumor. While in the past these subtypes were grouped together and designated as epithelial ovarian tumors, these tumor types are now known to be separate entities with distinct clinical and biologic behaviors. From a therapeutic standpoint, current regimens employ standard chemotherapy based on stage and grade rather than histotype. However, this landscape may change in the era of personalized therapy, given that most subtypes (with the exception of high-grade serous carcinoma) are relatively resistant to chemotherapy. It is now well-accepted that high-grade and low-grade serous carcinomas represent distinct entities rather than a spectrum of the same tumor type. While they are similar in that patients present with advanced-stage disease, their histologic and molecular features are entirely different. High-grade serous carcinoma is associated with TP53 mutations, whereas low-grade serous carcinomas are associated with BRAF and KRAS mutations. Endometrioid and clear cell carcinomas typically present as early-stage disease and are frequently associated with endometriosis. Mucinous carcinomas typically present as large unilateral masses and often show areas of mucinous cystadenoma and mucinous borderline tumor. It must be emphasized that primary mucinous carcinomas are uncommon tumors, and metastasis from other sites such as the appendix, colon, stomach, and pancreaticobiliary tract must always be considered in the differential diagnosis. Lastly, transitional cell tumors of the ovary, specifically malignant Brenner tumors, are quite uncommon. High-grade serous carcinoma often has a transitional cell pattern, and adequate sampling in most cases shows more typical areas of serous carcinoma. Immunohistochemical

Charged-Iron-Particles Found in Galactic Cosmic Rays are Potent Inducers of Epithelial Ovarian Tumors.

PubMed

Mishra, Birendra; Lawson, Gregory W; Ripperdan, Ryan; Ortiz, Laura; Luderer, Ulrike

2018-05-21

Astronauts traveling in deep space are exposed to high-charge and energy (HZE) particles from galactic cosmic rays. We have previously determined that irradiation of adult female mice with iron HZE particles induces DNA double-strand breaks, oxidative damage and apoptosis in ovarian follicles, causing premature ovarian failure. These effects occur at lower doses than with conventional photon irradiation. Ovarian failure with resultant loss of negative feedback and elevated levels of gonadotropin hormones is thought to play a role in the pathophysiology of ovarian cancer. Therefore, we hypothesized that charged-iron-particle irradiation induces ovarian tumorigenesis in mice. In this study, three-month-old female mice were exposed to 0 cGy (sham) or 50 cGy iron ions and aged to 18 months. The 50 cGy irradiated mice had increased weight gain with age and lack of estrous cycling, consistent with ovarian failure. A total of 47% and 7% of mice irradiated with 50 cGy had unilateral and bilateral ovarian tumors, respectively, whereas 14% of mice in the 0 cGy group had unilateral tumors. The tumors contained multiple tubular structures, which were lined with cells positive for the epithelial marker cytokeratin, and had few proliferating cells. In some tumors, packets of cells between the tubular structures were immunopositive for the granulosa cell marker FOXL2. Based on these findings, tumors were diagnosed as tubular adenomas or mixed tubular adenoma/granulosa cell tumors. In conclusion, charged-iron-particle-radiation induces ovarian tumors in mice, raising concerns about ovarian tumors as late sequelae of deep space travel in female astronauts.

Transformation of Epithelial Ovarian Cancer Stemlike Cells into Mesenchymal Lineage via EMT Results in Cellular Heterogeneity and Supports Tumor Engraftment

PubMed Central

Jiang, Hua; Lin, Xiaolong; Liu, Yingtao; Gong, Wenjia; Ma, Xiaoling; Yu, Yinhua; Xie, Yi; Sun, Xiaoxi; Feng, Youji; Janzen, Viktor; Chen, Tong

2012-01-01

Ovarian cancers are heterogeneous and contain stemlike cells that are able to self-renew and are responsible for sustained tumor growth. Metastasis in the peritoneal cavity occurs more frequently in ovarian cancer than in other malignancies, but the underlying mechanism remains largely unknown. We have identified that ovarian cancer stemlike cells (CSCs), which were defined as side population (SP) cells, were present in patients’ ascitic fluid and mesenchymally transformed cell lines, ES-2 and HO-8910PM. SP cells, which were sorted from both cell lines and implanted into immunocompromised mice, were localized to the xenografted tumor boundary. In addition, SP cells exhibited an epithelial phenotype and showed a distinct gene expression profile with reduced expression of cell adhesion molecules (CAMs), indicating that SP cells exert an important role in ovarian cancer progression on the basis of their delicate interaction with the surrounding microenvironment and anatomical localization in tumors. In contrast, non-SP cells exhibited a more mesenchymal phenotype and showed more increased invasive potential than SP cells. This heterogeneity was observed as an endogenous transformation via the epithelial–mesenchymal transition (EMT) process. Inhibition of the EMT process by Snail1 silencing reduced the SP cell frequency, and affected their invasive capacity and engraftment. These findings illustrate the interplay between epithelial ovarian CSCs and the EMT, and exert a link to explain tumor heterogeneity and its necessity for ovarian cancer maintenance, metastasis and progression. PMID:22801793

Combined panel of serum human tissue kallikreins and CA-125 for the detection of epithelial ovarian cancer.

PubMed

Koh, Stephen Chee Liang; Huak, Chan Yiong; Lutan, Delfi; Marpuang, Johny; Ketut, Suwiyoga; Budiana, Nyoma Gede; Saleh, Agustria Zainu; Aziz, Mohamad Farid; Winarto, Hariyono; Pradjatmo, Heru; Hoan, Nguyen Khac Han; Thanh, Pham Viet; Choolani, Mahesh

2012-07-01

To determine the predictive accuracy of the combined panels of serum human tissue kallikreins (hKs) and CA-125 for the detection of epithelial ovarian cancer. Serum specimens collected from 5 Indonesian centers and 1 Vietnamese center were analyzed for CA-125, hK6, and hK10 levels. A total of 375 specimens from patients presenting with ovarian tumors, which include 156 benign cysts, 172 epithelial ovarian cancers (stage I/II, n=72; stage III/IV, n=100), 36 germ cell tumors and 11 borderline tumors, were included in the study analysis. Receiver operating characteristic analysis were performed to determine the cutoffs for age, CA-125, hK6, and hK10. Sensitivity, specificity, negative, and positive predictive values were determined for various combinations of the biomarkers. The levels of hK6 and hK10 were significantly elevated in ovarian cancer cases compared to benign cysts. Combination of 3 markers, age/CA-125/hk6 or CA-125/hk6/hk10, showed improved specificity (100%) and positive predictive value (100%) for prediction of ovarian cancer, when compared to the performance of single markers having 80-92% specificity and 74-87% positive predictive value. Four-marker combination, age/CA-125/hK6/hK10 also showed 100% specificity and 100% positive predictive value, although it demonstrated low sensitivity (11.9%) and negative predictive value (52.8%). The combination of human tissue kallikreins and CA-125 showed potential for improving prediction of epithelial ovarian cancer in patients presenting with ovarian tumors.

Potential Role of Estrogen Receptor Beta as a Tumor Suppressor of Epithelial Ovarian Cancer

PubMed Central

Gaudin, Françoise; Machelon, Véronique; Brigitte, Madly; Jacquard, Carine; Pillon, Arnaud; Balaguer, Patrick; Balabanian, Karl; Lazennec, Gwendal

2012-01-01

Ovarian cancer is the gynecological cancer exhibiting the highest morbidity and improvement of treatments is still required. Previous studies have shown that Estrogen-receptor beta (ERβ) levels decreased along with ovarian carcinogenesis. Here, we present evidence that reintroduction of ERβ in BG-1 epithelial ovarian cancer cells, which express ERα, leads in vitro to a decrease of basal and estradiol-promoted cell proliferation. ERβ reduced the frequency of cells in S phase and increased the one of cells in G2/M phase. At the molecular level, we found that ERβ downregulated total retinoblastoma (Rb), phosphorylated Rb and phospho-AKT cellular content as well as cyclins D1 and A2. In addition, ERβ had a direct effect on ERα, by strongly inhibiting its expression and activity, which could explain part of the anti-proliferative action of ERβ. By developing a novel preclinical model of ovarian cancer based on a luminescent orthotopic xenograft in athymic Nude mice, we further revealed that ERβ expression reduces tumor growth and the presence of tumor cells in sites of metastasis, hence resulting in improved survival of mice. Altogether, these findings unveil a potential tumor-suppressor role of ERβ in ovarian carcinogenesis, which could be of potential clinical relevance for the selection of the most appropriate treatment for patients. PMID:22970307

Prognostic value of GLUT-1 expression in ovarian surface epithelial tumors: a morphometric study.

PubMed

Ozcan, Ayhan; Deveci, Mehmet Salih; Oztas, Emin; Dede, Murat; Yenen, Mufit Cemal; Korgun, Emin Turkay; Gunhan, Omer

2005-08-01

To investigate the reported increase in the expression of the glucose transporter GLUT-1 in borderline and malignant ovarian epithelial tumors and its relationship to prognosis. In this study, areas in which immunohistochemical membranous staining with GLUT-1 were most evident were selected, and the proportions of GLUT-1 expression in 46 benign, 11 borderline and 42 malignant cases of ovarian epithelial tumors were determined quantitatively with a computer and Zeiss Vision KS 400 3.0 (Göttingen, Germany) for Windows (Microsoft, Redmond, Washington, U.S.A.) image analysis. GLUT-1 expression was determined in all borderline tumors (11 of 11) and in 97.6% of malignant tumors (41 of 42). No GLUT-1 expression was observed in benign tumors. The intensity of GLUT-1 staining was lower in borderline tumors than in malignant cases. This was statistically significant (p = 0.005). As differentiation in malignant tumors increased, proportions of GLUT-1 expression showed a relative increase, but this difference was not statistically significant (p = 0.68). When GLUT-1 expression in borderline and malignant ovarian epithelial tumors was analyzed against prognosis, no statistically significant difference was identified. Assessment of GLUT-1 expression using the image analysis program was more reliable, with higher reproducibility than in previous studies.

Expression and Mutational Analysis of c-kit in Ovarian Surface Epithelial Tumors

PubMed Central

Lee, Myung-Hoon; Park, Tae-In; Bae, Han-Ik

2006-01-01

Coexpression of Kit ligand and c-kit has been reported in some gynecologic tumors. To determine whether imatinib mesylate is useful in ovarian epithelial tumors, we performed immunohistochemical and mutational analysis. The cases consisted of 33 cases, which included 13 serous cystadenocarcinomas, 1 borderline serous tumor, 8 mucinous cystadenocarcinomas, 6 borderline mucinous tumors and 5 clear cell carcinomas. Five cases of serous cystadenoma and 5 cases of mucinous cystadenoma were also included. In the immunohistochemical study, 3 cases (3/6, 50%) of borderline mucinous cystic tumor and two cases (2/8, 25%) of mucinous cystadenocarcinoma show positive staining for KIT protein. Only one case (1/13, 7.7%) of serous cystadenocarcinoma had positive staining. On mutational analysis, no mutation was identified at exon 11. However, two cases of borderline mucinous tumors and one case of mucinous cystadenocarcinoma had mutations at exon 17. In these cases, the immunohistochemistry also shows focal positive staining at epithelial component. Although, KIT protein expression showed higher incidence in mucinous tumors than serous tumors, they lack KIT-activating mutations in exon 11. Thus, ovarian surface epithelial tumors are unlikely to respond to imatinib mesylate. PMID:16479070

Histochemical and Immunohistochemical Study of α-SMA, Collagen, and PCNA in Epithelial Ovarian Neoplasm

PubMed

Anggorowati, Nungki; Ratna Kurniasari, Chatarina; Damayanti, Karina; Cahyanti, Titik; Widodo, Irianiwati; Ghozali, Ahmad; Romi, Muhammad Mansyur; Sari, Dwi Cahyani Ratna; Arfian, Nur

2017-03-01

Background: Alpha-smooth muscle actin (α-SMA) is an isoform of actin, positive in myofibroblasts and is an epithelial to mesenchymal transition (EMT) marker. EMT is a process by which tumor cells develop to be more hostile and able to metastasize. Progression of tumor cells is always followed by cell composition and extracellular matrix component alteration. Increased α-SMA expression and collagen alteration may predict the progressivity of ovarian neoplasms. Objective: The aim of this research was to analyse the characteristic of α-SMA and collagen in tumor cells and stroma of ovarian neoplasms. In this study, PCNA (proliferating cell nuclear antigen) expression was also investigated. Methods: Thirty samples were collected including serous, mucinous, endometrioid, and clear cell subtypes. The expression of α-SMA and PCNA were calculated in cells and stroma of ovarian tumors. Collagen was detected using Sirius Red staining and presented as area fraction. Results: The overexpressions of α-SMA in tumor cells were only detected in serous and clear cell ovarian carcinoma. The histoscore of α-SMA was higher in malignant than in benign or borderline ovarian epithelial neoplasms (105.3±129.9 vs. 17.3±17.1, P=0.011; mean±SD). Oppositely, stromal α-SMA and collagen area fractions were higher in benign than in malignant tumors (27.2±6.6 vs 20.5±8.4, P=0.028; 31.0±5.6 vs. 23.7±6.4, P=0.04). The percentages of epithelial and stromal PCNA expressions were not significantly different between benign and malignant tumors. Conclusion: Tumor cells of serous and clear cell ovarian carcinoma exhibit mesenchymal characteristic as shown by α-SMA positive expression. This expression might indicate that these subtypes were more aggressive. This research showed that collagen and α-SMA area fractions in stroma were higher in benign than in malignant neoplasms. 10.22034/APJCP.2017.18.3.667

Epithelial ovarian carcinoma diagnosis by desorption electrospray ionization mass spectrometry imaging

PubMed Central

Dória, Maria Luisa; McKenzie, James S.; Mroz, Anna; Phelps, David L.; Speller, Abigail; Rosini, Francesca; Strittmatter, Nicole; Golf, Ottmar; Veselkov, Kirill; Brown, Robert; Ghaem-Maghami, Sadaf; Takats, Zoltan

2016-01-01

Ovarian cancer is highly prevalent among European women, and is the leading cause of gynaecological cancer death. Current histopathological diagnoses of tumour severity are based on interpretation of, for example, immunohistochemical staining. Desorption electrospray mass spectrometry imaging (DESI-MSI) generates spatially resolved metabolic profiles of tissues and supports an objective investigation of tumour biology. In this study, various ovarian tissue types were analysed by DESI-MSI and co-registered with their corresponding haematoxylin and eosin (H&E) stained images. The mass spectral data reveal tissue type-dependent lipid profiles which are consistent across the n = 110 samples (n = 107 patients) used in this study. Multivariate statistical methods were used to classify samples and identify molecular features discriminating between tissue types. Three main groups of samples (epithelial ovarian carcinoma, borderline ovarian tumours, normal ovarian stroma) were compared as were the carcinoma histotypes (serous, endometrioid, clear cell). Classification rates >84% were achieved for all analyses, and variables differing statistically between groups were determined and putatively identified. The changes noted in various lipid types help to provide a context in terms of tumour biochemistry. The classification of unseen samples demonstrates the capability of DESI-MSI to characterise ovarian samples and to overcome existing limitations in classical histopathology. PMID:27976698

Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Symptoms, Tests, Prognosis, Stages (PDQ®)—Patient Version

Cancer.gov

Ovarian epithelial, fallopian tube, and primary peritoneal cancers form in the same type of tissue and use the same staging system. Risk factors include family history and inherited gene mutations. Learn more about why ovarian cancers are often found at advanced stages and the tests to diagnose and stage the cancer.

Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC).

PubMed

Jim, Heather S L; Lin, Hui-Yi; Tyrer, Jonathan P; Lawrenson, Kate; Dennis, Joe; Chornokur, Ganna; Chen, Zhihua; Chen, Ann Y; Permuth-Wey, Jennifer; Aben, Katja Kh; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V; Bean, Yukie T; Beckmann, Matthias W; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Bunker, Clareann H; Butzow, Ralf; Campbell, Ian G; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; du Bois, Andreas; Despierre, Evelyn; Sieh, Weiva; Doherty, Jennifer A; Dörk, Thilo; Dürst, Matthias; Easton, Douglas F; Eccles, Diana M; Edwards, Robert P; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Goodman, Marc T; Gronwald, Jacek; Harter, Philipp; Hasmad, Hanis N; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hillemanns, Peter; Hogdall, Claus K; Hogdall, Estrid; Hosono, Satoyo; Iversen, Edwin S; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kellar, Melissa; Kiemeney, Lambertus A; Krakstad, Camilla; Kjaer, Susanne K; Kupryjanczyk, Jolanta; Vierkant, Robert A; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lim, Boon Kiong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; McNeish, Ian; Menon, Usha; Milne, Roger L; Modugno, Francesmary; Thomsen, Lotte; Moysich, Kirsten B; Ness, Roberta B; Nevanlinna, Heli; Eilber, Ursula; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Orsulic, Sandra; Palmieri Weber, Rachel; Paul, James; Pearce, Celeste L; Pejovic, Tanja; Pelttari, Liisa M; Pike, Malcolm C; Poole, Elizabeth M; Schernhammer, Eva; Risch, Harvey A; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Song, Honglin; Southey, Melissa C; Spiewankiewicz, Beata; Sucheston-Campbell, Lara; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Tangen, Ingvild L; Tworoger, Shelley S; van Altena, Anne M; Vergote, Ignace; Walsh, Christine S; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Wu, Anna H; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Amankwah, Ernest; Berchuck, Andrew; Schildkraut, Joellen M; Kelemen, Linda E; Ramus, Susan J; Monteiro, Alvaro N A; Goode, Ellen L; Narod, Steven A; Gayther, Simon A; Pharoah, Paul D P; Sellers, Thomas A; Phelan, Catherine M

Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10 -4 ]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1 , may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.

The role of biomarkers in the management of epithelial ovarian cancer.

PubMed

Yang, Wei-Lei; Lu, Zhen; Bast, Robert C

2017-06-01

Despite advances in surgery and chemotherapy for ovarian cancer, 70% of women still succumb to the disease. Biomarkers have contributed to the management of ovarian cancer by monitoring response to treatment, detecting recurrence, distinguishing benign from malignant pelvic masses and attempting to detect disease at an earlier stage. Areas covered: This review focuses on recent advances in biomarkers and imaging for management of ovarian cancer with particular emphasis on early detection. Relevant literature has been reviewed and analyzed. Expert commentary: Rising or persistent CA125 blood levels provide a highly specific biomarker for epithelial ovarian cancer, but not an optimally sensitive biomarker. Addition of HE4, CA 72.4, anti-TP53 autoantibodies and other biomarkers can increase sensitivity for detecting early stage or recurrent disease. Detecting disease recurrence will become more important as more effective therapy is developed. Early detection will require the development not only of biomarker panels, but also of more sensitive and specific imaging strategies. Effective biomarker strategies are already available for distinguishing benign from malignant pelvic masses, but their use in identifying and referring patients with probable ovarian cancer to gynecologic oncologists for cytoreductive operations must be encouraged.

Stromal-epithelial interactions modulate the effect of ovarian steroids on goat uterine epithelial cell interleukin-18 release.

PubMed

Qi, X F; Nan, Z C; Jin, Y P; Qu, Y Y; Zhao, X J; Wang, A H

2012-05-01

A primary role of epithelial-stromal interactions in mediating steroid hormone action in the uterus has been established. The present study was undertaken to determine the mode of ovarian steroid action in regulating IL-18 release by goat endometrial epithelial cells (EECs) in the presence and absence of endometrial stromal cells (ESCs). Primary and telomerase-immortalized goat EECs grown alone or cocultured with ESCs were treated with two ovarian steroids, 17β-estradiol (E(2)) and progesterone (P(4)). The IL-18 mRNA and protein expression in EECs were studied by reverse transcript (RT) PCR, ELISA, and Western blot assay. The E(2) and/or P(4) treatment of EECs led to a significant increase in both IL-18 mRNA and protein expression either in the primary or in the immortalized EECs compared with that in EECs without the steroid treatment. However, in the presence of ESCs, IL-18 expression by EECs treated with steroids was significantly decreased compared with cells untreated with E(2) and/or P(4). In addition, significantly high abundance of IL-18 mRNA and protein expression by primary and telomerase-immortalized goat EECs was observed in the presence of ESCs compared with those cells without ESCs. These findings suggest that steroids are important for the control of IL-18 expression in goat EECs. Underlying ESCs are needed to mediate the inhibitory effects of steroids on the IL-18 secretory activity of goat EECs in vitro. The IL-18 abundance expressed by goat EECs in vitro are enhanced by underlying ESCs without the treatment of E(2) and/or P(4). Copyright © 2012 Elsevier Inc. All rights reserved.

Survivorship Care Planning in Improving Quality of Life in Survivors of Ovarian Cancer

ClinicalTrials.gov

2017-09-27

Cancer Survivor; Stage IA Ovarian Epithelial Cancer; Stage IB Ovarian Epithelial Cancer; Stage IC Ovarian Epithelial Cancer; Stage IIA Ovarian Epithelial Cancer; Stage IIB Ovarian Epithelial Cancer; Stage IIC Ovarian Epithelial Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIB Ovarian Epithelial Cancer; Stage IIIC Ovarian Epithelial Cancer

Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy

ClinicalTrials.gov

2014-12-29

Fatigue; Malignant Ovarian Mixed Epithelial Tumor; Neuropathy; Neurotoxicity Syndrome; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Pain; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma

[A survey of willingness about genetic counseling and tests in patients of epithelial ovarian cancer].

PubMed

Li, L; Qiu, L; Wu, M

2017-11-21

Objective: To analyze patients' tendency towards genetics counseling and tests based on a prospective cohort study on hereditary ovarian cancer. Methods: From February 2017 to June 2017, among 220 cases of epithelial ovarian cancer in Peking Union Medical College Hospital, we collected epidemiological, pathological and tendency towards genetics counseling and tests via medical records and questionnaire.All patients would get education about hereditary ovarian cancer by pamphlets and WeChat.If they would receive further counseling, a face to face interview and tests will be given. Results: Among all 220 patients, 10 (4.5%) denied further counseling.For 210 patients receiving genetic counseling, 170 (81%) accepted genetic tests.In multivariate analysis, risk factors relevant to acceptance of genetic tests included: being charged by physicians of gynecologic oncology for diagnosis and treatment, receiving counseling in genetic counseling clinics, and having family history of breast cancer.For patients denying genetic tests, there were many subjective reasons, among which, "still not understanding genetic tests" (25%) and "unable bear following expensive targeting medicine" . Conclusions: High proportion patients of epithelial ovarian cancer would accept genetic counseling and tests.Genetic counseling clinics for gynecologic oncology would further improve genetic tests for patients.

Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)

PubMed Central

Jim, Heather S.L.; Lin, Hui-Yi; Tyrer, Jonathan P.; Lawrenson, Kate; Dennis, Joe; Chornokur, Ganna; Chen, Zhihua; Chen, Ann Y.; Permuth-Wey, Jennifer; Aben, Katja KH.; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V.; Bean, Yukie T.; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bunker, Clareann H.; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; du Bois, Andreas; Despierre, Evelyn; Sieh, Weiva; Doherty, Jennifer A.; Dörk, Thilo; Dürst, Matthias; Easton, Douglas F.; Eccles, Diana M.; Edwards, Robert P.; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goodman, Marc T.; Gronwald, Jacek; Harter, Philipp; Hasmad, Hanis N.; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hogdall, Claus K.; Hogdall, Estrid; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y.; Kellar, Melissa; Kiemeney, Lambertus A.; Krakstad, Camilla; Kjaer, Susanne K.; Kupryjanczyk, Jolanta; Vierkant, Robert A.; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lim, Boon Kiong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Ian; Menon, Usha; Milne, Roger L.; Modugno, Francesmary; Thomsen, Lotte; Moysich, Kirsten B.; Ness, Roberta B.; Nevanlinna, Heli; Eilber, Ursula; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Palmieri Weber, Rachel; Paul, James; Pearce, Celeste L.; Pejovic, Tanja; Pelttari, Liisa M.; Pike, Malcolm C.; Poole, Elizabeth M.; Schernhammer, Eva; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B.; Siddiqui, Nadeem; Song, Honglin; Southey, Melissa C.; Spiewankiewicz, Beata; Sucheston-Campbell, Lara; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Tangen, Ingvild L.; Tworoger, Shelley S.; van Altena, Anne M.; Vergote, Ignace; Walsh, Christine S.; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wu, Anna H.; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Amankwah, Ernest; Berchuck, Andrew; Schildkraut, Joellen M.; Kelemen, Linda E.; Ramus, Susan J.; Monteiro, Alvaro N.A.; Goode, Ellen L.; Narod, Steven A.; Gayther, Simon A.; Pharoah, Paul D. P.; Sellers, Thomas A.; Phelan, Catherine M.

2016-01-01

Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68–0.90, p = 5.59 × 10−4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways. PMID:26807442

Alterations in expression pattern of splicing factors in epithelial ovarian cancer and its clinical impact.

PubMed

Iborra, Severine; Hirschfeld, Marc; Jaeger, Markus; Zur Hausen, Axel; Braicu, Iona; Sehouli, Jalid; Gitsch, Gerald; Stickeler, Elmar

2013-07-01

Alternative splicing represents an important nuclear mechanism in the posttranscriptional regulation of gene expression, which is frequently altered during tumorigenesis. Previously, we described marked changes in alternative splicing of the CD44 gene in ovarian and breast cancer as well as specific induction of distinct splicing factors during tumor development. The present study was focused on the expression profiles of different splicing factors, including classical serine-arginine (SR) proteins including ASF/SF2, hTra2β1, hTra2α, and Y-box-binding protein (YB-1) in physiological and malignant epithelial ovarian tissue to evaluate their expression pattern with regard to tumor development and disease progression. Expression levels of the different splicing factors were analyzed in physiological epithelial ovarian tissue samples, primary tumors, and metastatic samples of patients with a diagnosis of epithelial ovarian cancer using quantified reverse transcription polymerase chain reaction analysis. We examined more closely the splicing factor hTra2β1 using Western blot analysis and immunohistochemistry. The analysis revealed a marked and specific induction of ASF/SF2, SRp20, hTra2β1, and YB-1 in primary tumors as well as in their metastatic sites. However, in our patient cohort, no induction was seen for the other investigated splicing factors SRp55, SRp40, and hTra2α. Our results suggest a specific induction of distinct splicing factors in ovarian cancer tumorigenesis. The involvement of hTra2β1, YB-1, SRp20, and ASF/SF2 in exon recognition and alternative splicing may be important for gene regulation of alternatively spliced genes like CD44 with potential functional consequences in this tumor type leading to progression and metastasis.

Follicle Depletion Provides a Permissive Environment for Ovarian Carcinogenesis

PubMed Central

Wang, Ying; Cai, Kathy Qi; Smith, Elizabeth R.; Yeasky, Toni M.; Moore, Robert; Ganjei-Azar, Parvin; Klein-Szanto, Andres J.; Godwin, Andrew K.; Hamilton, Thomas C.

2016-01-01

We modeled the etiology of postmenopausal biology on ovarian cancer risk using germ cell-deficient white-spotting variant (Wv) mice, incorporating oncogenic mutations. Ovarian cancer incidence is highest in peri- and postmenopausal women, and epidemiological studies have established the impact of reproductive factors on ovarian cancer risk. Menopause as a result of ovarian follicle depletion is thought to contribute to higher cancer risk. As a consequence of follicle depletion, female Wv mice develop ovarian tubular adenomas, a benign epithelial tumor corresponding to surface epithelial invaginations and papillomatosis frequently found in postmenopausal human ovaries. Lineage tracing using MISR2-Cre indicated that the tubular adenomas that developed in Wv mice were largely derived from the MISR2 lineage, which marked only a fraction of ovarian surface and oviduct epithelial cells in wild-type tissues. Deletion of p27, either heterozygous or homozygous, was able to convert the benign tubular adenomas into more proliferative tumors. Restricted deletion of p53 in Wv/Wv mice by either intrabursal injection of adenoviral Cre or inclusion of the MISR2-Cre transgene also resulted in augmented tumor growth. This finding suggests that follicle depletion provides a permissive ovarian environment for oncogenic transformation of epithelial cells, presenting a mechanism for the increased ovarian cancer risk in postmenopausal women. PMID:27354067

[Expressions of Ras and Sos1 in epithelial ovarian cancer tissues and their clinical significance].

PubMed

Xiao, Zheng-Hua; Linghu, Hua; Liu, Qian-Fen

2016-11-20

To detect the expressions of Ras and Sos1 proteins in human epithelial ovarian cancer (EOC) tissues and explore their correlation with the clinicopathological features of the patients. The expressions of Ras and Sos1 proteins were detected immunohistochemically in 62 EOC tissues, 5 borderline ovarian cancer tissues, 15 benign epithelial ovarian neoplasm tissues, and 18 normal ovarian tissues. The EOC tissues showed significantly higher expression levels of both Ras and Sos1 than the other tissues tested (P<0.05). In EOC tissues, Ras and Sos1 proteins were expressed mostly on the cell membrane and in the cytoplasm. The expression level of Ras was correlated with pathological types of the tumor (P<0.05) and was the highest in serous cystadenomcarcinoma; Sos1 expression did not show significant correlation with the clinicopathological indexes of the patients. High expressions of both Ras and Sos1 proteins were associated with shorter progression-free survival of the patients, but this association was not statistically significant. Ras and Sos1 protein may participate in in the occurrence and development of EOC. The tissue-specific variation of Ras expression can lend support to a specific diagnosis of ovarian serous adenocarcinoma. The association of Ras and Sos1 protein expression with the tumor-free survival time of the patients awaits further investigation with a larger sample size.

Lysophosphatidic Acid Initiates Epithelial to Mesenchymal Transition and Induces β-Catenin-mediated Transcription in Epithelial Ovarian Carcinoma*

PubMed Central

Burkhalter, Rebecca J.; Westfall, Suzanne D.; Liu, Yueying; Stack, M. Sharon

2015-01-01

During tumor progression, epithelial ovarian cancer (EOC) cells undergo epithelial-to-mesenchymal transition (EMT), which influences metastatic success. Mutation-dependent activation of Wnt/β-catenin signaling has been implicated in gain of mesenchymal phenotype and loss of differentiation in several solid tumors; however, similar mutations are rare in most EOC histotypes. Nevertheless, evidence for activated Wnt/β-catenin signaling in EOC has been reported, and immunohistochemical analysis of human EOC tumors demonstrates nuclear staining in all histotypes. This study addresses the hypothesis that the bioactive lipid lysophosphatidic acid (LPA), prevalent in the EOC microenvironment, functions to regulate EMT in EOC. Our results demonstrate that LPA induces loss of junctional β-catenin, stimulates clustering of β1 integrins, and enhances the conformationally active population of surface β1 integrins. Furthermore, LPA treatment initiates nuclear translocation of β-catenin and transcriptional activation of Wnt/β-catenin target genes resulting in gain of mesenchymal marker expression. Together these data suggest that LPA initiates EMT in ovarian tumors through β1-integrin-dependent activation of Wnt/β-catenin signaling, providing a novel mechanism for mutation-independent activation of this pathway in EOC progression. PMID:26175151

Chemokine axes CXCL12/CXCR4 and CXCL16/CXCR6 correlate with lymph node metastasis in epithelial ovarian carcinoma

PubMed Central

Guo, Li; Cui, Zhu-Mei; Zhang, Jia; Huang, Yu

2011-01-01

Recent evidence suggests that the chemokine axis of CXC chemokine ligand-12 and its receptor CXC chemokine receptor-4 (CXCL12/CXCR4) is highly expressed in gynecological tumors and the axis of CXC chemokine ligand-16 and CXC chemokine receptor-6 (CXCL16/CXCR6) is overexpressed in inflammation-associated tumors. This study aimed to determine the relationship between CXCL12/CXCR4, CXCL16/CXCR6 and ovarian carcinoma's clinicopathologic features and prognosis. Accordingly, the expression of these proteins in ovarian tissues was detected by tissue microarray and immunohistochemistry. The expressions of CXCL12/CXCR4 and CXCL16/CXCR6 were significantly higher in epithelial ovarian carcinomas than in normal epithelial ovarian tissues or benign epithelial ovarian tumors. The expression of chemokines CXCL12 and CXCL16 were positively correlated with their receptors CXCR4 and CXCR6 in ovarian carcinoma, respectively (r = 0.300, P < 0.05; r = 0.395, P < 0.05). Moreover, the expression of CXCL12 was related to the occurrence of ascites (χ2 = 4.76, P < 0.05), the expression of CXCR4 was significantly related to lymph node metastasis (χ2 = 4.37, P < 0.05), the expression of CXCR6 was significantly related to lymph node metastasis (χ2 = 7.43, P < 0.05) and histological type (χ2 = 33.48, P < 0.05). In univariate analysis, the expression of CXCR4 and CXCL16 significantly correlated with reduced median survival (χ2 = 4.67, P < 0.05; χ2 = 4.48, P < 0.05). Therefore, we conclude that the chemokine axes CXCL12/CXCR4 and CXCL16/CXCR6 may play important roles in the growth, proliferation, invasion, and metastasis of epithelial ovarian carcinoma. PMID:21527066

Chemokine axes CXCL12/CXCR4 and CXCL16/CXCR6 correlate with lymph node metastasis in epithelial ovarian carcinoma.

PubMed

Guo, Li; Cui, Zhu-Mei; Zhang, Jia; Huang, Yu

2011-05-01

Recent evidence suggests that the chemokine axis of CXC chemokine ligand-12 and its receptor CXC chemokine receptor-4 (CXCL12/CXCR4) is highly expressed in gynecological tumors and the axis of CXC chemokine ligand-16 and CXC chemokine receptor-6 (CXCL16/CXCR6) is overexpressed in inflammation-associated tumors. This study aimed to determine the relationship between CXCL12/CXCR4, CXCL16/CXCR6 and ovarian carcinoma's clinicopathologic features and prognosis. Accordingly, the expression of these proteins in ovarian tissues was detected by tissue microarray and immunohistochemistry. The expressions of CXCL12/CXCR4 and CXCL16/CXCR6 were significantly higher in epithelial ovarian carcinomas than in normal epithelial ovarian tissues or benign epithelial ovarian tumors. The expression of chemokines CXCL12 and CXCL16 were positively correlated with their receptors CXCR4 and CXCR6 in ovarian carcinoma, respectively (r = 0.300, P < 0.05; r = 0.395, P < 0.05). Moreover, the expression of CXCL12 was related to the occurrence of ascites (Χ² = 4.76, P < 0.05), the expression of CXCR4 was significantly related to lymph node metastasis (Χ(2) = 4.37, P < 0.05), the expression of CXCR6 was significantly related to lymph node metastasis (Χ² = 7.43, P < 0.05) and histological type (Χ² = 33.48, P < 0.05). In univariate analysis, the expression of CXCR4 and CXCL16 significantly correlated with reduced median survival (Χ² = 4.67, P < 0.05; Χ² = 4.48, P < 0.05). Therefore, we conclude that the chemokine axes CXCL12/CXCR4 and CXCL16/CXCR6 may play important roles in the growth, proliferation, invasion, and metastasis of epithelial ovarian carcinoma.

Type II diabetes mellitus and the incidence of epithelial ovarian cancer in the cancer prevention study-II nutrition cohort.

PubMed

Gapstur, Susan M; Patel, Alpa V; Diver, W Ryan; Hildebrand, Janet S; Gaudet, Mia M; Jacobs, Eric J; Campbell, Peter T

2012-11-01

Despite consistent associations of type II diabetes mellitus with hormonally related cancers such as breast and endometrium, the relation between type II diabetes mellitus and ovarian cancer risk is unclear. Associations of type II diabetes mellitus status, duration, and insulin use with epithelial ovarian cancer overall, and with serous and nonserous histologic subtypes were examined in the Cancer Prevention Study-II Nutrition Cohort, a prospective study of U.S. men and women predominantly aged 50 years and older. Between 1992 and 2007, 524 incident epithelial ovarian cancer cases were identified among 63,440 postmenopausal women. Multivariable-adjusted relative risks (RR) and 95% confidence intervals (CI) were computed using extended Cox regression to update diabetes status and bilateral oophorectomy status during follow-up. Type II diabetes mellitus status (RR = 1.05; 95% CI, 0.75-1.46) and duration were not associated with epithelial ovarian cancer risk. Although not statistically significantly different (P(difference) = 0.39), the RR was higher for type II diabetes mellitus with insulin use (RR = 1.28; 95% CI, 0.74-2.24) than for type II diabetes mellitus without insulin use (RR = 0.96; 95% CI, 0.64-1.43). Diabetes seemed to be more strongly associated with nonserous (RR = 1.41; 95% CI, 0.70-2.85) than serous (RR = 0.71; 95% CI, 0.41-1.23) histologic subtypes. Type II diabetes mellitus was not associated with risk of epithelial ovarian cancer, although higher risks with nonserous subtypes and among insulin users cannot be ruled out. Larger studies are needed to clarify associations of type II diabetes mellitus with or without insulin use with risk of ovarian cancer overall and by histologic subtypes. ©2012 AACR.

The role of MicroRNA molecules and MicroRNA-regulating machinery in the pathogenesis and progression of epithelial ovarian cancer.

PubMed

Wang, Xiyin; Ivan, Mircea; Hawkins, Shannon M

2017-11-01

MicroRNA molecules are small, single-stranded RNA molecules that function to regulate networks of genes. They play important roles in normal female reproductive tract biology, as well as in the pathogenesis and progression of epithelial ovarian cancer. DROSHA, DICER, and Argonaute proteins are components of the microRNA-regulatory machinery and mediate microRNA production and function. This review discusses aberrant expression of microRNA molecules and microRNA-regulating machinery associated with clinical features of epithelial ovarian cancer. Understanding the regulation of microRNA molecule production and function may facilitate the development of novel diagnostic and therapeutic strategies to improve the prognosis of women with epithelial ovarian cancer. Additionally, understanding microRNA molecules and microRNA-regulatory machinery associations with clinical features may influence prevention and early detection efforts. Copyright © 2017 Elsevier Inc. All rights reserved.

TLR8 Agonist VTX-2337 and Pegylated Liposomal Doxorubicin Hydrochloride or Paclitaxel in Treating Patients With Recurrent or Persistent Ovarian Epithelial, Fallopian Tube, or Peritoneal Cavity Cancer

ClinicalTrials.gov

2014-12-23

Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Ovarian Carcinoma

Circulating 25-Hydroxyvitamin D and Risk of Epithelial Ovarian Cancer

PubMed Central

Zheng, Wei; Danforth, Kim N.; Tworoger, Shelley S.; Goodman, Marc T.; Arslan, Alan A.; Patel, Alpa V.; McCullough, Marjorie L.; Weinstein, Stephanie J.; Kolonel, Laurence N.; Purdue, Mark P.; Shu, Xiao-Ou; Snyder, Kirk; Steplowski, Emily; Visvanathan, Kala; Yu, Kai; Zeleniuch-Jacquotte, Anne; Gao, Yu-Tang; Hankinson, Susan E.; Harvey, Chinonye; Hayes, Richard B.; Henderson, Brian E.; Horst, Ronald L.; Helzlsouer, Kathy J.

2010-01-01

A role for vitamin D in ovarian cancer etiology is supported by ecologic studies of sunlight exposure, experimental mechanism studies, and some studies of dietary vitamin D intake and genetic polymorphisms in the vitamin D receptor. However, few studies have examined the association of circulating 25-hydroxyvitamin D (25(OH)D), an integrated measure of vitamin D status, with ovarian cancer risk. A nested case-control study was conducted among 7 prospective studies to evaluate the circulating 25(OH)D concentration in relation to epithelial ovarian cancer risk. Logistic regression models were used to estimate odds ratios and 95% confidence intervals among 516 cases and 770 matched controls. Compared with 25(OH)D concentrations of 50–<75 nmol/L, no statistically significant associations were observed for <37.5 (odds ratio (OR) = 1.21, 95% confidence interval (CI): 0.87, 1.70), 37.5–<50 (OR = 1.03, 95% CI: 0.75, 1.41), or ≥75 (OR = 1.11, 95% CI: 0.79, 1.55) nmol/L. Analyses stratified by tumor subtype, age, body mass index, and other variables were generally null but suggested an inverse association between 25(OH)D and ovarian cancer risk among women with a body mass index of ≥25 kg/m2 (Pinteraction < 0.01). In conclusion, this large pooled analysis did not support an overall association between circulating 25(OH)D and ovarian cancer risk, except possibly among overweight women. PMID:20562186

Lymph node metastasis in grossly apparent clinical stage Ia epithelial ovarian cancer: Hacettepe experience and review of literature

PubMed Central

2010-01-01

Background Lymphadenectomy is an integral part of the staging system of epithelial ovarian cancer. However, the extent of lymphadenectomy in the early stages of ovarian cancer is controversial. The objective of this study was to identify the lymph node involvement in unilateral epithelial ovarian cancer apparently confined to the one ovary (clinical stage Ia). Methods A prospective study of clinical stage I ovarian cancer patients is presented. Patient's characteristics and tumor histopathology were the variables evaluated. Results Thirty three ovarian cancer patients with intact ovarian capsule were evaluated. Intraoperatively, neither of the patients had surface involvement, adhesions, ascites or palpable lymph nodes (supposed to be clinical stage Ia). The mean age of the study group was 55.3 ± 11.8. All patients were surgically staged and have undergone a systematic pelvic and paraaortic lymphadenectomy. Final surgicopathologic reports revealed capsular involvement in seven patients (21.2%), contralateral ovarian involvement in two (6%) and omental metastasis in one (3%) patient. There were two patients (6%) with lymph node involvement. One of the two lymph node metastasis was solely in paraaortic node and the other metastasis was in ipsilateral pelvic lymph node. Ovarian capsule was intact in all of the patients with lymph node involvement and the tumor was grade 3. Conclusion In clinical stage Ia ovarian cancer patients, there may be a risk of paraaortic and pelvic lymph node metastasis. Further studies with larger sample size are needed for an exact conclusion. PMID:21114870

Survival Advantage Associated with Decrease in Stage at Detection from Stage IIIC to Stage IIIA Epithelial Ovarian Cancer

PubMed Central

Lefringhouse, Jason; Pavlik, Edward; Miller, Rachel; DeSimone, Christopher; Ueland, Frederick; Kryscio, Richard; van Nagell, J. R.

2014-01-01

Objective. The aim of this study was to document the survival advantage of lowering stage at detection from Stage IIIC to Stage IIIA epithelial ovarian cancer. Methods. Treatment outcomes and survival were evaluated in patients with Stage IIIA and Stage IIIC epithelial ovarian cancer treated from 2000 to 2009 at the University of Kentucky Markey Cancer Center (UKMCC) and SEER institutions. Results. Cytoreduction to no visible disease (P < 0.0001) and complete response to platinum-based chemotherapy (P < 0.025) occurred more frequently in Stage IIIA than in Stage IIIC cases. Time to progression was shorter in patients with Stage IIIC ovarian cancer (17 ± 1 months) than in those with Stage II1A disease (36 ± 8 months). Five-year overall survival (OS) improved from 41% in Stage IIIC patients to 60% in Stage IIIA patients treated at UKMCC and from 37% to 56% in patients treated at SEER institutions for a survival advantage of 19% in both data sets. 53% of Stage IIIA and 14% of Stage IIIC patients had NED at last followup. Conclusions. Decreasing stage at detection from Stage IIIC to stage IIIA epithelial ovarian cancer is associated with a 5-year survival advantage of nearly 20% in patients treated by surgical tumor cytoreduction and platinum-based chemotherapy. PMID:25254047

Ovarian, Fallopian Tube, and Primary Peritoneal Cancer—Patient Version

Cancer.gov

Ovarian epithelial cancer is the most common type of ovarian cancer. Cancer can also form at the end of the fallopian tube near the ovary or the peritoneum and spread to the ovary. Start here to find information on ovarian cancer treatment, causes and prevention, screening, research, and statistics.

Impact and mechanistic role of oral contraceptive pills on the number and epithelial type of ovarian cortical inclusion cysts; a clinicopathology and immunohistochemical study.

PubMed

DastranjTabrizi, Ali; MostafaGharabaghi, Parvin; SheikhzadehHesari, Farzam; Sadeghi, Liela; Zamanvandi, Sharareh; Sarbakhsh, Parvin; Ghojazadeh, Morteza

2016-03-22

Ovarian epithelial cancers are among the most lethal women's cancers. There is no doubt about the preventive role of oral contraceptive pills (OCPs) in development of ovarian cancers. But, there are limited numbers of studies to address the effect of these agents on the number of cortical inclusion cysts (CICs), their epithelial type and suppression of the metaplastic phenomenon by these pills. The aim of this study was to clarify the role of these agents in the prevention of these cyst formation and tubal metaplasia and also examine the mesenchymal-epithelial transition theory in this context by immunohistochemical methods. The representative section(s) of ovarian cortex from a total number of 201 consecutive total abdominal hysterectomy with bilateral or unilateral salpingo-oophorectomy specimens were examined for mean number of CICs and their epithelial type between two groups of the patients. Group A included the patients who were on oral contraceptive pills for more than 5 years. All of the subjects with other contraceptive methods or a history of less than 5 years contraceptive pills usage were stratified in group B. Sections from 20 cases in which more than five inclusion cysts were found, were selected for IHC staining with calretinine and PAX8 as markers for mesothelium and mullerian epithelium respectively. The mean age of the patients was 51.67 years with no significant differences between two groups. The mean number of cysts were 1.27 and 3.23 in group A and B respectively (P =0.0001). Similarly the mean number of CICs, lined by tubal epithelium, was significantly different between two groups (0.65 vs 2.65, P =0.0001). In IHC staining 123 out of 150 CICs (82 %) were PAX+ while only 7 CICs (4.8 %) showed positive reaction for calretinin irrespective of type of epithelium. Our findings showed that the use of OCP for more than five years in women, significantly prevents development of cortical inclusion cysts in the ovaries which lined by tubal

Multicellular detachment generates metastatic spheroids during intra-abdominal dissemination in epithelial ovarian cancer.

PubMed

Al Habyan, Sara; Kalos, Christina; Szymborski, Joseph; McCaffrey, Luke

2018-05-23

Ovarian cancer is the most lethal gynecological cancer, where survival rates have had modest improvement over the last 30 years. Metastasis of cancer cells is a major clinical problem, and patient mortality occurs when ovarian cancer cells spread beyond the confinement of ovaries. Disseminated ovarian cancer cells typically spread within the abdomen, where ascites accumulation aids in their transit. Metastatic ascites contain multicellular spheroids, which promote chemo-resistance and recurrence. However, little is known about the origin and mechanisms through which spheroids arise. Using live-imaging of 3D culture models and animal models, we report that epithelial ovarian cancer (EOC) cells, the most common type of ovarian cancer, can spontaneously detach as either single cells or clusters. We report that clusters are more resistant to anoikis and have a potent survival advantage over single cells. Using in vivo lineage tracing, we found that multicellular spheroids arise preferentially from collective detachment, rather than aggregation in the abdomen. Finally, we report that multicellular spheroids from collective detachment are capable of seeding intra-abdominal metastases that retain intra-tumoral heterogeneity from the primary tumor.

p14 expression differences in ovarian benign, borderline and malignant epithelial tumors.

PubMed

Cabral, Vinicius Duarte; Cerski, Marcelle Reesink; Sa Brito, Ivana Trindade; Kliemann, Lucia Maria

2016-10-22

Abnormalities in tumor suppressors p14, p16 and p53 are reported in several human cancers. In ovarian epithelial carcinogenesis, p16 and p53 show higher immunohistochemical staining frequencies in malignant tumors and are associated with poor prognoses. p14 was only analyzed in carcinomas, with conflicting results. There are no reports on its expression in benign and borderline tumors. This study aims to determine p14, p16 and p53 expression frequencies in ovarian benign, borderline and malignant tumors and their associations with clinical parameters. A cross-sectional study utilizing immunohistochemistry was performed on paraffin-embedded ovarian epithelial tumor samples. Clinical data were collected from medical records. Fisher's exact test and the Bonferroni correction were performed for frequency associations. Survival comparisons utilized Kaplan-Meier and log rank testing. Associations were considered significant when p < 0.05. p14 absent expression was associated with malignant tumors (60 % positive) (p = 0.000), while 93 % and 94 % of benign and borderline tumors, respectively, were positive. p16 was positive in 94.6 % of carcinomas, 75 % of borderline and 45.7 % of benign tumors (p = 0.000). p53 negative staining was associated with benign tumors (2.9 % positive) (p = 0.016) but no difference was observed between borderline (16.7 %) and malignant tumors (29.7 %) (p = 0.560). No associations were found between expression rates, disease-free survival times or clinical variables. Carcinoma subtypes showed no difference in expression. This is the first description of p14 expression in benign and borderline tumors. It remains stable in benign and borderline tumors, while carcinomas show a significant absence of staining. This may indicate that p14 abnormalities occur later in carcinogenesis. p16 and p53 frequencies increase from benign to borderline and malignant tumors, similarly to previous reports, possibly reflecting the

MicroRNA-219-5p inhibits the proliferation, migration, and invasion of epithelial ovarian cancer cells by targeting the Twist/Wnt/β-catenin signaling pathway.

PubMed

Wei, Chunyan; Zhang, Xi; He, Sai; Liu, Bianli; Han, Hongfang; Sun, Xuejun

2017-12-30

MicroRNAs are emerging as critical regulators in various fundamental biological processes, including tumor progression. MicroRNA-219-5p (miR-219-5p) has been suggested as a novel tumor suppressing miRNA for many types of human cancers. However, the expression and functional significance of miR-219-5p in epithelial ovarian cancer remain poorly understood. In this study, we sought to explore the potential functions of miR-219-5p in epithelial ovarian cancer. Herein, we found that miR-219-5p levels were significantly decreased in epithelial ovarian cancer tissues and cell lines. Further experiments showed that overexpression of miR-219-5p inhibited epithelial ovarian cancer cell proliferation, migration, and invasion, and suppressed the Wnt/β-catenin signaling pathway. By contrast, suppression of miR-219-5p exhibited the opposite effects. Twist was identified as a downstream target of miR-219-5p, and its expression was directly regulated by miR-219-5p. Restoration of Twist expression in miR-219-5p-overexpresing cells significantly reversed the antitumor effects of miR-219-5p. Taken together, our results revealed a tumor suppressive role for miR-219-5p in epithelial ovarian cancer that includes suppression of cell proliferation, migration, and invasion through downregulation of the Twist/Wnt/β-catenin signaling pathway. Our study suggests that miR-219-5p may have potential applications in the diagnosis and treatment of epithelial ovarian cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

Expression and clinical implication of Beclin1, HMGB1, p62, survivin, BRCA1 and ERCC1 in epithelial ovarian tumor tissues.

PubMed

Ju, L-L; Zhao, C Y; Ye, K-F; Yang, H; Zhang, J

2016-05-01

The aim of the present study is to investigate the differential expression of Beclin1, HMGB1, p62, survivin, ERCC1 and BRCA1 protein in epithelial ovarian cancer (EOC) and to evaluate the relationship between autophagy and platinum resistance of EOC patients during platinum-based chemotherapy with the protein expression. Expression of Beclin1, HMGB1, p62, survivin, ERCC1 and BRCA1 were detected with immunohistochemistry in 60 patients, including 39 with epithelial ovarian cancer (EOC), 13 benign epithelial ovarian tumor tissue (BET) and 8 borderline ovarian tumor tissue. Beclin, p62 and ERCC1 expression was significantly higher in the EOC than the BET (p<0.05). No statistical significance was detected with HMGB1 or survivin expression among BET, borderline tumor and EOC (p>0.05). BRCA1 expression was lower in EOC than BET (p<0.05). The expression of Beclin, p62 and survivin significantly correlated with FIGO stage (p<0.05), while the expression of HMGB1 correlated with pathological type. For platinum-sensitive EOC patients, positive expression of Beclin1 and BRCA1 was lower, and positive P62 expression was higher than in platinum-resistant patients (p<0.05). BRCA1 expression was negatively correlated with Beclin1 and p62 expression (p<0.05). Inhibition of expression of beclin1 may suppress autophagy to enhance the efficiency of platinum-sensitive ovarian cancer. HMGB1, survivin and p62 are implicated in the development of ovarian cancer. ERCC1 might be a potential predictive marker for neoadjuvant treatment in the early stage of ovarian cancer, and BRCA1, Beclin1 and p62 as a biomarker to predict platinum resistance and prognosis of epithelial ovarian cancer.

High Grade Serous Cystadenocarcinoma of Testis-Case Report of a Rare Ovarian Epithelial Type Tumour

PubMed Central

Nayanar, Sangeetha K; Varadharajaperumal, R; Satheeshbabu, TV; Balasubramanian, Satheesan

2017-01-01

Ovarian epithelial type tumour of testis are extremely rare tumours that resemble ovarian surface epithelial tumours. They usually present as testicular or paratesticular tumours and can be serous, mucinous, endometrioid or Brenner tumour. Serous and mucinous types account for the majority of tumours. The tumours are benign, borderline or malignant, commonly borderline. Here, we report a case of high grade serous cyst adenocarcinoma of testis which manifested as extensive metastasis in supraclavicular, mediastinal and abdominopelvic groups of lymph nodes, lung and adrenal gland without clinical evidence of an overt primary tumour. We report this case so as to make clinicians and pathologists aware of this rare entity and to stress on the fact that this rare entity should be kept in mind when evaluating cases of metastatic adenocarcinoma in male patients. PMID:28764180

Adipose-derived mesenchymal stem cells promote cell proliferation and invasion of epithelial ovarian cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chu, Yijing; Tang, Huijuan; Guo, Yan

Adipose-derived mesenchymal stem cell (ADSC) is an important component of tumor microenvironment. However, whether ADSCs have a hand in ovarian cancer progression remains unclear. In this study, we investigated the impact of human ADSCs derived from the omentum of normal donors on human epithelial ovarian cancer (EOC) cells in vitro and in vivo. Direct and indirect co-culture models including ADSCs and human EOC cell lines were established and the effects of ADSCs on EOC cell proliferation were evaluated by EdU incorporation and flow cytometry. Transwell migration assays and detection of MMPs were performed to assess the invasion activity of EOCmore » cells in vitro. Mouse models were established by intraperitoneal injection of EOC cells with or without concomitant ADSCs to investigate the role of ADSCs in tumor progression in vivo. We found that ADSCs significantly promoted proliferation and invasion of EOC cells in both direct and indirect co-culture assays. In addition, after co-culture with ADSCs, EOC cells secreted higher levels of matrix metalloproteinases (MMPs), and inhibition of MMP2 and MMP9 partially relieved the tumor-promoting effects of ADSCs in vitro. In mouse xenograft models, we confirmed that ADSCs promoted EOC growth and metastasis and elevated the expression of MMP2 and MMP9. Our findings indicate that omental ADSCs play a promotive role during ovarian cancer progression. - Highlights: • Omental adipose derived stem cells enhanced growth and invasion properties of ovarian cancer cells. • Adipose derived stem cells promoted the growth and metastasis of ovarian cancer in mice models. • Adipose derived stem cells promoted MMPs expression and secretion of ovarian cancer cells. • Elevated MMPs mediated the tumor promoting effects of ADSCs.« less

Fruit and vegetable consumption associated with reduced risk of epithelial ovarian cancer in southern Chinese women.

PubMed

Tang, Li; Lee, Andy H; Su, Dada; Binns, Colin W

2014-01-01

To investigate the association between fruit and vegetable consumption and the risk of epithelial ovarian cancer in southern Chinese women. A case-control study was undertaken in Guangzhou, Guangdong Province, between 2006 and 2008. Participants were 500 incident ovarian cancer patients and 500 hospital-based controls. Information on habitual fruit and vegetable consumption was obtained by face-to-face interview using a validated and reliable food frequency questionnaire. Unconditional logistic regression analyses were performed to assess the association between fruit and vegetable intakes and the ovarian cancer risk. The mean fruit and vegetable daily intakes of ovarian cancer patients (324.2g (SD 161.9) and 582.7 g (SD 250.2)) were significantly lower (p<0.001) than those of controls (477.3g (SD 362.1) and 983.3g (SD 739.9)). The adjusted odds ratios were 0.30 (95% confidence interval (CI) 0.21 to 0.44) and 0.07 (95% CI 0.04 to 0.12) for more than 490 g of fruits and 970 g of vegetables per day, relative to at most 320 g and 690 g per day, respectively. With the exception of lycopene, substantial risk reductions were evident for a variety of nutrients derived from fruits and vegetables. Consumption of fruits and vegetables was inversely associated with the incidence of epithelial ovarian cancer in southern Chinese women. © 2013.

Higher Numbers of T-Bet+ Tumor-Infiltrating Lymphocytes Associate with Better Survival in Human Epithelial Ovarian Cancer.

PubMed

Xu, Yun; Chen, Lujun; Xu, Bin; Xiong, Yuqi; Yang, Min; Rui, Xiaohui; Shi, Liangrong; Wu, Changping; Jiang, Jingting; Lu, Binfeng

2017-01-01

T-bet, a member of the T-box family of transcription factors, is a key marker of type I immune response within the tumor microenvironment, and has been previously reported by us to serve as an important prognostic indicator for human gastric cancer patients and a potential biomarker for immunotherapy. In the present study, we aimed to assess the clinical significance and prognostic value of T-bet+ tumor-infiltrating lymphocytes in human epithelial ovarian cancer. The immunohistochemistry was used to analyze the infiltration density of T-bet+ lymphoid cells in human epithelial ovarian cancer tissues, and the flow cytometry analysis was used to further analyze the presence of T-bet+ tumor-infiltrating lymphocytes subgroups in cancer tissues. Our immunohistochemistry analysis showed increased number of T-bet+ lymphoid cells in the human epithelial ovarian cancer tissues, and the flow cytometry analysis further demonstrated the presence of T-bet+ tumor-infiltrating lymphocytes subgroups including CD4+ , CD8+ T cells and NK cells. In addition, we also observed a significant association of T-bet+ tumor-infiltrating lymphocytes density in the tumor nest of cancer with not only serum CA125 levels but also with distant metastasis. However no association was observed with other characteristics like patients' age, pathological type, FIGO stage, tumor site and tumor size. Furthermore, the survival analysis showed that higher density of T-bet+ tumor-infiltrating lymphocytes both in tumor nest and tumor stroma of cancer tissues was significantly associated with better patient survival. In addition, the density of T-bet+ tumor-infiltrating lymphocytes in tumor nest appeared to be an independent risk factor for predicting patients' postoperative prognoses. Our data indicated that the key transcription factor T-bet might play an important role in the type I immune cells mediated antitumor response, and the density of T-bet+ lymphocytes in human epithelial ovarian cancer tissues

Loss of heterozygosity at 7q22 and mutation analysis of the CDP gene in human epithelial ovarian tumors.

PubMed

Neville, P J; Thomas, N; Campbell, I G

2001-02-01

Many tumor types including that of the ovary show loss of heterozygosity (LOH) on chromosome arm 7q, which suggests the existence of at least one tumor suppressor gene (TSG) on this chromosome arm. We have studied the region surrounding the putative tumor suppressor gene CUTL1 at 7q22 in 127 epithelial ovarian tumors. LOH was found across 7q22 in 31% of malignant and 14% of benign ovarian tumors. In 16% of the tumors the LOH appeared to be centered on the CUTL1 gene. This gene has been implicated previously as a TSG in both uterine leiomyomas and breast carcinoma. However, mutation analysis of the CUTL1 gene in 47 tumors with 7q22 LOH failed to identify any somatic alterations in the coding regions. This finding suggests that CUTL1 may not be the target of the 7q22 LOH in ovarian cancers.

An mDia2/ROCK Signaling Axis Regulates Invasive Egress from Epithelial Ovarian Cancer Spheroids

PubMed Central

Pettee, Krista M.; Dvorak, Kaitlyn M.; Nestor-Kalinoski, Andrea L.; Eisenmann, Kathryn M.

2014-01-01

Multi-cellular spheroids are enriched in ascites of epithelial ovarian cancer (OvCa) patients. They represent an invasive and chemoresistant cellular population fundamental to metastatic dissemination. The molecular mechanisms triggering single cell invasive egress from spheroids remain enigmatic. mDia formins are Rho GTPase effectors that are key regulators of F-actin cytoskeletal dynamics. We hypothesized that mDia2-driven F-actin dynamics promote single cell invasive transitions in clinically relevant three-dimensional (3D) OvCa spheroids. The current study is a dissection of the contribution of the F-actin assembly factor mDia2 formin in invasive transitions and using a clinically relevant ovarian cancer spheroid model. We show that RhoA-directed mDia2 activity is required for tight spheroid organization, and enrichment of mDia2 in the invasive cellular protrusions of collagen-embedded OVCA429 spheroids. Depleting mDia2 in ES-2 spheroids enhanced invasive dissemination of single amoeboid-shaped cells. This contrasts with spheroids treated with control siRNA, where a mesenchymal invasion program predominated. Inhibition of another RhoA effector, ROCK, had no impact on ES-2 spheroid formation but dramatically inhibited spheroid invasion through induction of a highly elongated morphology. Concurrent inhibition of ROCK and mDia2 blocked single cell invasion from ES-2 spheroids more effectively than inhibition of either protein alone, indicating that invasive egress of amoeboid cells from mDia2-depleted spheroids is ROCK-dependent. Our findings indicate that multiple GTPase effectors must be suppressed in order to fully block invasive egress from ovarian cancer spheroids. Furthermore, tightly regulated interplay between ROCK and mDia2 signaling pathways dictates the invasive capacities and the type of invasion program utilized by motile spheroid-derived ovarian cancer cells. As loss of the gene encoding mDia2, DRF3, has been linked to cancer progression and

An mDia2/ROCK signaling axis regulates invasive egress from epithelial ovarian cancer spheroids.

PubMed

Pettee, Krista M; Dvorak, Kaitlyn M; Nestor-Kalinoski, Andrea L; Eisenmann, Kathryn M

2014-01-01

Multi-cellular spheroids are enriched in ascites of epithelial ovarian cancer (OvCa) patients. They represent an invasive and chemoresistant cellular population fundamental to metastatic dissemination. The molecular mechanisms triggering single cell invasive egress from spheroids remain enigmatic. mDia formins are Rho GTPase effectors that are key regulators of F-actin cytoskeletal dynamics. We hypothesized that mDia2-driven F-actin dynamics promote single cell invasive transitions in clinically relevant three-dimensional (3D) OvCa spheroids. The current study is a dissection of the contribution of the F-actin assembly factor mDia2 formin in invasive transitions and using a clinically relevant ovarian cancer spheroid model. We show that RhoA-directed mDia2 activity is required for tight spheroid organization, and enrichment of mDia2 in the invasive cellular protrusions of collagen-embedded OVCA429 spheroids. Depleting mDia2 in ES-2 spheroids enhanced invasive dissemination of single amoeboid-shaped cells. This contrasts with spheroids treated with control siRNA, where a mesenchymal invasion program predominated. Inhibition of another RhoA effector, ROCK, had no impact on ES-2 spheroid formation but dramatically inhibited spheroid invasion through induction of a highly elongated morphology. Concurrent inhibition of ROCK and mDia2 blocked single cell invasion from ES-2 spheroids more effectively than inhibition of either protein alone, indicating that invasive egress of amoeboid cells from mDia2-depleted spheroids is ROCK-dependent. Our findings indicate that multiple GTPase effectors must be suppressed in order to fully block invasive egress from ovarian cancer spheroids. Furthermore, tightly regulated interplay between ROCK and mDia2 signaling pathways dictates the invasive capacities and the type of invasion program utilized by motile spheroid-derived ovarian cancer cells. As loss of the gene encoding mDia2, DRF3, has been linked to cancer progression and

Bevacizumab and Intravenous or Intraperitoneal Chemotherapy in Treating Patients With Stage II-III Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

ClinicalTrials.gov

2018-05-25

Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Undifferentiated Ovarian Carcinoma

Does serum CA125 have clinical value for follow-up monitoring of postoperative patients with epithelial ovarian cancer? Results of a 12-year study.

PubMed

Guo, Na; Peng, Zhilan

2017-03-11

The detection of CA125 has been used in the follow up of ovarian cancer. At present, some scholars believe that serum CA125 has no clinical value for the follow-up monitoring the recurrence for postoperative patients with epithelial ovarian cancer, but in our clinical follow-up found that when the serum CA125 value is <35 U/ml, postoperative patients of epithelial ovarian carcinoma had already showed recurrent lesions in some ecological and imaging examinations or in laparotomy exploration and biopsy, and we given the patients timely treatment, the prognosis were improved. Retrospective analysis the values of serum CA125 of 342 postoperative patients of epithelial ovarian carcinoma, consisting of 296 non-recurrent and 46 recurrent cases, as well as 3175 cases of menopausal women and 603 cases of postoperative patients of gynecological malignant tumor for the follow-up from January 2005 to December 2016. The median value of CA125 for non-recurrent patients of epithelial ovarian carcinoma is 8.9 U/ml, the median value of CA125 for non-recurrent patients of epithelial ovarian carcinoma is 29.7 U/ml; for menopausal women, 8.1 U/ml; and for postoperative patients of gynecological malignant tumor, 7.2 U/ml, whereas the mean ± standard deviation is 9.0 ± 1.9 U/ml, 31.3 ± 16.2U/ml, 8.0 ± 1.1 U/ml, and 6.8 ± 2.1 U/ml, respectively. If the value of the CA125 for postoperative patients of epithelial ovarian carcinoma between 10 and 35 U/ml indicates a relative risk of recurrence. When the value of CA125 is higher than 10 U/ml and continuously increased, need to be vigilant and should be combined with imaging examination (PET-CT). This result may improve the prognosis for recurrent patients because of the early detection of recurrent lesions and early retreatment.

Vascular endothelial growth factor polymorphisms and a synchronized examination of plasma and tissue expression in epithelial ovarian cancers.

PubMed

Bhaskari, J; Premalata, C S; Shilpa, V; Rahul, B; Pallavi, V R; Ramesh, G; Krishnamoorthy, Lakshmi

2016-01-01

In this study, we have analyzed six genetic polymorphisms of the VEGF-A gene and correlated the genetic data with plasma and tissue expression of VEGF-A in epithelial ovarian carcinomas. A total of 130 cases including 95 malignant carcinomas, 17 low malignant potential and 18 benign tumours were studied. rs699947, rs833061, rs1570360, rs2010963, rs1413711 and rs3025039 were studied by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Plasma levels of VEGF-A were estimated by enzyme-linked immunosorbent assay (ELISA) and tissue expression of VEGF-A by immunohistochemistry (IHC). Four polymorphisms of the above excluding rs699947 and rs3025039 showed significant association with malignancy, and we observed the presence of positive correlation between haplotype CCGGCC and increased expression of VEGF-A in both plasma and tissues which also correlated with poor prognosis and recurrence suggesting a probable increase in resistance to treatment in such carriers. Highly upregulated tissue expression of VEGF-A was seen in all epithelial ovarian carcinomas with intensity of expression increasing from benign to malignant cases. ELISA data from our study showed an increase in circulating levels of VEGF-A in malignancies. VEGF-A plasma levels can be employed as a biomarker for high-grade malignancy in epithelial ovarian cancers alongside tissue expression and CA-125 levels. This study is unique due to the fact that a simultaneous analysis of plasma and tissue expression has been demonstrated and is a first such study in epithelial ovarian cancers and representing the Indian population (South-east Asian) synchronized with genetic polymorphism data as well.

Current state of biomarker development for clinical application in epithelial ovarian cancer

PubMed Central

Moore, Richard G.; MacLaughlan, Shannon; Bast, Robert C.

2011-01-01

Each year in the United States over 15,000 women die of epithelial ovarian cancer (EOC)and 22,000 are diagnosed with the disease. The incidence of ovarian cancer has remained stable over the past decade however, survival rates have improved steadily. Increases in survival rates can be attributed to the advances in surgical management, development of effective cytotoxic drugs and the route of administration of chemotherapy. Ovarian cancer survival rates could also be improved through screening and early detection. Disappointingly, effective screening methods have not been established and continue to be elusive. Historically the goal of a screening test was to achieve a positive predictive value (PPV) greater than 10% in order be considered cost effective and have an acceptable risk for the population being screened. Despite the inability of currently available screening algorithms to achieve the desired PPV there may be an advantage in producing a stage migration to lower stages at the time of diagnoses, thereby resulting in improved survival. Equally important recent studies have demonstrated that women who have their initial surgery performed by gynecologic oncologists, and women who have their surgeries at centers experienced in the treatment of ovarian cancer have higher survival rates. For these reasons it is essential that all women at high risk for ovarian cancer receive their initial care by gynecologic oncologists and at centers with multidisciplinary teams experienced in the optimal care of ovarian cancer patients. With this in mind, methods that facilitate the accurate triage of women who will ultimately be diagnosed with ovarian cancer could play a significant role in improving survival rates for these patients. This review article will examine the current state of biomarker use in ovarian cancer screening, risk assessment and for monitoring ovarian cancer patients. PMID:19879639

Emodin Inhibits the Epithelial to Mesenchymal Transition of Epithelial Ovarian Cancer Cells via ILK/GSK-3β/Slug Signaling Pathway

PubMed Central

Lu, Jingjing; Xu, Ying; Wei, Xuan; Zhao, Zhe; Xue, Jing

2016-01-01

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Despite the anticancer capabilities of emodin observed in many cancers, including EOC, the underlying molecular mechanism remains to be elucidated. A crucial link has been discovered between the acquisition of metastatic traits and the epithelial-mesenchymal transition (EMT). The present study aimed to determine whether emodin could inhibit the EMT of EOC cells and explore the underlying mechanism. The CCK-8 assay and transwell assay showed that emodin effectively repressed the abilities of proliferation, invasion, and migration in A2780 and SK-OV-3 cells. The Western blot showed that emodin upregulated epithelial markers (E-cadherin and Claudin) while it downregulated mesenchymal markers (N-cadherin and Vimentin) and transcription factor (Slug) in a dose-dependent fashion. After transfection of siRNA-Slug, both Slug and N-cadherin were downregulated in EOC cells while E-cadherin was upregulated, which was intensified by emodin. Besides, emodin decreased the expression of ILK, p-GSK-3β, β-catenin, and Slug. Transfection of siRNA-ILK also achieved the same effects, which was further strengthened by following emodin treatment. Nevertheless, SB216763, an inhibitor of GSK-3β, could reverse the effects of emodin except for ILK expression. These findings suggest that emodin inhibited the EMT of EOC cells via ILK/GSK-3β/Slug signaling pathway. PMID:28097141

Emodin Inhibits the Epithelial to Mesenchymal Transition of Epithelial Ovarian Cancer Cells via ILK/GSK-3β/Slug Signaling Pathway.

PubMed

Lu, Jingjing; Xu, Ying; Wei, Xuan; Zhao, Zhe; Xue, Jing; Liu, Peishu

2016-01-01

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Despite the anticancer capabilities of emodin observed in many cancers, including EOC, the underlying molecular mechanism remains to be elucidated. A crucial link has been discovered between the acquisition of metastatic traits and the epithelial-mesenchymal transition (EMT). The present study aimed to determine whether emodin could inhibit the EMT of EOC cells and explore the underlying mechanism. The CCK-8 assay and transwell assay showed that emodin effectively repressed the abilities of proliferation, invasion, and migration in A2780 and SK-OV-3 cells. The Western blot showed that emodin upregulated epithelial markers (E-cadherin and Claudin) while it downregulated mesenchymal markers (N-cadherin and Vimentin) and transcription factor (Slug) in a dose-dependent fashion. After transfection of siRNA-Slug, both Slug and N-cadherin were downregulated in EOC cells while E-cadherin was upregulated, which was intensified by emodin. Besides, emodin decreased the expression of ILK, p-GSK-3 β , β -catenin, and Slug. Transfection of siRNA-ILK also achieved the same effects, which was further strengthened by following emodin treatment. Nevertheless, SB216763, an inhibitor of GSK-3 β , could reverse the effects of emodin except for ILK expression. These findings suggest that emodin inhibited the EMT of EOC cells via ILK/GSK-3 β /Slug signaling pathway.

Detection of high mobility group A2 specific mRNA in the plasma of patients affected by epithelial ovarian cancer

PubMed Central

Pasquinelli, Rosa; Pignata, Sandro; Greggi, Stefano; Vuttariello, Emilia; Bello, Anna Maria; Calise, Celeste; Scaffa, Cono; Pisano, Carmela; Losito, Nunzia Simona; Fusco, Alfredo; Califano, Daniela; Chiappetta, Gennaro

2015-01-01

Ovarian cancer is the most lethal gynecological malignancy and the high mortality rate is associated with advanced-stage disease at the time of the diagnosis. In order to find new tools to make diagnosis of Epithelial Ovarian Cancer (EOC) at early stages we have analyzed the presence of specific HMGA2 mRNA in the plasma of patients affected by this neoplasm. HMGA2 overexpression represents a feature of several malignances including ovarian carcinomas. Notably, we detected HMGA2 specific mRNA in the plasma of 40 out 47 patients with EOC, but not in the plasma of healthy donors. All cases found positive for HMGA2 mRNA in the plasma showed HMGA2 protein expression in EOC tissues. Therefore, on the basis of these results, the analysis of circulating HMGA2 specific mRNA might be considered a very promising tool for the early diagnosis of EOC. PMID:25749380

Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

PubMed Central

Shen, Hui; Fridley, Brooke L.; Song, Honglin; Lawrenson, Kate; Cunningham, Julie M.; Ramus, Susan J.; Cicek, Mine S.; Tyrer, Jonathan; Stram, Douglas; Larson, Melissa C.; Köbel, Martin; Ziogas, Argyrios; Zheng, Wei; Yang, Hannah P.; Wu, Anna H.; Wozniak, Eva L.; Woo, Yin Ling; Winterhoff, Boris; Wik, Elisabeth; Whittemore, Alice S.; Wentzensen, Nicolas; Weber, Rachel Palmieri; Vitonis, Allison F.; Vincent, Daniel; Vierkant, Robert A.; Vergote, Ignace; Van Den Berg, David; Van Altena, Anne M.; Tworoger, Shelley S.; Thompson, Pamela J.; Tessier, Daniel C.; Terry, Kathryn L.; Teo, Soo-Hwang; Templeman, Claire; Stram, Daniel O.; Southey, Melissa C.; Sieh, Weiva; Siddiqui, Nadeem; Shvetsov, Yurii B.; Shu, Xiao-Ou; Shridhar, Viji; Wang-Gohrke, Shan; Severi, Gianluca; Schwaab, Ira; Salvesen, Helga B.; Rzepecka, Iwona K.; Runnebaum, Ingo B.; Rossing, Mary Anne; Rodriguez-Rodriguez, Lorna; Risch, Harvey A.; Renner, Stefan P.; Poole, Elizabeth M.; Pike, Malcolm C.; Phelan, Catherine M.; Pelttari, Liisa M.; Pejovic, Tanja; Paul, James; Orlow, Irene; Omar, Siti Zawiah; Olson, Sara H.; Odunsi, Kunle; Nickels, Stefan; Nevanlinna, Heli; Ness, Roberta B.; Narod, Steven A.; Nakanishi, Toru; Moysich, Kirsten B.; Monteiro, Alvaro N.A.; Moes-Sosnowska, Joanna; Modugno, Francesmary; Menon, Usha; McLaughlin, John R.; McGuire, Valerie; Matsuo, Keitaro; Adenan, Noor Azmi Mat; Massuger, Leon F.A. G.; Lurie, Galina; Lundvall, Lene; Lubiński, Jan; Lissowska, Jolanta; Levine, Douglas A.; Leminen, Arto; Lee, Alice W.; Le, Nhu D.; Lambrechts, Sandrina; Lambrechts, Diether; Kupryjanczyk, Jolanta; Krakstad, Camilla; Konecny, Gottfried E.; Kjaer, Susanne Krüger; Kiemeney, Lambertus A.; Kelemen, Linda E.; Keeney, Gary L.; Karlan, Beth Y.; Karevan, Rod; Kalli, Kimberly R.; Kajiyama, Hiroaki; Ji, Bu-Tian; Jensen, Allan; Jakubowska, Anna; Iversen, Edwin; Hosono, Satoyo; Høgdall, Claus K.; Høgdall, Estrid; Hoatlin, Maureen; Hillemanns, Peter; Heitz, Florian; Hein, Rebecca; Harter, Philipp; Halle, Mari K.; Hall, Per; Gronwald, Jacek; Gore, Martin; Goodman, Marc T.; Giles, Graham G.; Gentry-Maharaj, Aleksandra; Garcia-Closas, Montserrat; Flanagan, James M.; Fasching, Peter A.; Ekici, Arif B.; Edwards, Robert; Eccles, Diana; Easton, Douglas F.; Dürst, Matthias; du Bois, Andreas; Dörk, Thilo; Doherty, Jennifer A.; Despierre, Evelyn; Dansonka-Mieszkowska, Agnieszka; Cybulski, Cezary; Cramer, Daniel W.; Cook, Linda S.; Chen, Xiaoqing; Charbonneau, Bridget; Chang-Claude, Jenny; Campbell, Ian; Butzow, Ralf; Bunker, Clareann H.; Brueggmann, Doerthe; Brown, Robert; Brooks-Wilson, Angela; Brinton, Louise A.; Bogdanova, Natalia; Block, Matthew S.; Benjamin, Elizabeth; Beesley, Jonathan; Beckmann, Matthias W.; Bandera, Elisa V.; Baglietto, Laura; Bacot, François; Armasu, Sebastian M.; Antonenkova, Natalia; Anton-Culver, Hoda; Aben, Katja K.; Liang, Dong; Wu, Xifeng; Lu, Karen; Hildebrandt, Michelle A.T.; Schildkraut, Joellen M.; Sellers, Thomas A.; Huntsman, David; Berchuck, Andrew; Chenevix-Trench, Georgia; Gayther, Simon A.; Pharoah, Paul D.P.; Laird, Peter W.; Goode, Ellen L.; Pearce, Celeste Leigh

2013-01-01

HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR) = 1.13, P = 3.1 × 10−10) and clear cell (rs11651755 OR = 0.77, P = 1.6 × 10−8) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes. PMID:23535649

OY-TES-1 expression and serum immunoreactivity in epithelial ovarian cancer.

PubMed

Tammela, Jonathan; Uenaka, Akiko; Ono, Toshiro; Noguchi, Yuji; Jungbluth, Achim A; Mhawech-Fauceglia, Paulette; Qian, Feng; Schneider, Sally; Sharma, Sameer; Driscoll, Deborah; Lele, Shashikant; Old, Lloyd J; Nakayama, Eiichi; Odunsi, Kunle

2006-10-01

OY-TES-1 is a novel target that belongs to the family of 'cancer/testis' (CT) antigens. Our goal was to examine the expression and immunogenicity of OY-TES-1 in epithelial ovarian cancer (EOC) to determine its potential as a target for vaccine therapy. OY-TES-1 expression was determined by one-step reverse transcriptase PCR on 100 EOC samples, 5 EOC cell lines, and a panel of normal tissues. Immunohistochemistry (IHC) was performed on the same panel of EOC tissues. Sera from a sub-group of patients were tested for OY-TES-1 antibody by ELISA. Thymus and leukocytes were weakly positive for OY-TES-1 while the remaining 5 normal tissues were negative. Expression of OY-TES-1 by either RT-PCR and/or IHC was demonstrable in 69/100 (69%) tumors. Humoral immunity to OY-TES-1 was demonstrated in 1/10 (10%) serum samples from patients whose tumors expressed the antigen. The median follow-up of the patient population was 34 months. There was no correlation between antigen expression and stage, grade, histology and survival. OY-TES-1 is expressed in 69% of patients with EOC, is absent from normal ovarian tissue, and a proportion of patients show evidence of a specific humoral immune response. These findings make OY-TES-1 an attractive target for antigen-specific immunotherapy in EOC.

All-Cause Mortality After Fertility-Sparing Surgery for Stage I Epithelial Ovarian Cancer.

PubMed

Melamed, Alexander; Rizzo, Anthony E; Nitecki, Roni; Gockley, Allison A; Bregar, Amy J; Schorge, John O; Del Carmen, Marcela G; Rauh-Hain, J Alejandro

2017-07-01

To compare all-cause mortality between women who underwent fertility-sparing surgery with those who underwent conventional surgery for stage I ovarian cancer. In a cohort study using the National Cancer Database, we identified women younger than 40 years diagnosed with stage IA and unilateral IC epithelial ovarian cancer between 2004 and 2012. Fertility-sparing surgery was defined as conservation of one ovary and the uterus. The primary outcome was time from diagnosis to death. We used propensity score methods to assemble a cohort of women who underwent fertility-sparing or conventional surgery but were otherwise similar on observed covariates and conducted survival analyses using the Kaplan-Meier method and Cox proportional hazard models. We identified 1,726 women with stage IA and unilateral IC epithelial ovarian cancer of whom 825 (47.8%) underwent fertility-sparing surgery. Fertility-sparing surgery was associated with younger age, residence in the northeastern and western United States, and serous or mucinous histology (P<.05 for all). Propensity score matching yielded a cohort of 904 women who were balanced on observed covariates. We observed 30 deaths among women who underwent fertility-sparing surgery and 37 deaths among propensity-matched women who underwent conventional surgery after a median follow-up of 63 months. Fertility-sparing surgery was not associated with hazard of death (hazard ratio 0.80, 95% confidence interval [CI] 0.49-1.29, P=.36). The probability of survival 10 years after diagnosis was 88.5% (95% CI 82.4-92.6) in the fertility-sparing group and 88.9% (95% CI 84.9-92.0) in the conventional surgery group. In patients with high-risk features such as clear cell histology, grade 3, or stage IC, 10-year survival was 80.5% (95% CI 68.5-88.3) among women who underwent fertility-sparing surgery and 83.4% (95% 76.0-88.7) among those who had conventional surgery (hazard ratio 0.86, 95% CI 0.49-1.53, P=.61). Compared with conventional surgery

Association between tumour infiltrating lymphocytes, histotype and clinical outcome in epithelial ovarian cancer.

PubMed

James, Fiona R; Jiminez-Linan, Mercedes; Alsop, Jennifer; Mack, Marie; Song, Honglin; Brenton, James D; Pharoah, Paul D P; Ali, H Raza

2017-09-20

There is evidence that some ovarian tumours evoke an immune response, which can be assessed by tumour infiltrating lymphocytes (TILs). To facilitate adoption of TILs as a clinical biomarker, a standardised method for their H&E visual evaluation has been validated in breast cancer. We sought to investigate the prognostic significance of TILs in a study of 953 invasive epithelial ovarian cancer tumour samples, both primary and metastatic, from 707 patients from the prospective population-based SEARCH study. TILs were analysed using a standardised method based on H&E staining producing a percentage score for stromal and intratumoral compartments. We used Cox regression to estimate hazard ratios of the association between TILs and survival. The extent of stromal and intra-tumoral TILs were correlated in the primary tumours (n = 679, Spearman's rank correlation = 0.60, P < 0.001) with a similar correlation in secondary tumours (n = 224, Spearman's rank correlation = 0.62, P < 0.001). There was a weak correlation between stromal TIL levels in primary and secondary tumour samples (Spearman's rank correlation = 0.29, P < 0.001) and intra-tumoral TIL levels in primary and secondary tumour samples (Spearman's rank correlation = 0.19, P = 0.0094). The extent of stromal TILs differed between histotypes (Pearson chi2 (12d.f.) 54.1, P < 0.0001) with higher levels of stromal infiltration in the high-grade serous and endometriod cases. A significant association was observed for higher intratumoral TIL levels and a favourable prognosis (HR 0.74 95% CI 0.55-1.00 p = 0.047). This study is the largest collection of epithelial ovarian tumour samples evaluated for TILs. We have shown that stromal and intratumoral TIL levels are correlated and that their levels correlate with clinical variables such as tumour histological subtype. We have also shown that increased levels of both intratumoral and stromal TILs are associated with a better prognosis; however, this is

Aspirin, Nonaspirin Nonsteroidal Anti-inflammatory Drug, and Acetaminophen Use and Risk of Invasive Epithelial Ovarian Cancer: A Pooled Analysis in the Ovarian Cancer Association Consortium

PubMed Central

2014-01-01

Background Regular aspirin use is associated with reduced risk of several malignancies. Epidemiologic studies analyzing aspirin, nonaspirin nonsteroidal anti-inflammatory drug (NSAID), and acetaminophen use and ovarian cancer risk have been inconclusive. Methods We analyzed pooled data from 12 population-based case–control studies of ovarian cancer, including 7776 case patients and 11843 control subjects accrued between 1992 and 2007. Odds ratios (ORs) for associations of medication use with invasive epithelial ovarian cancer were estimated in individual studies using logistic regression and combined using random effects meta-analysis. Associations between frequency, dose, and duration of analgesic use and risk of ovarian cancer were also assessed. All statistical tests were two-sided. Results Aspirin use was associated with a reduced risk of ovarian cancer (OR = 0.91; 95% confidence interval [CI] = 0.84 to 0.99). Results were similar but not statistically significant for nonaspirin NSAIDs, and there was no association with acetaminophen. In seven studies with frequency data, the reduced risk was strongest among daily aspirin users (OR = 0.80; 95% CI = 0.67 to 0.96). In three studies with dose information, the reduced risk was strongest among users of low dose (<100mg) aspirin (OR = 0.66; 95% CI = 0.53 to 0.83), whereas for nonaspirin NSAIDs, the reduced risk was strongest for high dose (≥500mg) usage (OR = 0.76; 95% CI = 0.64 to 0.91). Conclusions Aspirin use was associated with a reduced risk of ovarian cancer, especially among daily users of low-dose aspirin. These findings suggest that the same aspirin regimen proven to protect against cardiovascular events and several cancers could reduce the risk of ovarian cancer 20% to 34% depending on frequency and dose of use. PMID:24503200

Tetraploid cells from cytokinesis failure induce aneuploidy and spontaneous transformation of mouse ovarian surface epithelial cells.

PubMed

Lv, Lei; Zhang, Tianwei; Yi, Qiyi; Huang, Yun; Wang, Zheng; Hou, Heli; Zhang, Huan; Zheng, Wei; Hao, Qiaomei; Guo, Zongyou; Cooke, Howard J; Shi, Qinghua

2012-08-01

Most ovarian cancers originate from the ovarian surface epithelium and are characterized by aneuploid karyotypes. Aneuploidy, a consequence of chromosome instability, is an early event during the development of ovarian cancers. However, how aneuploid cells are evolved from normal diploid cells in ovarian cancers remains unknown. In the present study, cytogenetic analyses of a mouse syngeneic ovarian cancer model revealed that diploid mouse ovarian surface epithelial cells (MOSECs) experienced an intermediate tetraploid cell stage, before evolving to aneuploid (mainly near-tetraploid) cells. Using long-term live-cell imaging followed by fluorescence in situ hybridization (FISH), we demonstrated that tetraploid cells originally arose from cytokinesis failure of bipolar mitosis in diploid cells, and gave rise to aneuploid cells through chromosome mis-segregation during both bipolar and multipolar mitoses. Injection of the late passage aneuploid MOSECs resulted in tumor formation in C57BL/6 mice. Therefore, we reveal a pathway for the evolution of diploid to aneuploid MOSECs and elucidate a mechanism for the development of near-tetraploid ovarian cancer cells.

Sugary food and beverage consumption and epithelial ovarian cancer risk: a population-based case-control study.

PubMed

King, Melony G; Olson, Sara H; Paddock, Lisa; Chandran, Urmila; Demissie, Kitaw; Lu, Shou-En; Parekh, Niyati; Rodriguez-Rodriguez, Lorna; Bandera, Elisa V

2013-02-27

Ovarian cancer is the deadliest gynecologic cancer in the US. The consumption of refined sugars has increased dramatically over the past few decades, accounting for almost 15% of total energy intake. Yet, there is limited evidence on how sugar consumption affects ovarian cancer risk. We evaluated ovarian cancer risk in relation to sugary foods and beverages, and total and added sugar intakes in a population-based case-control study. Cases were women with newly diagnosed epithelial ovarian cancer, older than 21 years, able to speak English or Spanish, and residents of six counties in New Jersey. Controls met same criteria as cases, but were ineligible if they had both ovaries removed. A total of 205 cases and 390 controls completed a phone interview, food frequency questionnaire, and self-recorded waist and hip measurements. Based on dietary data, we computed the number of servings of dessert foods, non-dessert foods, sugary drinks and total sugary foods and drinks for each participant. Total and added sugar intakes (grams/day) were also calculated. Multiple logistic regression models were used to estimate odds ratios and 95% confidence intervals for food and drink groups and total and added sugar intakes, while adjusting for major risk factors. We did not find evidence of an association between consumption of sugary foods and beverages and risk, although there was a suggestion of increased risk associated with sugary drink intake (servings per 1,000 kcal; OR=1.63, 95% CI: 0.94-2.83). Overall, we found little indication that sugar intake played a major role on ovarian cancer development.

Cancer-testis antigen expression is shared between epithelial ovarian cancer tumors.

PubMed

Garcia-Soto, Arlene E; Schreiber, Taylor; Strbo, Natasa; Ganjei-Azar, Parvin; Miao, Feng; Koru-Sengul, Tulay; Simpkins, Fiona; Nieves-Neira, Wilberto; Lucci, Joseph; Podack, Eckhard R

2017-06-01

Cancer-testis (CT) antigens have been proposed as potential targets for cancer immunotherapy. Our objective was to evaluate the expression of a panel of CT antigens in epithelial ovarian cancer (EOC) tumor specimens, and to determine if antigen sharing occurs between tumors. RNA was isolated from EOC tumor specimens, EOC cell lines and benign ovarian tissue specimens. Real time-PCR analysis was performed to determine the expression level of 20 CT antigens. A total of 62 EOC specimens, 8 ovarian cancer cell lines and 3 benign ovarian tissues were evaluated for CT antigen expression. The majority of the specimens were: high grade (62%), serous (68%) and advanced stage (74%). 58 (95%) of the EOC tumors analyzed expressed at least one of the CT antigens evaluated. The mean number of CT antigen expressed was 4.5 (0-17). The most frequently expressed CT antigen was MAGE A4 (65%). Antigen sharing analysis showed the following: 9 tumors shared only one antigen with 62% of the evaluated specimens, while 37 tumors shared 4 or more antigens with 82%. 5 tumors expressed over 10 CT antigens, which were shared with 90% of the tumor panel. CT antigens are expressed in 95% of EOC tumor specimens. However, not a single antigen was universally expressed across all samples. The degree of antigen sharing between tumors increased with the total number of antigens expressed. These data suggest a multi-epitope approach for development of immunotherapy for ovarian cancer treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Ovarian, Fallopian Tube, and Primary Peritoneal Cancer—Health Professional Version

Cancer.gov

Ovarian epithelial, fallopian tube, and peritoneal cancers are diseases in which malignant cells form in the tissue covering the ovary, lining the fallopian tube, or peritoneum. Find evidence-based information on ovarian cancer treatment, causes and prevention, screening, research, genetics and statistics.

Prevalence of endometriosis in epithelial ovarian cancer. Analysis of the associated clinical features and study on molecular mechanisms involved in the possible causality.

PubMed

Machado-Linde, F; Sánchez-Ferrer, M L; Cascales, P; Torroba, A; Orozco, R; Silva Sánchez, Y; Nieto, A; Fiol, G

2015-01-01

To determine the prevalence of endometriosis in patients with epithelial ovarian cancer and explore the differences between women with endometrioid and clear-cell histologic subtypes with and without associated endometriosis. The medical charts of 496 patients with epithelial ovarian cancer at the Hospital Virgin de la Arrixaca (Murcia, Spain) between 1971 and 2010 were reviewed. Endometriosis was present in 27 (5.4%) of the 496 cases (p < 0001), and was associated with the endometrioid histotype in 13/45 cases (29%) and with the clear cell histotype in 7/22 (32%). The prevalence of an association with endometriosis according to histologic type was 28.8% (13/45) for endometrioid carcinoma and 31.8% (7/22) for clear-cell carcinoma. Both endometrioid and clear-cell ovarians tumours are associated with pelvic endometriosis. Patients with endometiosis associated ovarian cancer differ from non-endometiosis associated ovarian cancer in their clinical characteristics.

[Immunotherapy in epithelial ovarian carcinoma: hope and reality].

PubMed

Lavoué, V; Foucher, F; Henno, S; Bauville, E; Catros, V; Cabillic, F; Levêque, J

2014-03-01

Epithelial ovarian carcinoma (EOC) has a worst prognosis with little progress in terms of survival for the last two decades. Immunology received little interest in EOC in the past, but now appears very important in the natural history of this cancer. This review is an EOC immunology state of art and focuses on the place of immunotherapy in future. A systematic review of published studies was performed. Medline baseline interrogation was performed with the following keywords: "Ovarian carinoma, immunotherapy, T-lymphocyte, regulator T-lymphocyte, dendritic cells, macrophage, antigen, chemotherapy, surgery, clinical trials". Identified publications (English or French) were assessed for the understanding of EOC immunology and the place of conventional treatment and immunotherapy strategy. Intratumoral infiltration by immune cells is a strong prognotic factor in EOC. Surgery and chemotherapy in EOC decrease imunosuppression in patients. The antitumoral immunity is a part of the therapeutic action of surgery and chemotherapy. Until now, immunotherapy gave some disappointing results, but the new drugs that target the tolerogenic tumoral microenvironnement rise and give a new hope in the treatment of cancer. Immunology controls the EOC natural history. The modulation of immunosuppressive microenvironment associated with the stimulation of antitumoral immunity could be the next revolution in the treatment of cancer. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Emerging Therapeutics to Overcome Chemoresistance in Epithelial Ovarian Cancer: A Mini-Review.

PubMed

Cornelison, Robert; Llaneza, Danielle C; Landen, Charles N

2017-10-18

Ovarian cancer is the fifth leading cause of cancer death among women and the most lethal gynecologic malignancy. One of the leading causes of death in high-grade serous ovarian cancer (HGSOC) is chemoresistant disease, which may present as intrinsic or acquired resistance to therapies. Here we discuss some of the known molecular mechanisms of chemoresistance that have been exhaustively investigated in chemoresistant ovarian cancer, including drug efflux pump multidrug resistance protein 1 (MDR1), the epithelial-mesenchymal transition, DNA damage and repair capacity. We also discuss novel therapeutics that may address some of the challenges in bringing approaches that target chemoresistant processes from bench to bedside. Some of these new therapies include novel drug delivery systems, targets that may halt adaptive changes in the tumor, exploitation of tumor mutations that leave cancer cells vulnerable to irreversible damage, and novel drugs that target ribosomal biogenesis, a process that may be uniquely different in cancer versus non-cancerous cells. Each of these approaches, or a combination of them, may provide a greater number of positive outcomes for a broader population of HGSOC patients.

Polymorphisms in BRCA1 and BRCA2 and risk of epithelial ovarian cancer.

PubMed

Wenham, Robert M; Schildkraut, Joellen M; McLean, Kia; Calingaert, Brian; Bentley, Rex C; Marks, Jeffrey; Berchuck, Andrew

2003-10-01

Because inherited BRCA1 or BRCA2 mutations strikingly increase ovarian cancer risk, polymorphisms in these genes could represent low penetrance susceptibility alleles. Previous studies of the BRCA2 N372H polymorphism suggested that HH homozygotes have a modestly increased risk of both breast and ovarian cancer. We have examined whether BRCA2 N372H or common amino acid-changing polymorphisms in BRCA1 predispose to ovarian cancer. A population-based, case control study of ovarian cancer was performed in North Carolina. Cases included 312 women with ovarian cancer (76% invasive and 24% borderline) and 401 age- and race-matched controls. Blood DNA from subjects was genotyped for BRCA2 N372H and BRCA1 Q356R and P871L. There was no association between BRCA2 N372H and risk of borderline or invasive epithelial ovarian cancer. The overall odds ratio (OR) for HH homozygotes was 0.8 [95% confidence interval (CI) = 0.4-1.5] and was similar in all subsets, including invasive serous cases. In addition, neither the BRCA1 Q356R (OR = 0.9, 95% CI 0.5-1.4) nor P871L (OR = 0.9, 95% CI 0.6-1.9) polymorphisms were associated with ovarian cancer risk. There was a significant racial difference in allele frequencies of the P871L polymorphism (P = 0.64 in Caucasians, L = 0.76 in African-Americans, P < 0.0001). In this population-based, case control study, common amino acid changing BRCA1 and 2 polymorphisms were not found to affect the risk of developing ovarian cancer.

Apatinib treatment combined with chemotherapy for advanced epithelial ovarian cancer: a case report.

PubMed

Deng, Linghui; Wang, Yue; Lu, Wenbin; Liu, Qian; Wu, Jie; Jin, Jianhua

2017-01-01

Apatinib is a novel oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, which has been proved by clinical trials to be effective and safe for patients with chemotherapy-refractory gastric cancer. To date, there is no study or case report on apatinib treatment for patients with ovarian cancer. Here, we present the case of a 50-year-old Chinese woman with advanced ovarian cancer, who received apatinib at a daily dose of 500 mg for 28 days per cycle after failure of fourth-line chemotherapy. Favorable oncologic outcome was achieved in this case after treatment with apatinib. The patient's progression-free survival is now 11.3 months, and she is taking apatinib and capecitabine as maintenance treatment. The common side effect of apatinib was fatigue; however, the toxicity of apatinib was controllable and tolerable. Thus, apatinib may be an option for chemotherapy-refractory advanced epithelial ovarian cancer, but this still warrants further investigation.

[Association between obesity and ovarian cancer].

PubMed

Valladares, Macarena; Corsini, Gino; Romero, Carmen

2014-05-01

Obesity is a risk factor for cancer. Epidemiological evidences associate ovarian cancer with obesity. Epithelial ovarian cancer (EOC) is the most common type of ovarian cancer and accounts for a high rate of mortality. The association between ovarian cancer and obesity could be explained by molecular factors secreted by adipose tissue such as leptin. In EOC, leptin increases cell proliferation and inhibits apoptosis. Additionally, adipose tissue synthesizes endogenous estrogens, which increase cell proliferation of epithelial ovarian cells. Also, obesity associated hyperinsulinism could increase ovarian estrogen secretion.

Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer.

PubMed

Jaaback, Kenneth; Johnson, Nick; Lawrie, Theresa A

2011-11-09

Ovarian cancer tends to be chemosensitive and confine itself to the surface of the peritoneal cavity for much of its natural history. These features have made it an obvious target for intraperitoneal (IP) chemotherapy. Chemotherapy for ovarian cancer is usually given as an intravenous (IV) infusion repeatedly over five to eight cycles. Intraperitoneal chemotherapy is given by infusion of the chemotherapeutic agent directly into the peritoneal cavity. There are biological reasons why this might increase the anticancer effect and reduce some systemic adverse effects in comparison to IV therapy. To determine if adding a component of the chemotherapy regime into the peritoneal cavity affects overall survival, progression-free survival, quality of life (QOL) and toxicity in the primary treatment of epithelial ovarian cancer. We searched the Gynaecological Cancer Review Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2011, MEDLINE (1951 to May 2011) and EMBASE (1974 to May 2011). We updated these searches in February 2007, August 2010 and May 2011. In addition, we handsearched and cascade searched the major gynaecological oncology journals. The analysis was restricted to randomised controlled trials (RCTs) assessing women with a new diagnosis of primary epithelial ovarian cancer, of any FIGO stage, following primary cytoreductive surgery. Standard IV chemotherapy was compared with chemotherapy that included a component of IP administration. We extracted data on overall survival, disease-free survival, adverse events and QOL and performed meta-analyses of hazard ratios (HR) for time-to-event variables and relative risks (RR) for dichotomous outcomes using RevMan software. Nine randomised trials studied 2119 women receiving primary treatment for ovarian cancer. We considered six trials to be of high quality. Women were less likely to die if they received an IP component to chemotherapy (eight studies, 2026 women; HR = 0

Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer

PubMed Central

Jaaback, Kenneth; Johnson, Nick; Lawrie, Theresa A

2014-01-01

Background Ovarian cancer tends to be chemosensitive and confine itself to the surface of the peritoneal cavity for much of its natural history. These features have made it an obvious target for intraperitoneal (IP) chemotherapy. Chemotherapy for ovarian cancer is usually given as an intravenous (IV) infusion repeatedly over five to eight cycles. Intraperitoneal chemotherapy is given by infusion of the chemotherapeutic agent directly into the peritoneal cavity. There are biological reasons why this might increase the anticancer effect and reduce some systemic adverse effects in comparison to IV therapy. Objectives To determine if adding a component of the chemotherapy regime into the peritoneal cavity affects overall survival, progression-free survival, quality of life (QOL) and toxicity in the primary treatment of epithelial ovarian cancer. Search methods We searched the Gynaecological Cancer Review Group’s Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2011, MEDLINE (1951 to May 2011) and EMBASE (1974 to May 2011). We updated these searches in February 2007, August 2010 and May 2011. In addition, we handsearched and cascade searched the major gynaecological oncology journals. Selection criteria The analysis was restricted to randomised controlled trials (RCTs) assessing women with a new diagnosis of primary epithelial ovarian cancer, of any FIGO stage, following primary cytoreductive surgery. Standard IV chemotherapy was compared with chemotherapy that included a component of IP administration. Data collection and analysis We extracted data on overall survival, disease-free survival, adverse events and QOL and performed meta-analyses of hazard ratios (HR) for time-to-event variables and relative risks (RR) for dichotomous outcomes using RevMan software. Main results Nine randomised trials studied 2119 women receiving primary treatment for ovarian cancer. We considered six trials to be of high quality. Women were less

Computed tomography findings of ovarian metastases from colon cancer: comparison with primary malignant ovarian tumors.

PubMed

Choi, Hyuck Jae; Lee, Joo-Hyuk; Seo, Sang-Soo; Lee, Sun; Kim, Seok Ki; Kim, Joo-Young; Lee, Jong Seok; Park, Sang-Yoon; Kim, Young Hoon

2005-01-01

The computed tomography (CT) findings of ovarian metastases from colon cancer were evaluated and were compared with those of primary malignant ovarian tumors. Sixteen patients with 21 masses from colon cancer and 20 patients with 31 primary malignant ovarian tumors were included in this study. The CT findings (laterality, size, margin, shape, mass characteristic, strong enhancement of cyst wall, enhancement of solid portion, amount of ascites, peritoneal seeding, lymph node enlargement, and metastasis) and ages of the patients in both groups were compared. Univariate analysis, the Pearson chi test, and the independent-samples t test were used to distinguish them. A smooth margin of the tumor (odds ratio=24.3, 95% confidence interval: 2.9-204.2) and cystic nature of the mass (Pearson chi=12.96, P=0.005) were strong predictors of ovarian metastasis from colon cancer. Ovarian metastases from colon cancer show a smooth margin and more cystic nature on CT compared with primary malignant ovarian tumors.

Mediation analysis of alcohol consumption, DNA methylation, and epithelial ovarian cancer.

PubMed

Wu, Dongyan; Yang, Haitao; Winham, Stacey J; Natanzon, Yanina; Koestler, Devin C; Luo, Tiane; Fridley, Brooke L; Goode, Ellen L; Zhang, Yanbo; Cui, Yuehua

2018-03-01

Epigenetic factors and consumption of alcohol, which suppresses DNA methylation, may influence the development and progression of epithelial ovarian cancer (EOC). However, there is a lack of understanding whether these factors interact to affect the EOC risk. In this study, we aimed to gain insight into this relationship by identifying leukocyte-derived DNA methylation markers acting as potential mediators of alcohol-associated EOC. We implemented a causal inference test (CIT) and the VanderWeele and Vansteelandt multiple mediator model to examine CpG sites that mediate the association between alcohol consumption and EOC risk. We modified one step of the CIT by adopting a high-dimensional inference procedure. The data were based on 196 cases and 202 age-matched controls from the Mayo Clinic Ovarian Cancer Case-Control Study. Implementation of the CIT test revealed two CpG sites (cg09358725, cg11016563), which represent potential mediators of the relationship between alcohol consumption and EOC case-control status. Implementation of the VanderWeele and Vansteelandt multiple mediator model further revealed that these two CpGs were the key mediators. Decreased methylation at both CpGs was more common in cases who drank alcohol at the time of enrollment vs. those who did not. cg11016563 resides in TRPC6 which has been previously shown to be overexpressed in EOC. These findings suggest two CpGs may serve as novel biomarkers for EOC susceptibility.

VGLL3 expression is associated with a tumor suppressor phenotype in epithelial ovarian cancer.

PubMed

Gambaro, Karen; Quinn, Michael C J; Wojnarowicz, Paulina M; Arcand, Suzanna L; de Ladurantaye, Manon; Barrès, Véronique; Ripeau, Jean-Sébastien; Killary, Ann M; Davis, Elaine C; Lavoie, Josée; Provencher, Diane M; Mes-Masson, Anne-Marie; Chevrette, Mario; Tonin, Patricia N

2013-06-01

Previous studies have implicated vestigial like 3 (VGLL3), a chromosome 3p12.3 gene that encodes a putative transcription co-factor, as a candidate tumor suppressor gene (TSG) in high-grade serous ovarian carcinomas (HGSC), the most common type of epithelial ovarian cancer. A complementation analysis based on microcell-mediated chromosome transfer (MMCT) using a centric fragment of chromosome 3 (der3p12-q12.1) into the OV-90 ovarian cancer cell line haploinsufficient for 3p and lacking VGLL3 expression was performed to assess the effect on tumorigenic potential and growth characteristics. Genetic characterization of the derived MMCT hybrids revealed that only the hybrid that contained an intact VGLL3 locus exhibited alterations of tumorigenic potential in a nude mouse xenograft model and various in vitro growth characteristics. Only stable OV-90 transfectant clones expressing low levels of VGLL3 were derived. These clones exhibited an altered cytoplasmic morphology characterized by numerous single membrane bound multivesicular-bodies (MVB) that were not attributed to autophagy. Overexpression of VGLL3 in OV-90 was achieved using a lentivirus-based tetracycline inducible gene expression system, which also resulted in MVB formation in the infected cell population. Though there was no significant differences in various in vitro and in vivo growth characteristics in a comparison of VGLL3-expressing clones with empty vector transfectant controls, loss of VGLL3 expression was observed in tumors derived from mouse xenograft models. VGLL3 gene and protein expression was significantly reduced in HGSC samples (>98%, p < 0.05) relative to either normal ovarian surface epithelial cells or epithelial cells of the fallopian tube, possible tissues of origin of HGSC. Also, there appeared to be to be more cases with higher staining levels in stromal tissue component from HGSC cases that had a prolonged disease-free survival. The results taken together suggest that VGLL3 is involved

Sugary food and beverage consumption and epithelial ovarian cancer risk: a population-based case–control study

PubMed Central

2013-01-01

Background Ovarian cancer is the deadliest gynecologic cancer in the US. The consumption of refined sugars has increased dramatically over the past few decades, accounting for almost 15% of total energy intake. Yet, there is limited evidence on how sugar consumption affects ovarian cancer risk. Methods We evaluated ovarian cancer risk in relation to sugary foods and beverages, and total and added sugar intakes in a population-based case–control study. Cases were women with newly diagnosed epithelial ovarian cancer, older than 21 years, able to speak English or Spanish, and residents of six counties in New Jersey. Controls met same criteria as cases, but were ineligible if they had both ovaries removed. A total of 205 cases and 390 controls completed a phone interview, food frequency questionnaire, and self-recorded waist and hip measurements. Based on dietary data, we computed the number of servings of dessert foods, non-dessert foods, sugary drinks and total sugary foods and drinks for each participant. Total and added sugar intakes (grams/day) were also calculated. Multiple logistic regression models were used to estimate odds ratios and 95% confidence intervals for food and drink groups and total and added sugar intakes, while adjusting for major risk factors. Results We did not find evidence of an association between consumption of sugary foods and beverages and risk, although there was a suggestion of increased risk associated with sugary drink intake (servings per 1,000 kcal; OR=1.63, 95% CI: 0.94-2.83). Conclusions Overall, we found little indication that sugar intake played a major role on ovarian cancer development. PMID:23442818

Carboplatin and Paclitaxel With or Without Bevacizumab in Treating Patients With Stage III or Stage IV Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube Cancer

ClinicalTrials.gov

2017-10-23

Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Serous Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma

Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk.

PubMed

Amankwah, Ernest K; Lin, Hui-Yi; Tyrer, Jonathan P; Lawrenson, Kate; Dennis, Joe; Chornokur, Ganna; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V; Bean, Yukie T; Beckmann, Matthias W; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Bunker, Clareann H; Butzow, Ralf; Campbell, Ian G; Carty, Karen; Chen, Zhihua; Chen, Y Ann; Chang-Claude, Jenny; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; du Bois, Andreas; Despierre, Evelyn; Dicks, Ed; Doherty, Jennifer A; Dörk, Thilo; Dürst, Matthias; Easton, Douglas F; Eccles, Diana M; Edwards, Robert P; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Goodman, Marc T; Gronwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis N; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hillemanns, Peter; Hogdall, Claus K; Hogdall, Estrid; Hosono, Satoyo; Iversen, Edwin S; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Jim, Heather; Kellar, Melissa; Kiemeney, Lambertus A; Krakstad, Camilla; Kjaer, Susanne K; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lim, Boon Kiong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; McNeish, Ian; Menon, Usha; Milne, Roger L; Modugno, Francesmary; Moysich, Kirsten B; Ness, Roberta B; Nevanlinna, Heli; Eilber, Ursula; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Paul, James; Pearce, Celeste L; Pejovic, Tanja; Pelttari, Liisa M; Permuth-Wey, Jennifer; Pike, Malcolm C; Poole, Elizabeth M; Risch, Harvey A; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Schernhammer, Eva; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C; Spiewankiewicz, Beata; Sucheston-Campbell, Lara; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Thomsen, Lotte; Tangen, Ingvild L; Tworoger, Shelley S; van Altena, Anne M; Vierkant, Robert A; Vergote, Ignace; Walsh, Christine S; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Wu, Anna H; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Kelemen, Linda E; Berchuck, Andrew; Schildkraut, Joellen M; Ramus, Susan J; Goode, Ellen L; Monteiro, Alvaro N A; Gayther, Simon A; Narod, Steven A; Pharoah, Paul D P; Sellers, Thomas A; Phelan, Catherine M

2015-12-01

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC. © 2015 WILEY PERIODICALS, INC.

Non-steroidal anti-inflammatory drug use and ovarian cancer risk: findings from the NIH-AARP Diet and Health Study and systematic review.

PubMed

Murphy, Megan A; Trabert, Britton; Yang, Hannah P; Park, Yikyung; Brinton, Louise A; Hartge, Patricia; Sherman, Mark E; Hollenbeck, Albert; Wentzensen, Nicolas

2012-11-01

Chronic inflammation has been proposed as a risk factor for ovarian cancer. Some data suggest that anti-inflammatory medications may be protective against ovarian cancer; however, results have been inconsistent. We evaluated the risk of epithelial ovarian cancer with regular use of NSAIDs prospectively in the NIH-AARP Diet and Health Study, using Cox proportional hazard models. We also examined the risk of common subtypes of epithelial ovarian cancer (serous, mucinous, endometrioid, clear cell, and other epithelial) with regular use of NSAIDs. In addition, we performed meta-analyses summarizing the risk of ovarian cancer with "regular use" of NSAIDs in previously published studies. We did not observe a significant association between regular use of NSAIDs with ovarian cancer risk in the AARP cohort (aspirin: RR 1.06, 95 % CI 0.87-1.29; non-aspirin NSAIDs: RR 0.93, 95 % CI 0.74-1.15); however, summary estimates from prospective cohort studies demonstrated that use of non-aspirin NSAIDs may reduce the risk of ovarian cancer (RR 0.88, 95 % CI 0.77-1.01). Although not significant, we found that mucinous tumors were inversely associated with non-aspirin NSAID use (RR 0.69, 95 % CI 0.23-2.10) in the AARP cohort, which was supported by the meta-analysis (RR 0.69, CI 0.50-0.94.) Although results from the NIH-AARP cohort study were not statistically significant, our meta-analysis suggests that non-aspirin NSAIDs may be protective against ovarian cancer. Additional analyses, focusing on dose, duration, and frequency of NSAID use and accounting for ovarian cancer heterogeneity are necessary to further elucidate the association between NSAID use and ovarian cancer risk.

ABT-510 induces tumor cell apoptosis and inhibits ovarian tumor growth in an orthotopic, syngeneic model of epithelial ovarian cancer.

PubMed

Greenaway, James; Henkin, Jack; Lawler, Jack; Moorehead, Roger; Petrik, Jim

2009-01-01

Epithelial ovarian cancer (EOC) is the fifth most common cancer in women and is characterized by a low 5-year survival rate. One strategy that can potentially improve the overall survival rate in ovarian cancer is the use of antitumor agents such as ABT-510. ABT-510 is a small mimetic peptide of the naturally occurring antiangiogenic compound thrombospondin-1 and has been shown to significantly reduce tumor growth and burden in preclinical mouse models and in naturally occurring tumors in dogs. This is the first evaluation of ABT-510 in a preclinical model of human EOC. Tumorigenic mouse surface epithelial cells were injected into the bursa of C57BL/6 mice that were treated with either 100 mg/kg ABT-510 or an equivalent amount of PBS. ABT-510 caused a significant reduction in tumor size, ascites fluid volume, and secondary lesion dissemination when compared with PBS controls. Analysis of the vasculature of ABT-510-treated mice revealed vascular remodeling with smaller diameter vessels and lower overall area, increased number of mature vessels, and decreased tissue hypoxia. Tumors of ABT-510-treated mice had a significantly higher proportion of apoptotic tumor cells compared with the PBS-treated controls. Immunoblot analysis of cell lysates revealed a reduction in vascular endothelial growth factor, vascular endothelial growth factor receptor-2, and proliferating cell nuclear antigen protein expression as well as expression of members of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase survival pathways. In vitro, ABT-510 induced tumor cell apoptosis in mouse and human ovarian cancer cells. This study shows ABT-510 as a promising candidate for inhibiting tumor growth and ascites formation in human EOC.

Epithelial borderline ovarian tumor: Diagnosis and treatment strategy.

PubMed

Ushijima, Kimio; Kawano, Kouichiro; Tsuda, Naotake; Nishio, Shin; Terada, Atsumu; Kato, Hiroyuki; Tasaki, Kazuto; Matsukuma, Ken

2015-05-01

Epithelial borderline ovarian tumors (BOT) are distinctive from benign tumors and carcinoma. They occur in younger women more often than carcinoma, and there is some difficulty making correct diagnosis of BOT. Two subtypes of BOT, serous and mucinous borderline tumor have different characteristics and very different clinical behavior. Serous borderline tumor (SBT) with micropapillary pattern shows more incidence of extra ovarian disease and often coexists with invasive implant. SBT with micropapillary pattern in advanced stage has showed a worse prognosis than typical SBT. Huge mucinous borderline tumors have histologic heterogeneity, and the accuracy of frozen section diagnosis is relatively low. Extensive sampling is required to reach a correct pathological diagnosis. Mucinous adenoma (intestinal type) also runs the risk of recurrence after cystectomy, or intraoperative rupture of cyst. Laparoscopic procedure for BOT has not increased the risk of recurrence. Fertility preserving procedures are generally accepted, except in advanced stage SBT with invasive implants. Only cystectomy shows a significant risk of recurrence. Re-staging surgery and full staging surgery is not necessary for all BOT. We should not attempt to treat them uniformly, by the single diagnosis of "borderline tumor". It depends on histologic type. Close communication with the pathologist is necessary to gain more detail and ask more pathological samples in order to make the optimal treatment strategy for each individual patients.

Long non-coding RNA ZFAS1 interacts with miR-150-5p to regulate Sp1 expression and ovarian cancer cell malignancy.

PubMed

Xia, Bairong; Hou, Yan; Chen, Hong; Yang, Shanshan; Liu, Tianbo; Lin, Mei; Lou, Ge

2017-03-21

We reported that long non-coding RNA ZFAS1 was upregulated in epithelial ovarian cancer tissues, and was negatively correlated to the overall survival rate of patients with epithelial ovarian cancer in this study. While depletion of ZFAS1 inhibited proliferation, migration, and development of chemoresistance, overexpression of ZFAS1 exhibited an even higher proliferation rate, migration activity, and chemoresistance in epithelial ovarian cancer cell lines. We further found miR-150-5p was a potential target of ZFAS1, which was downregulated in epithelial ovarian cancer tissue. MiR-150-5p subsequently inhibited expression of transcription factor Sp1, as evidence by luciferase assays. Inhibition of miR-150-5p rescued the suppressed proliferation and migration induced by depletion of ZFAS1 in epithelial ovarian cancer cells, at least in part. Taken together, our findings revealed a critical role of ZFAS1/miR-150-5p/Sp1 axis in promoting proliferation rate, migration activity, and development of chemoresistance in epithelial ovarian cancer. And ZFAS1/miR-150-5p may serve as novel markers and therapeutic targets of epithelial ovarian cancer.

Computed tomography findings of gaseous necrosis in epithelial ovarian cancer: a report of three cases.

PubMed

Cronin, Paul; Crosse, Barbara; Lane, Geoff; Spencer, John A

2002-01-01

Necrosis in pathologic specimens of ovarian cancer is well documented; however, computed tomography (CT) evidence of gaseous necrosis in the absence of fistulation with bowel has not yet been described. We report three cases of ovarian adenocarcinoma that on CT showed evidence of gross gaseous necrosis, mimicking a pelvic abscess.

MyD88 and TLR4 Expression in Epithelial Ovarian Cancer

PubMed Central

Block, Matthew S.; Vierkant, Robert A.; Rambau, Peter F.; Winham, Stacey J.; Wagner, Philipp; Traficante, Nadia; Tołoczko, Aleksandra; Tiezzi, Daniel G.; Taran, Florin Andrei; Sinn, Peter; Sieh, Weiva; Sharma, Raghwa; Rothstein, Joseph H.; Cajal, Teresa Ramón y; Paz-Ares, Luis; Oszurek, Oleg; Orsulic, Sandra; Ness, Roberta B.; Nelson, Gregg; Modugno, Francesmary; Menkiszak, Janusz; McGuire, Valerie; McCauley, Bryan M.; Mack, Marie; Lubiński, Jan; Longacre, Teri A.; Li, Zheng; Lester, Jenny; Kennedy, Catherine J.; Kalli, Kimberly R.; Jung, Audrey Y.; Johnatty, Sharon E.; Jimenez-Linan, Mercedes; Jensen, Allan; Intermaggio, Maria P.; Hung, Jillian; Herpel, Esther; Hernandez, Brenda Y.; Hartkopf, Andreas D.; Harnett, Paul R.; Ghatage, Prafull; García-Bueno, José M.; Gao, Bo; Fereday, Sian; Eilber, Ursula; Edwards, Robert P.; de Sousa, Christiani B.; de Andrade, Jurandyr M.; Chudecka-Głaz, Anita; Chenevix-Trench, Georgia; Cazorla, Alicia; Brucker, Sara Y.; Alsop, Jennifer; Whittemore, Alice S.; Steed, Helen; Staebler, Annette; Moysich, Kirsten B.; Menon, Usha; Koziak, Jennifer M.; Kommoss, Stefan; Kjaer, Susanne K.; Kelemen, Linda E.; Karlan, Beth Y.; Huntsman, David G.; Høgdall, Estrid; Gronwald, Jacek; Goodman, Marc T.; Gilks, Blake; García, María José; Fasching, Peter A.; de Fazio, Anna; Deen, Suha; Chang-Claude, Jenny; Candido dos Reis, Francisco J.; Campbell, Ian G.; Brenton, James D.; Bowtell, David D.; Benítez, Javier; Pharoah, Paul D.P.; Köbel, Martin; Ramus, Susan J.; Goode, Ellen L.

2018-01-01

Objective To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival. Patients and Methods We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong). Results Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01–1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29–0.84] and 0.44 [0.21–0.89], respectively; P=.009 and P=.02, respectively). Conclusion Results are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes. PMID:29502561

MyD88 and TLR4 Expression in Epithelial Ovarian Cancer.

PubMed

Block, Matthew S; Vierkant, Robert A; Rambau, Peter F; Winham, Stacey J; Wagner, Philipp; Traficante, Nadia; Tołoczko, Aleksandra; Tiezzi, Daniel G; Taran, Florin Andrei; Sinn, Peter; Sieh, Weiva; Sharma, Raghwa; Rothstein, Joseph H; Ramón Y Cajal, Teresa; Paz-Ares, Luis; Oszurek, Oleg; Orsulic, Sandra; Ness, Roberta B; Nelson, Gregg; Modugno, Francesmary; Menkiszak, Janusz; McGuire, Valerie; McCauley, Bryan M; Mack, Marie; Lubiński, Jan; Longacre, Teri A; Li, Zheng; Lester, Jenny; Kennedy, Catherine J; Kalli, Kimberly R; Jung, Audrey Y; Johnatty, Sharon E; Jimenez-Linan, Mercedes; Jensen, Allan; Intermaggio, Maria P; Hung, Jillian; Herpel, Esther; Hernandez, Brenda Y; Hartkopf, Andreas D; Harnett, Paul R; Ghatage, Prafull; García-Bueno, José M; Gao, Bo; Fereday, Sian; Eilber, Ursula; Edwards, Robert P; de Sousa, Christiani B; de Andrade, Jurandyr M; Chudecka-Głaz, Anita; Chenevix-Trench, Georgia; Cazorla, Alicia; Brucker, Sara Y; Alsop, Jennifer; Whittemore, Alice S; Steed, Helen; Staebler, Annette; Moysich, Kirsten B; Menon, Usha; Koziak, Jennifer M; Kommoss, Stefan; Kjaer, Susanne K; Kelemen, Linda E; Karlan, Beth Y; Huntsman, David G; Høgdall, Estrid; Gronwald, Jacek; Goodman, Marc T; Gilks, Blake; García, María José; Fasching, Peter A; de Fazio, Anna; Deen, Suha; Chang-Claude, Jenny; Candido Dos Reis, Francisco J; Campbell, Ian G; Brenton, James D; Bowtell, David D; Benítez, Javier; Pharoah, Paul D P; Köbel, Martin; Ramus, Susan J; Goode, Ellen L

2018-03-01

To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival. We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong). Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively). Results are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes. Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

YKL-40 in Serum Samples From Patients With Newly Diagnosed Stage III-IV Ovarian Epithelial, Primary Peritoneal Cavity, or Fallopian Tube Cancer Receiving Chemotherapy

ClinicalTrials.gov

2018-05-21

Fallopian Tube Adenocarcinoma; Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Serous Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Malignant Ovarian Brenner Tumor; Malignant Ovarian Clear Cell Tumor; Malignant Ovarian Endometrioid Tumor; Malignant Ovarian Mixed Epithelial Tumor; Malignant Ovarian Mucinous Tumor; Malignant Ovarian Neoplasm; Malignant Ovarian Serous Tumor; Malignant Ovarian Transitional Cell Tumor; Ovarian Adenocarcinoma; Primary Peritoneal Serous Adenocarcinoma; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma

[Expression and clinical significance of Xiap and Caspase-3 protien in primary epithelia ovarian cancer].

PubMed

Chen, Wei; Peng, Ping

2010-07-01

To study the expression and clinical significance of Xiap, Caspase-3 protein in primary epithelia ovarian cancer. The Xiap and Caspase-3 were detected by immunohistochemical in 40 cases of epithelial ovarian cancer 20 cases of borderline ovarian tumor, 15 cases of benign ovarian tumor, and 15 normal ovarian tissues. There were significantly different between the expression of Xiap in epithelial ovarian cancer, borderline ovarian tumor, benign ovarian tumor and normal ovarian tissues. The expression of Caspase-3 in epithelial ovarian cancer and borderline ovarian tumor was significantly lower than that in benign ovarian tumor and normal ovarian tissue (P<0.01). The expression of Xiap in epithelial ovarian cancer was related to clinc stage, pathological grade and living. The expression of caspase-3 in epithelial ovarian cancer was related to clinc stage and living (P<0.01). The expressions of Xiap and Caspase-3 may be important roles for the formation and development of epithelia ovarian cancer. The expressions of Xiap and Caspase-3 are the poor prognostic factors in epithelial ovarian carcinomas.

Biological Function of Ribosomal Protein L10 on Cell Behavior in Human Epithelial Ovarian Cancer

PubMed Central

Shi, Jimin; Zhang, Lingyun; Zhou, Daibing; Zhang, Jinguo; Lin, Qunbo; Guan, Wencai; Zhang, Jihong; Ren, Weimin; Xu, Guoxiong

2018-01-01

Ribosomal protein L10 (RPL10) is one of large ribosomal proteins and plays a role in Wilms' tumor and premature ovarian failure. However, the function of RPL10 in human epithelial ovarian cancer (EOC) remains unknown. The purpose of this study was to examine the expression level and function of RPL10 in EOC. RPL10 protein expression was detected by immunohistochemistry and Western blot. The association RPL10 expression with clinical features was analyzed. Loss-of-function and gain-of-function approaches were applied in cellular assays, including cell viability, migration, invasion, and apoptosis. Our study demonstrated for the first time that RPL10 was upregulated in human EOC compared with normal ovarian tissues. Knockdown of RPL10 inhibited cell viability, migration, and invasion, and increased cell apoptosis. On the contrary, upregulation of RPL10 increased cell viability, migration, invasion, and decreased cell apoptosis. Furthermore, miR-143-3p regulated RPL10 expression. Our data indicate that RPL10 is a potential tissue biomarker of patients with EOC and may be a therapeutic target of ovarian cancer. PMID:29556332

Metformin and Chemotherapy in Treating Patients With Stage III-IV Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

ClinicalTrials.gov

2018-04-17

Brenner Tumor; Malignant Ascites; Malignant Pleural Effusion; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Recurrent Fallopian Tube Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Primary Peritoneal Cavity Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIA Ovarian Germ Cell Tumor; Stage IIIA Primary Peritoneal Cavity Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Epithelial Cancer; Stage IIIB Ovarian Germ Cell Tumor; Stage IIIB Primary Peritoneal Cavity Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Epithelial Cancer; Stage IIIC Ovarian Germ Cell Tumor; Stage IIIC Primary Peritoneal Cavity Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Primary Peritoneal Cavity Cancer

Palliative Care in Improving Quality of Life and Symptoms in Patients With Stage III-IV Pancreatic or Ovarian Cancer

ClinicalTrials.gov

2014-12-18

Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Stage III Pancreatic Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIA Ovarian Germ Cell Tumor; Stage IIIB Ovarian Epithelial Cancer; Stage IIIB Ovarian Germ Cell Tumor; Stage IIIC Ovarian Epithelial Cancer; Stage IIIC Ovarian Germ Cell Tumor; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Pancreatic Cancer

ABT-510 induces tumor cell apoptosis and inhibits ovarian tumor growth in an orthotopic, syngeneic model of epithelial ovarian cancer

PubMed Central

Greenaway, James; Henkin, Jack; Lawler, Jack; Moorehead, Roger; Petrik, Jim

2012-01-01

Epithelial ovarian cancer (EOC) is the fifth most common cancer in women and is characterized by a low 5-year survival rate. One strategy that can potentially improve the overall survival rate in ovarian cancer is the use of antitumor agents such as ABT-510. ABT-510 is a small mimetic peptide of the naturally occurring antiangiogenic compound thrombospondin-1 and has been shown to significantly reduce tumor growth and burden in preclinical mouse models and in naturally occurring tumors in dogs. This is the first evaluation of ABT-510 in a preclinical model of human EOC. Tumorigenic mouse surface epithelial cells were injected into the bursa of C57BL/6 mice that were treated with either 100 mg/kg ABT-510 or an equivalent amount of PBS. ABT-510 caused a significant reduction in tumor size, ascites fluid volume, and secondary lesion dissemination when compared with PBS controls. Analysis of the vasculature of ABT-510-treated mice revealed vascular remodeling with smaller diameter vessels and lower overall area, increased number of mature vessels, and decreased tissue hypoxia. Tumors of ABT-510-treated mice had a significantly higher proportion of apoptotic tumor cells compared with the PBS-treated controls. Immunoblot analysis of cell lysates revealed a reduction in vascular endothelial growth factor, vascular endothelial growth factor receptor-2, and proliferating cell nuclear antigen protein expression as well as expression of members of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase survival pathways. In vitro, ABT-510 induced tumor cell apoptosis in mouse and human ovarian cancer cells. This study shows ABT-510 as a promising candidate for inhibiting tumor growth and ascites formation in human EOC. PMID:19139114

Ultrasonic findings in polycystic ovarian disease.

PubMed

Orsini, L F; Venturoli, S; Lorusso, R; Pluchinotta, V; Paradisi, R; Bovicelli, L

1985-05-01

The uterus and ovaries of 50 patients with polycystic ovarian disease (PCOD) and 30 eumenorrheic women were studied with a real-time ultrasound mechanical sector scanner. Uterine and ovarian volumes (UV and OV) and the OV/UV ratio were calculated, and ovarian morphology was classified as prevalently solid and cystic. Both ovaries were displayed in 44 of the PCOD and in 25 of the normal patients and appeared bilaterally solid, cystic, or with different morphology, respectively, in 43.2%, 47.7%, and 9.1% of cases in the former group and in 76%, 20%, and 4% in the latter group. Statistically significant differences between normal and PCOD patients were found in OV, UV, and OV/UV ratio. Bilaterally enlarged ovaries with multiple tiny cysts, the classic ultrasonographic picture of the polycystic ovary, were found in only 16 (36.3%) of the PCOD cases, while 34 (77.3%) had an OV/UV ratio greater than 1 standard deviation above the mean. Four ultrasonographic ovarian patterns were observed in the PCOD patients: enlarged cystic; enlarged solid; normal-sized cystic; and normal-sized solid. These findings emphasize the need for a reconsideration of the ultrasonographic criteria of PCOD.

The impact of EpCAM expression on response to chemotherapy and clinical outcomes in patients with epithelial ovarian cancer.

PubMed

Tayama, Shingo; Motohara, Takeshi; Narantuya, Dashdemberel; Li, Chenyan; Fujimoto, Koichi; Sakaguchi, Isao; Tashiro, Hironori; Saya, Hideyuki; Nagano, Osamu; Katabuchi, Hidetaka

2017-07-04

Epithelial ovarian cancer is a highly lethal malignancy; moreover, overcoming chemoresistance is the major challenging in treating ovarian cancer patients. The cancer stem cell (CSC) hypothesis considers CSCs to be the main culprits in driving tumor initiation, metastasis, and resistance to conventional therapy. Although growing evidence suggest that CSCs are responsible for chemoresistance, the contribution of CSC marker EpCAM to resistance to chemotherapy remains unresolved.Here we have demonstrated that ovarian cancers containing high levels of EpCAM have a significantly much lower probability of achieving overall responsive rates after first-line chemotherapy. In addition, multivariate analysis revealed that EpCAM expression is an independent risk factor for chemoresistance, indicating that EpCAM expression is a predictive biomarker of chemotherapeutic response. Consistent with these clinical observations, in vitro assays, we found that the subpopulation of EpCAM-positive ovarian cancer cells shows a significantly higher viability compared with EpCAM-negative cells in response to cisplatin treatment by preventing chemotherapy-induced apoptosis, which is regulated by EpCAM-Bcl-2 axis. Furthermore, in an in vivo mouse model, platinum agents preferentially eliminated EpCAM-negative cells in comparison with EpCAM-positive cells, suggesting that the remaining subpopulation of EpCAM-positive cells contributes to tumor recurrence after chemotherapy. Finally, we also found that an increased expression of EpCAM is associated with poor prognosis in ovarian cancer patients.Our findings highlight the clinical significance of EpCAM in the resistance to chemotherapy and provide a rationale for EpCAM-targeted therapy to improve chemoresistance. Targeting EpCAM should be a promising approach to effectively extirpate the CSCs as the putative root of ovarian cancer.

ETV5 transcription factor is overexpressed in ovarian cancer and regulates cell adhesion in ovarian cancer cells.

PubMed

Llauradó, Marta; Abal, Miguel; Castellví, Josep; Cabrera, Sílvia; Gil-Moreno, Antonio; Pérez-Benavente, Asumpció; Colás, Eva; Doll, Andreas; Dolcet, Xavier; Matias-Guiu, Xavier; Vazquez-Levin, Mónica; Reventós, Jaume; Ruiz, Anna

2012-04-01

Epithelial ovarian cancer is the most lethal gynecological malignancy and the fifth leading cause of cancer deaths in women in the Western world. ETS transcription factors are known to act as positive or negative regulators of the expression of genes that are involved in various biological processes, including those that control cellular proliferation, differentiation, apoptosis, tissue remodeling, angiogenesis and transformation. ETV5 belongs to the PEA3 subfamily. PEA3 subfamily members are able to activate the transcription of proteases, matrix metalloproteinases and tissue inhibitor of metalloproteases, which is central to both tumor invasion and angiogenesis. Here, we examined the role of the ETV5 transcription factor in epithelial ovarian cancer and we found ETV5 was upregulated in ovarian tumor samples compared to ovarian tissue controls. The in vitro inhibition of ETV5 decreased cell proliferation in serum-deprived conditions, induced EMT and cell migration and decreased cell adhesion to extracellular matrix components. ETV5 inhibition also decreased cell-cell adhesion and induced apoptosis in anchorage-independent conditions. Accordingly, upregulation of ETV5 induced the expression of cell adhesion molecules and enhanced cell survival in a spheroid model. Our findings suggest that the overexpression of ETV5 detected in ovarian cancer cells may contribute to ovarian tumor progression through the ability of ETV5 to enhance proliferation of ovarian cancer cells. In addition, upregulation of ETV5 would play a role in ovarian cancer cell dissemination and metastasis into the peritoneal cavity by protecting ovarian cancer cells from apoptosis and by increasing the adhesion of ovarian cancer cells to the peritoneal wall through the regulation of cell adhesion molecules. Copyright © 2011 UICC.

Influence of body weight changes on survival in patients undergoing chemotherapy for epithelial ovarian cancer.

PubMed

Mardas, M; Stelmach-Mardas, M; Zalewski, K; Grabowski, J P; Czapka-Matyasik, M; Steffen, A; Boeing, H; Mądry, R

2016-05-01

Epithelial ovarian cancer is a highly fatal gynecologic malignancy with a poor prognosis. Therefore, identification of new modifiable prognostic factors is important. Due to the fact that the effect of body weight changes during chemotherapy for EOC is still not very well known we aimed to describe, considering evidence, role of body weight changes in relation to survival. Between October 2014 and August 2015 we systematically searched the following databases: Medline, Scopus, Web of Science and EMBASE to identify the studies describing the influence of body weight changes on survival in patients undergoing chemotherapy for EOC. We identified 601 potentially relevant publications, however finally only one article was included for data extraction and analysis. The overall survival in the selected paper was significantly associated with body weight changes during the first-line chemotherapy. Nevertheless, no influence on progression free survival was found. The analyzed data provides initial evidence, showing poorer overall survival  associated with body weight loss and improved overall survival associated with body weight gain during primary chemotherapy for epithelial ovarian cancer. Prospective and retrospective trials are an urgent calling to confirm this conclusion.

Drug resistance in epithelial ovarian cancer: P-glycoprotein and glutation S-transferase. Can they play an important role in detecting response to platinum-based chemotherapy as a first-line therapy.

PubMed

Simşek, T; Ozbilim, G; Gülkesen, H; Kaya, H; Sargin, F; Karaveli, S

2001-01-01

Drug resistance is important for the treatment of ovarian cancer. P-glycoprotein and glutation S-transferase as resistance markers play an important role in the effectivity of chemotherapeutical agents. The role of P-glycoprotein and glutation S-transferase in the treatment of epithelial ovarian cancer is not well understood. We investigated the relation between P-glycoprotein and glutation S-transferase level for response to platinum-based chemotherapy in epithelial ovarian cancer. We reviewed 30 cases diagnosed as epithelial ovarian cancer and treated with platinum-based chemotherapy in the Department of Obstetrics and Gynecology, Akdeniz University School of Medicine. The material was attained from initial parafin-embeded blocks stained for P-glycoprotein and glutation S-transferase. The cases that were diagnosed and treated before attending our clinic were not enrolled in the study. Mean age was 58.2 (25-70) and mean gravida 4.1 (0-10). Twenty-four patients (80%) were glutation S-transferase positive. Three cases (10%) out of 30 had positive reaction for P-glycoprotein. No difference was revealed regarding chemotherapy response rate among the cases showing glutation S-transferase positivity and P-glycoprotein negativity. Detection of glutation S-transferase and P-glycoprotein levels in epithelial ovarian cancer tissue is not important for response to platinum-based chemotherapy as a first line.

Interval debulking surgery in advanced epithelial ovarian cancer.

PubMed

Pecorelli, Sergio; Odicino, Franco; Favalli, Giuseppe

2002-08-01

Cytoreductive surgery and chemotherapy are the mainstay for the treatment of advanced epithelial ovarian cancer. In order to minimize the tumour burden before chemotherapy, cytoreductive surgery is usually performed first. The importance of the amount of residual disease as the main prognostic factor for patients suffering from advanced disease has been almost universally accepted even in the absence of prospective randomized trials addressing the benefit of cytoreductive surgery. In the last decade, the value of debulking surgery after induction chemotherapy - interval debulking surgery, IDS - has been widely debated, especially after the completion of a prospective randomized study from the EORTC addressing the introduction of a surgical procedure with debulking intent preceded and followed by cytoreductive chemotherapy. The rationale of such a strategy in the context of the primary treatment of advanced ovarian cancer lies in a higher cytoreductibility to the 'optimal' status forwarded, and possibly facilitated, by chemotherapy. The results demonstrated a prolongation of both progression-free survival and median survival in favour of patients randomized to IDS (5 and 6 months, respectively). Multivariate analysis revealed IDS to be an independent prognostic factor which reduced the risk of death by 33% at 3 years and by 48% in subsequent re-evaluation after more than 6 years of observation. Despite the above, results have been questioned by many, leading the GOG to perform a similar study which has been concluded very recently. Nevertheless, the main concern regarding the application of IDS in all instances relates to the morbidity of two major surgical procedures integrated within a short period during which cytotoxic chemotherapy is also administered. Neoadjuvant chemotherapy has been recently proposed to avoid a non-useful surgical procedure in patients considered 'optimally unresectable' after diagnosis of advanced ovarian cancer. Whether or not this newer

Thalidomide distinctly affected TNF-α, IL-6 and MMP secretion by an ovarian cancer cell line (SKOV-3) and primary ovarian cancer cells.

PubMed

Piura, Benjamin; Medina, Liat; Rabinovich, Alex; Dyomin, Victor; Huleihel, Mahmoud

2013-01-01

Thalidomide inhibits TNF-α production in lipopolysaccharide-stimulated monocytes. The aim of this study was to evaluate the effect of thalidomide on TNF-α, IL-6 and MMP secretion in epithelial ovarian carcinoma cells. SKOV-3 cells and primary epithelial ovarian carcinoma cells were cultured in the presence of various concentrations of thalidomide. Cell proliferation was examined by MTT proliferation assay. TNF-α and IL-6 levels were determined in the supernatants of the cell cultures by ELISA, and MMP activity was examined by gelatin zymography. Thalidomide did not significantly affect the proliferation and growth of SKOV-3 cells. However, it decreased significantly the capacity of SKOV-3 cells and primary epithelial ovarian carcinoma cells to secrete TNF-α. Thalidomide also significantly decreased the capacity of SKOV-3 cells, but not primary epithelial ovarian carcinoma cells, to secrete MMP-9 and MMP-2. However, thalidomide did not affect IL-6 secretion in SKOV-3 cells or primary epithelial ovarian carcinoma cells. Our study suggests that thalidomide distinctly affected TNF-α, IL-6 and MMPs secretion by an ovarian carcinoma cell line (SKOV-3) and primary ovarian cancer cells. This might suggest a different susceptibility of these two types of cells to thalidomide, and/or that the mechanisms of secretion of the factors examined are differently regulated in these cells. Our results may deepen our understanding the mechanism/s of action of thalidomide in ovarian carcinoma cells. The results might have important implications in future therapeutic strategies that will incorporate thalidomide and other cytokine inhibitors in the treatment of epithelial ovarian carcinoma.

Statin treatment is associated with survival in a nationally representative population of elderly women with epithelial ovarian cancer.

PubMed

Vogel, Tilley Jenkins; Goodman, Marc T; Li, Andrew J; Jeon, Christie Y

2017-08-01

Observational studies suggest that statin therapy for cardio-protection is associated with improved survival in cancer patients. We sought to evaluate the impact of statin treatment on ovarian cancer survival in a nationally representative elderly population. The linked Surveillance, Epidemiology, and End Results (SEER) registries and Medicare claims data on patients diagnosed with epithelial ovarian cancer in 2007-2009 were used to extract data on statin prescription fills, population characteristics, primary treatment, comorbidity and survival. Cox regression models were used to examine the association between statin treatment and overall survival. Among the 1431 ovarian cancer patients who underwent surgical resection, 609 (42.6%) filled prescriptions for statin. The majority of statin-users (89%) were prescribed a lipophilic formulation. Mean overall survival among statin-users was 32.3months compared to 28.8months for non-users (p<0.0001). A 34% reduction in death was associated with statin therapy, independent of age, race, neighborhood median household income, stage, platinum therapy and comorbid conditions (HR=0.66, 95% CI 0.55-0.81). Improved overall survival with statin use was observed for both serous (HR=0.69, 95% CI 0.54-0.87) and non-serous (HR=0.63, 95% CI 0.44-0.90) histologies. When statin treatment was categorized by lipophilicity and intensity, a significant survival benefit was limited to lipophilic statin users and those who took statins of moderate intensity. This SEER-Medicare analysis demonstrates improvement in overall survival with lipophilic statin use after surgery in elderly patients with epithelial ovarian cancer. A clinical trial to evaluate the impact of statin treatment in ovarian cancer survival is warranted. Copyright © 2017 Elsevier Inc. All rights reserved.

Prognostic significance of normal-sized ovary in advanced serous epithelial ovarian cancer.

PubMed

Paik, E Sun; Kim, Ji Hye; Kim, Tae Joong; Lee, Jeong Won; Kim, Byoung Gie; Bae, Duk Soo; Choi, Chel Hun

2018-01-01

We compared survival outcomes of advanced serous type epithelial ovarian cancer (EOC) patients with normal-sized ovaries and enlarged-ovarian tumors by propensity score matching analysis. The medical records of EOC patients treated at Samsung Medical Center between 2002 and 2015 were reviewed retrospectively. We investigated EOC patients with high grade serous type histology and International Federation of Gynecology and Obstetrics (FIGO) stage IIIB, IIIC, or IV who underwent primary debulking surgery (PDS) and adjuvant chemotherapy to identify patients with normal-sized ovaries. Propensity score matching was performed to compare patients with normal-sized ovaries to patients with enlarged-ovarian tumors (ratio, 1:3) according to age, FIGO stage, initial cancer antigen (CA)-125 level, and residual disease status after PDS. Of the 419 EOC patients, 48 patients had normal-sized ovary. Patients with enlarged-ovarian tumor were younger (54.0±10.3 vs. 58.4±9.2 years, p=0.005) than those with normal-sized ovary, and there was a statistically significant difference in residual disease status between the 2 groups. In total cohort with a median follow-up period of 43 months (range, 3-164 months), inferior overall survival (OS) was shown in the normal-sized ovary group (median OS, 71.2 vs. 41.4 months; p=0.003). After propensity score matching, the group with normal-sized ovary showed inferior OS compared to the group with enlarged-ovarian tumor (median OS, 72.1 vs. 41.4 months; p=0.031). In multivariate analysis for OS, normal-sized ovary remained a significant factor. Normal-sized ovary was associated with poor OS compared with the common presentation of enlarged ovaries in EOC, independent of CA-125 level or residual disease. Copyright © 2018. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology

Management of brain metastasis in a patient with advanced epithelial ovarian carcinoma by gamma-knife radiosurgery.

PubMed

Nikolaoul, Marinos; Stamenković, Srdjan; Stergiou, Christos; Skarleas, Christos; Torrens, Michael

2015-01-01

Brain metastases from epithelial ovarian cancer (EOC) are rare events. We present a rare case of single ovarian cancer metastasis to the brain treated with gamma-knife radiosurgery (GKRS). A 65-year-old woman with advanced EOC presented with severe neurologic symptoms. A single brain metastasis of 3.2 cm with surrounding edema in the left parietal lobe was detected by brain magnetic resonance imaging (MRI) scan during the work-up. The decision to perform GKRS was due to a surgical inaccessibility of intracranial lesion. Twelve weeks after the procedure, the MRI scan showed reduction in the diameter of brain metastasis and surrounding edema and the patient returned to good mental and motor performance.The patient survived for 22 months following treatment and died from a progressive intra-abdominal disease. Prognosis of ovarian cancer patients with brain metastases is generally poor regardless of treatment. Our case shows that GKRS as primary treatment modality for the control of ovarian cancer metastases to the brain was effective and can be considered as a treatment of choice if international selection criteria are followed.

Leukocyte-associated immunoglobulin-like receptor-1 expressed in epithelial ovarian cancer cells and involved in cell proliferation and invasion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cao, Qizhi; Fu, Aili; The People's Liberation Army 107 Hospital, Affiliated Hospital of Bin Zhou Medical University, Yantai

Previous studies have shown that leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is expressed on most types of hamatopoietic cells and negatively regulate immune response, but the roles of LAIR-1 in tumor of the non-hematopoietic lineage have not been determined. Despite advances in therapy of epithelial ovarian cancer (EOC), many questions relating to EOC pathogenesis remain unanswered. The aim of this study was to investigate the clinical significance of LAIR-1 expression in EOC and explore the possible association between LAIR-1 and cancer. In this study, a tissue microarray containing 78 ovarian cancer cases was stained following a standard immunohistochemical protocol for LAIR-1 andmore » the correlation of LAIR-1 expression with clinicopathologic features was assessed. LAIR-1 was detected to express in tumor cells of ovarian cancer tissues (73.1%) and EOC cell lines COC1 and HO8910, not in normal ovarian tissues. In addition, LAIR-1 expression correlates significantly with tumor grade (p = 0.004). Furthermore, down-regulation of LAIR-1 in HO8910 cells increased cell proliferation, colony formation and cell invasion. These data suggest that LAIR-1 has a relevant impact on EOC progression and may be helpful for a better understanding of molecular pathogenesis of cancer. - Highlights: • LAIR-1 is expressed in epithelial ovarian cancer cells. • LAIR-1 expression correlates significantly with tumor grade. • Down-regulation of LAIR-1 expression increased cell proliferation and invasion. • LAIR-1 may be a novel candidate for cancer diagnosis and therapy.« less

ABCA Transporter Gene Expression and Poor Outcome in Epithelial Ovarian Cancer

PubMed Central

Hedditch, Ellen L.; Gao, Bo; Russell, Amanda J.; Lu, Yi; Emmanuel, Catherine; Beesley, Jonathan; Johnatty, Sharon E.; Chen, Xiaoqing; Harnett, Paul; George, Joshy; Williams, Rebekka T.; Flemming, Claudia; Lambrechts, Diether; Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace; Karlan, Beth; Lester, Jenny; Orsulic, Sandra; Walsh, Christine; Fasching, Peter; Beckmann, Matthias W.; Ekici, Arif B.; Hein, Alexander; Matsuo, Keitaro; Hosono, Satoyo; Nakanishi, Toru; Yatabe, Yasushi; Pejovic, Tanja; Bean, Yukie; Heitz, Florian; Harter, Philipp; du Bois, Andreas; Schwaab, Ira; Hogdall, Estrid; Kjaer, Susan K.; Jensen, Allan; Hogdall, Claus; Lundvall, Lene; Engelholm, Svend Aage; Brown, Bob; Flanagan, James; Metcalf, Michelle D; Siddiqui, Nadeem; Sellers, Thomas; Fridley, Brooke; Cunningham, Julie; Schildkraut, Joellen; Iversen, Ed; Weber, Rachel P.; Berchuck, Andrew; Goode, Ellen; Bowtell, David D.; Chenevix-Trench, Georgia; deFazio, Anna; Norris, Murray D.; MacGregor, Stuart; Haber, Michelle; Henderson, Michelle J.

2014-01-01

Background ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown. Methods The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA–mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan–Meier analysis and log-rank tests. All statistical tests were two-sided. Results Associations with outcome were observed with ABC transporters of the “A” subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e−6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration. Conclusions Expression of ABCA transporters was associated with poor

ABCA transporter gene expression and poor outcome in epithelial ovarian cancer.

PubMed

Hedditch, Ellen L; Gao, Bo; Russell, Amanda J; Lu, Yi; Emmanuel, Catherine; Beesley, Jonathan; Johnatty, Sharon E; Chen, Xiaoqing; Harnett, Paul; George, Joshy; Williams, Rebekka T; Flemming, Claudia; Lambrechts, Diether; Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace; Karlan, Beth; Lester, Jenny; Orsulic, Sandra; Walsh, Christine; Fasching, Peter; Beckmann, Matthias W; Ekici, Arif B; Hein, Alexander; Matsuo, Keitaro; Hosono, Satoyo; Nakanishi, Toru; Yatabe, Yasushi; Pejovic, Tanja; Bean, Yukie; Heitz, Florian; Harter, Philipp; du Bois, Andreas; Schwaab, Ira; Hogdall, Estrid; Kjaer, Susan K; Jensen, Allan; Hogdall, Claus; Lundvall, Lene; Engelholm, Svend Aage; Brown, Bob; Flanagan, James; Metcalf, Michelle D; Siddiqui, Nadeem; Sellers, Thomas; Fridley, Brooke; Cunningham, Julie; Schildkraut, Joellen; Iversen, Ed; Weber, Rachel P; Berchuck, Andrew; Goode, Ellen; Bowtell, David D; Chenevix-Trench, Georgia; deFazio, Anna; Norris, Murray D; MacGregor, Stuart; Haber, Michelle; Henderson, Michelle J

2014-07-01

ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown. The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA-mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan-Meier analysis and log-rank tests. All statistical tests were two-sided. Associations with outcome were observed with ABC transporters of the "A" subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e-6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration. Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid

Basigin-2 is the predominant basigin isoform that promotes tumor cell migration and invasion and correlates with poor prognosis in epithelial ovarian cancer

PubMed Central

2013-01-01

Background Basigin, which has four isoforms, has been demonstrated to be involved in progression of various human cancers. The aim of this study was to examine the prognostic value of basigin-2 protein expression in epithelial ovarian cancer. Furthermore, the function of basigin-2 in ovarian cancer was further investigated in cell culture models. Methods Immunohistochemistry staining was performed to investigate basigin-2 expression in a total of 146 ovarian tissue specimens. Kaplan Meier analysis and Cox proportional hazards model were applied to assess the relationship between basigin-2 and progression-free survival (PFS) and overall survival (OS). Real-time PCR, RT-PCR and western blot were used to explore basigin-2, basigin-3 and basigin-4 expression in ovarian cancer cell lines and tissues. To evaluate possible contributions of basigin-2 to MMP secretion and cell migration and invasion, the overexpression vectors pcDNA3.1-basigin-2 and basigin-2 siRNA were transfected into HO-8910 and HO-8910 PM cells respectively. Results High basigin-2 expression was associated with lymph-vascular space involvement, lymph node metastasis and poor prognosis of epithelial ovarian cancer. Multivariate analyses indicated that basigin-2 positivity was an independent prognostic factor for PFS (P = 0.006) and OS (P = 0.019), respectively. Overexpression of basigin-2 increased the secretion of MMP-2/9 and cancer cell migration and invasion of HO-8910 cells, whereas knockdown of basigin-2 reduced active MMP-2/9 production, migration and invasion of HO-8910 PM cells. Conclusions The expression of basigin-2 might be an independent prognostic marker and basigin-2 inhibition would be a potential strategy for epithelial ovarian cancer patients, especially in inhibiting and preventing cancer cell invasion and metastasis. PMID:23566400

Biological Basis for Chemoprevention of Ovarian Cancer

DTIC Science & Technology

1999-10-01

potent apoptotic effect on ovarian epithelial cells, the use of levonorgestrel in chemoprevention of ovarian cancer is being explored in chickens and...women. A chemoprevention trial is ongoing in chickens and we will begin a trial to determine whether levonorgestrel induces apoptosis in the ovarian...subsequent studies performed in vitro, we have induced apoptosis in epithelial cells treated with the progestin levonorgestrel . Progestin mediated apoptotic

Arid1a Inactivation in an Apc and Pten-defective Mouse Ovarian Cancer Model Enhances Epithelial Differentiation and Prolongs Survival

PubMed Central

Zhai, Yali; Kuick, Rork; Tipton, Courtney; Wu, Rong; Sessine, Michael; Wang, Zhong; Baker, Suzanne J.; Fearon, Eric R.; Cho, Kathleen R.

2015-01-01

Inactivation of the ARID1A tumor suppressor gene is frequent in ovarian endometrioid (OEC) and clear cell carcinomas (OCCC), often in conjunction with mutations activating the PI3K/AKT and/or canonical Wnt signaling pathways. Prior work has shown that conditional bi-allelic inactivation of the Apc and Pten tumor suppressor genes in the mouse ovarian surface epithelium (OSE) promotes outgrowth of tumors that reflect the biological behavior and gene expression profiles of human OECs harboring comparable Wnt and PI3K/AKT pathway defects, though the mouse tumors are more poorly differentiated than their human tumor counterparts. We found that conditional inactivation of one or both Arid1a alleles in OSE concurrently with Apc and Pten inactivation unexpectedly prolonged survival of tumor-bearing mice and promoted striking epithelial differentiation of the cancer cells, resulting in morphological features akin to those in human OECs. Enhanced epithelial differentiation was linked to reduced expression of mesenchymal markers N-cadherin and vimentin, and increased expression of epithelial markers Crb3 and E-cadherin. Global gene expression profiling showed enrichment for genes associated with mesenchymal-to-epithelial transition in the Arid1a-deficient tumors. We also found that an activating (E545K) Pik3ca mutation, unlike Pten inactivation or Pik3ca H1047R mutation, cannot cooperate with Arid1a loss to promote ovarian cancer development in the mouse. Our results indicate the Arid1a tumor suppressor gene has a key role in regulating OEC differentiation, and paradoxically the mouse cancers with more initiating tumor suppressor gene defects had a less aggressive phenotype than cancers arising from fewer gene alterations. PMID:26279473

Expression of Tissue Factor in Epithelial Ovarian Carcinoma Is Involved in the Development of Venous Thromboembolism.

PubMed

Sakurai, Manabu; Matsumoto, Koji; Gosho, Masahiko; Sakata, Akiko; Hosokawa, Yoshihiko; Tenjimbayashi, Yuri; Katoh, Takashi; Shikama, Ayumi; Komiya, Haruna; Michikami, Hiroo; Tasaka, Nobutaka; Akiyama-Abe, Azusa; Nakao, Sari; Ochi, Hiroyuki; Onuki, Mamiko; Minaguchi, Takeo; Yoshikawa, Hiroyuki; Satoh, Toyomi

2017-01-01

Our 2007 study of 32 patients with ovarian cancer reported the possible involvement of tissue factor (TF) in the development of venous thromboembolism (VTE) before treatment, especially in clear cell carcinoma (CCC). This follow-up study further investigated this possibility in a larger cohort. We investigated the intensity of TF expression (ITFE) and other variables for associations with VTE using univariate and multivariate analyses in 128 patients with epithelial ovarian cancer initially treated between November 2004 and December 2010, none of whom had received neoadjuvant chemotherapy. Before starting treatment, all patients were ultrasonographically screened for VTE. The ITFE was graded based on immunostaining of surgical specimens. Histological types were serous carcinoma (n = 42), CCC (n = 12), endometrioid carcinoma (n = 15), mucinous carcinoma (n = 53), and undifferentiated carcinoma (n = 6). The prevalence of VTE was significantly higher in CCC (34%) than in non-CCC (17%, P = 0.03). As ITFE increased, the frequencies of CCC and VTE increased significantly (P < 0.001 and P = 0.014, respectively). Multivariate analysis identified TF expression and pretreatment dimerized plasmin fragment D level as significant independent risk factors for VTE development. These factors showed particularly strong impacts on advanced-stage disease (P = 0.021). The 2007 cohort was small, preventing multivariate analysis. This study of a larger cohort yielded stronger evidence that the development of VTE in epithelial ovarian cancer may involve TF expression in cancer tissues.

Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer

PubMed Central

Winter-Roach, Brett A; Kitchener, Henry C; Lawrie, Theresa A

2014-01-01

trials were included in the meta-analyses and we considered them to be at a low risk of bias. Meta-analysis of five-year data from three trials indicated that women who received adjuvant platinum-based chemotherapy had better overall survival (OS) than those who did not (1008 women; hazard ratio (HR) 0.71; 95% confidence interval (CI) 0.53 to 0.93). Likewise, meta-analysis of five-year data from four trials indicated that women who received adjuvant chemotherapy had better progression-free survival (PFS) than those who did not (1170 women; HR 0.67; 95% CI 0.53 to 0.84). The trials included in these meta-analyses gave consistent estimates of the effects of chemotherapy. In addition, these findings were robust over time (10-year PFS: two trials, 925 women; HR 0.67; 95% CI 0.54 to 0.84). Subgroup analysis suggested that women who had optimal surgical staging of their disease were unlikely to benefit from adjuvant chemotherapy (HR for OS 1.22; 95% CI 0.63 to 2.37; two trials, 234 women) whereas those who had sub-optimal staging did (HR for OS 0.63; 95% CI 0.46 to 0.85; two trials, 772 women). One trial showed a benefit from adjuvant chemotherapy among women at high risk (HR for OS 0.48; 95% CI 0.32 to 0.72) but not among those at low/medium risk (HR for OS 0.95; 95% CI 0.54 to 1.66). However, these subgroup findings could be due to chance and should be interpreted with caution. Authors’ conclusions Adjuvant platinum-based chemotherapy is effective in prolonging the survival of the majority of patients who are assessed as having early (FIGO stage I/IIa) epithelial ovarian cancer. However, it may be withheld from women in whom there is well-differentiated encapsulated unilateral disease (stage 1a grade 1) or those with comprehensively staged Ib, well or moderately differentiated (grade 1/2) disease. Others with unstaged early disease or those with poorly differentiated tumours should be offered chemotherapy. A pragmatic approach may be necessary in clinical settings where

Characterization of three new serous epithelial ovarian cancer cell lines

PubMed Central

Ouellet, Véronique; Zietarska, Magdalena; Portelance, Lise; Lafontaine, Julie; Madore, Jason; Puiffe, Marie-Line; Arcand, Suzanna L; Shen, Zhen; Hébert, Josée; Tonin, Patricia N; Provencher, Diane M; Mes-Masson, Anne-Marie

2008-01-01

Background Cell lines constitute a powerful model to study cancer, and here we describe three new epithelial ovarian cancer (EOC) cell lines derived from poorly differentiated serous solid tumors (TOV-1946, and TOV-2223G), as well as the matched ascites for one case (OV-1946). Methods In addition to growth parameters, the cell lines were characterized for anchorage independent growth, migration and invasion potential, ability to form spheroids and xenografts in SCID mice. Results While all cell lines were capable of anchorage independent growth, only the TOV-1946 and OV-1946 cell lines were able to form spheroid and produce tumors. Profiling of keratins, p53 and Her2 protein expression was assessed by immunohistochemistry and western blot analyses. Somatic TP53 mutations were found in all cell lines, with TOV-1946 and OV-1946 harboring the same mutation, and none harbored the commonly observed somatic mutations in BRAF, KRAS or germline BRCA1/2 mutations found to recur in the French Canadian population. Conventional cytogenetics and spectral karyotype (SKY) analyses revealed complex karyotypes often observed in ovarian disease. Conclusion This is the first report of the establishment of matched EOC cell lines derived from both solid tumor and ascites of the same patient. PMID:18507860

Comparison of plasma amino acid profile-based index and CA125 in the diagnosis of epithelial ovarian cancers and borderline malignant tumors.

PubMed

Miyagi, Etsuko; Maruyama, Yasuyo; Mogami, Tae; Numazaki, Reiko; Ikeda, Atsuko; Yamamoto, Hiroshi; Hirahara, Fumiki

2017-02-01

We previously developed a new plasma amino acid profile-based index (API) to detect ovarian, cervical, and endometrial cancers. Here, we compared API to serum cancer antigen 125 (CA125) for distinguishing epithelial ovarian malignant tumors from benign growths. API and CA125 were measured preoperatively in patients with ovarian tumors, which were later classified into 59 epithelial ovarian cancers, 21 epithelial borderline malignant tumors, and 97 benign tumors including 40 endometriotic cysts. The diagnostic accuracy and cutoff points of API were evaluated using receiver operating characteristic (ROC) curves. The area under the ROC curves showed the equivalent performance of API and CA125 to discriminate between malignant/borderline malignant and benign tumors (both 0.77), and API was superior to CA125 for discrimination between malignant/borderline malignant lesions and endometriotic cysts (API, 0.75 vs. CA125, 0.59; p < 0.05). At the API cutoff level of 6.0, API and CA125 had equal positive rates of detecting cancers and borderline malignancies (API, 0.71 vs. CA125, 0.74; p = 0.84) or cancers alone (API, 0.73 vs. CA125, 0.85; p = 0.12). However, API had a significantly lower detection rate of benign endometriotic cysts (0.35; 95 % CI, 0.21-0.52) compared with that of CA125 (0.65; 95 % CI, 0.48-0.79) (p < 0.05). API is an effective new tumor marker to detect ovarian cancers and borderline malignancies with a low false-positive rate for endometriosis. A large-scale prospective clinical study using the cutoff value of API determined in this study is warranted to validate API for practical clinical use.

The O-Linked Glycome and Blood Group Antigens ABO on Mucin-Type Glycoproteins in Mucinous and Serous Epithelial Ovarian Tumors

PubMed Central

Vitiazeva, Varvara; Kattla, Jayesh J.; Flowers, Sarah A.; Lindén, Sara K.; Premaratne, Pushpa; Weijdegård, Birgitta; Sundfeldt, Karin; Karlsson, Niclas G.

2015-01-01

Background Mucins are heavily O-glycosylated proteins where the glycosylation has been shown to play an important role in cancer. Normal epithelial ovarian cells do not express secreted mucins, but their abnormal expression has previously been described in epithelial ovarian cancer and may relate to tumor formation and progression. The cyst fluids were shown to be a rich source for acidic glycoproteins. The study of these proteins can potentially lead to the identification of more effective biomarkers for ovarian cancer. Methods In this study, we analyzed the expression of the MUC5AC and the O-glycosylation of acidic glycoproteins secreted into ovarian cyst fluids. The samples were obtained from patients with serous and mucinous ovarian tumors of different stages (benign, borderline, malignant) and grades. The O-linked oligosaccharides were released and analyzed by negative-ion graphitized carbon Liquid Chromatography (LC) coupled to Electrospray Ionization tandem Mass Spectrometry (ESI-MSn). The LC-ESI-MSn of the oligosaccharides from ovarian cyst fluids displayed differences in expression of fucose containing structures such as blood group ABO antigens and Lewis-type epitopes. Results The obtained data showed that serous and mucinous benign adenomas, mucinous low malignant potential carcinomas (LMPs, borderline) and mucinous low-grade carcinomas have a high level of blood groups and Lewis type epitopes. In contrast, this type of fucosylated structures were low abundant in the high-grade mucinous carcinomas or in serous carcinomas. In addition, the ovarian tumors that showed a high level of expression of blood group antigens also revealed a strong reactivity towards the MUC5AC antibody. To visualize the differences between serous and mucinous ovarian tumors based on the O-glycosylation, a hierarchical cluster analysis was performed using mass spectrometry average compositions (MSAC). Conclusion Mucinous benign and LMPs along with mucinous low-grade carcinomas

Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

PubMed

Kuchenbaecker, Karoline B; Ramus, Susan J; Tyrer, Jonathan; Lee, Andrew; Shen, Howard C; Beesley, Jonathan; Lawrenson, Kate; McGuffog, Lesley; Healey, Sue; Lee, Janet M; Spindler, Tassja J; Lin, Yvonne G; Pejovic, Tanja; Bean, Yukie; Li, Qiyuan; Coetzee, Simon; Hazelett, Dennis; Miron, Alexander; Southey, Melissa; Terry, Mary Beth; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Neuhausen, Susan L; Ding, Yuan Chun; Hansen, Thomas V O; Jønson, Lars; Gerdes, Anne-Marie; Ejlertsen, Bent; Barrowdale, Daniel; Dennis, Joe; Benitez, Javier; Osorio, Ana; Garcia, Maria Jose; Komenaka, Ian; Weitzel, Jeffrey N; Ganschow, Pamela; Peterlongo, Paolo; Bernard, Loris; Viel, Alessandra; Bonanni, Bernardo; Peissel, Bernard; Manoukian, Siranoush; Radice, Paolo; Papi, Laura; Ottini, Laura; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Frost, Debra; Perkins, Jo; Platte, Radka; Ellis, Steve; Godwin, Andrew K; Schmutzler, Rita Katharina; Meindl, Alfons; Engel, Christoph; Sutter, Christian; Sinilnikova, Olga M; Damiola, Francesca; Mazoyer, Sylvie; Stoppa-Lyonnet, Dominique; Claes, Kathleen; De Leeneer, Kim; Kirk, Judy; Rodriguez, Gustavo C; Piedmonte, Marion; O'Malley, David M; de la Hoya, Miguel; Caldes, Trinidad; Aittomäki, Kristiina; Nevanlinna, Heli; Collée, J Margriet; Rookus, Matti A; Oosterwijk, Jan C; Tihomirova, Laima; Tung, Nadine; Hamann, Ute; Isaccs, Claudine; Tischkowitz, Marc; Imyanitov, Evgeny N; Caligo, Maria A; Campbell, Ian G; Hogervorst, Frans B L; Olah, Edith; Diez, Orland; Blanco, Ignacio; Brunet, Joan; Lazaro, Conxi; Pujana, Miquel Angel; Jakubowska, Anna; Gronwald, Jacek; Lubinski, Jan; Sukiennicki, Grzegorz; Barkardottir, Rosa B; Plante, Marie; Simard, Jacques; Soucy, Penny; Montagna, Marco; Tognazzo, Silvia; Teixeira, Manuel R; Pankratz, Vernon S; Wang, Xianshu; Lindor, Noralane; Szabo, Csilla I; Kauff, Noah; Vijai, Joseph; Aghajanian, Carol A; Pfeiler, Georg; Berger, Andreas; Singer, Christian F; Tea, Muy-Kheng; Phelan, Catherine M; Greene, Mark H; Mai, Phuong L; Rennert, Gad; Mulligan, Anna Marie; Tchatchou, Sandrine; Andrulis, Irene L; Glendon, Gord; Toland, Amanda Ewart; Jensen, Uffe Birk; Kruse, Torben A; Thomassen, Mads; Bojesen, Anders; Zidan, Jamal; Friedman, Eitan; Laitman, Yael; Soller, Maria; Liljegren, Annelie; Arver, Brita; Einbeigi, Zakaria; Stenmark-Askmalm, Marie; Olopade, Olufunmilayo I; Nussbaum, Robert L; Rebbeck, Timothy R; Nathanson, Katherine L; Domchek, Susan M; Lu, Karen H; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; Hein, Alexander; Ekici, Arif B; Beckmann, Matthias W; Fasching, Peter A; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Lambrechts, Sandrina; Dicks, Ed; Doherty, Jennifer A; Wicklund, Kristine G; Rossing, Mary Anne; Rudolph, Anja; Chang-Claude, Jenny; Wang-Gohrke, Shan; Eilber, Ursula; Moysich, Kirsten B; Odunsi, Kunle; Sucheston, Lara; Lele, Shashi; Wilkens, Lynne R; Goodman, Marc T; Thompson, Pamela J; Shvetsov, Yurii B; Runnebaum, Ingo B; Dürst, Matthias; Hillemanns, Peter; Dörk, Thilo; Antonenkova, Natalia; Bogdanova, Natalia; Leminen, Arto; Pelttari, Liisa M; Butzow, Ralf; Modugno, Francesmary; Kelley, Joseph L; Edwards, Robert P; Ness, Roberta B; du Bois, Andreas; Heitz, Florian; Schwaab, Ira; Harter, Philipp; Matsuo, Keitaro; Hosono, Satoyo; Orsulic, Sandra; Jensen, Allan; Kjaer, Susanne Kruger; Hogdall, Estrid; Hasmad, Hanis Nazihah; Azmi, Mat Adenan Noor; Teo, Soo-Hwang; Woo, Yin-Ling; Fridley, Brooke L; Goode, Ellen L; Cunningham, Julie M; Vierkant, Robert A; Bruinsma, Fiona; Giles, Graham G; Liang, Dong; Hildebrandt, Michelle A T; Wu, Xifeng; Levine, Douglas A; Bisogna, Maria; Berchuck, Andrew; Iversen, Edwin S; Schildkraut, Joellen M; Concannon, Patrick; Weber, Rachel Palmieri; Cramer, Daniel W; Terry, Kathryn L; Poole, Elizabeth M; Tworoger, Shelley S; Bandera, Elisa V; Orlow, Irene; Olson, Sara H; Krakstad, Camilla; Salvesen, Helga B; Tangen, Ingvild L; Bjorge, Line; van Altena, Anne M; Aben, Katja K H; Kiemeney, Lambertus A; Massuger, Leon F A G; Kellar, Melissa; Brooks-Wilson, Angela; Kelemen, Linda E; Cook, Linda S; Le, Nhu D; Cybulski, Cezary; Yang, Hannah; Lissowska, Jolanta; Brinton, Louise A; Wentzensen, Nicolas; Hogdall, Claus; Lundvall, Lene; Nedergaard, Lotte; Baker, Helen; Song, Honglin; Eccles, Diana; McNeish, Ian; Paul, James; Carty, Karen; Siddiqui, Nadeem; Glasspool, Rosalind; Whittemore, Alice S; Rothstein, Joseph H; McGuire, Valerie; Sieh, Weiva; Ji, Bu-Tian; Zheng, Wei; Shu, Xiao-Ou; Gao, Yu-Tang; Rosen, Barry; Risch, Harvey A; McLaughlin, John R; Narod, Steven A; Monteiro, Alvaro N; Chen, Ann; Lin, Hui-Yi; Permuth-Wey, Jenny; Sellers, Thomas A; Tsai, Ya-Yu; Chen, Zhihua; Ziogas, Argyrios; Anton-Culver, Hoda; Gentry-Maharaj, Aleksandra; Menon, Usha; Harrington, Patricia; Lee, Alice W; Wu, Anna H; Pearce, Celeste L; Coetzee, Gerry; Pike, Malcolm C; Dansonka-Mieszkowska, Agnieszka; Timorek, Agnieszka; Rzepecka, Iwona K; Kupryjanczyk, Jolanta; Freedman, Matt; Noushmehr, Houtan; Easton, Douglas F; Offit, Kenneth; Couch, Fergus J; Gayther, Simon; Pharoah, Paul P; Antoniou, Antonis C; Chenevix-Trench, Georgia

2015-02-01

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

[Analysis of familial aggregation of ovarian and breast cancer in patients with ovarian cancer].

PubMed

Ichikawa, Y; Nishida, M; Sugita, M; Arisawa, Y; Satoh, T; Oki, A; Kohno, K; Shigemitsu, S; Tsunoda, H; Kubo, T

1995-09-01

In 118 patients with common epithelial ovarian tumors (carcinomas and tumors of borderline malignancy) treated at Tsukuba University Hospital and Tsukuba-Gakuen Hospital, family histories of ovarian and breast cancer were obtained from medical records or in interviews, and familial aggregation of these cancers was examined. 1. A positive family history was found in 10 patients (8.5%). The high incidences of familial ovarian cancer and ovarian cancer in patients who were previously affected with breast cancer were statistically significant. 2. Patients with serous adenocarcinoma showed a significantly greater rate of positive family history than those with mucinous adenocarcinoma. 3. No significant correlation was seen between the clinical stage and a positive family history. 4. Every patient except one with a positive family history had onset of ovarian cancer after menopause. The age at onset for familial ovarian cancer cases was younger than that for the patients' relatives who were affected previously. 5. There were 14 healthy women considered to be at high risk for ovarian cancer among 5 familial ovarian and 2 familial ovarian and breast cancer aggregations. These preliminary findings suggest that screening for early ovarian cancer should be conducted in high risk relatives of familial cancer patients and women affected with breast cancer previously. More detailed studies are needed to define the occurrence of familial or hereditary ovarian and breast cancers in Japan.

Expression patterns of emmprin and monocarboxylate transporter-1 in ovarian epithelial tumors.

PubMed

Fukuoka, Miyoko; Hamasaki, Makoto; Koga, Kaori; Hayashi, Hiroyuki; Aoki, Mikiko; Kawarabayashi, Tatsuhiko; Miyamoto, Shingo; Nabeshima, Kazuki

2012-10-01

Emmprin is a transmembrane glycoprotein known as a matrix metalloproteinase inducer and is highly up-regulated in malignant cancer cells. The monocarboxylate transporters (MCTs) are responsible for H(+)-linked transport of monocarboxylates across the cell membrane. It was recently demonstrated that proper plasma membrane localization and activity of MCTs require the presence of emmprin as a chaperone and that MCT-1 also acts as chaperone for emmprin. The objectives of this study were to clarify emmprin and MCT-1 expression patterns in ovarian epithelial tumors and to elucidate the clinicopathological significance of co-localization of the two molecules. Immunohistochemical analysis of 205 epithelial tumors indicated that emmprin is always localized in cell membranes but its distribution differs according to tumor type: in lateral membranes in 89 % of adenomas, in lateral and basal membranes in 76 % of borderline tumors, and in membranes surrounding the entire cell in 98 % of carcinomas. Most carcinomas in situ also showed a lateral and basal expression pattern. In only 21 % of the carcinomas, the cells expressing membranous MCT-1 showed co-localized emmprin expression. Poor co-localization of the two molecules was more frequently found in serous carcinomas. However, the overall survival was not significantly different for the good and poor co-localization carcinoma groups. These findings indicate that the emmprin expression pattern might discriminate between invasive carcinomas and borderline tumors including carcinoma in situ. Moreover, there may be an as yet unidentified regulatory mechanism(s), for localization of MCT-1 and emmprin in cell membranes in vivo.

Paclitaxel and Carboplatin With or Without Bevacizumab in Treating Patients With Stage II, Stage III, or Stage IV Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer

ClinicalTrials.gov

2017-12-28

Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Adenocarcinofibroma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Undifferentiated Ovarian Carcinoma

Associations between residual disease and survival in epithelial ovarian cancer by histologic type.

PubMed

Melamed, Alexander; Manning-Geist, Beryl; Bregar, Amy J; Diver, Elisabeth J; Goodman, Annekathryn; Del Carmen, Marcela G; Schorge, John O; Rauh-Hain, J Alejandro

2017-11-01

Surgical cytoreduction has been postulated to affect survival by increasing the efficacy of chemotherapy in ovarian cancer. We hypothesized that women with high-grade serous ovarian cancer, which usually responds to chemotherapy, would derive greater benefit from complete cytoreduction than those with histologic subtypes that are less responsive to chemotherapy, such as mucinous and clear cell carcinoma. We conducted a retrospective cohort study of patients who underwent primary cytoreductive surgery and adjuvant chemotherapy for stage IIIC or IV epithelial ovarian cancer from 2011 to 2013 using data from the National Cancer Database. We constructed multivariable models to quantify the magnitude of associations between residual disease status (no residual disease, ≤1cm, or >1cm) and all-cause mortality by histologic type among women with clear cell, mucinous, and high-grade serous ovarian cancer. Because 26% of the sample had unknown residual disease status, we used multiple imputations in the primary analysis. We identified 6,013 women with stage IIIC and IV high-grade serous, 307 with clear cell, and 140 with mucinous histology. The association between residual disease status and mortality hazard did not differ significantly among histologic subtypes of ovarian cancer (p for interaction=0.32). In covariate adjusted models, compared to suboptimal cytoreduction, cytoreduction to no gross disease was associated with a hazard reduction of 42% in high-grade serous carcinoma (hazard ratio [HR]=0.58, 95% confidence interval [CI]=0.49-0.68), 61% in clear cell carcinoma (HR=0.39, 95% CI=0.22-0.69), and 54% in mucinous carcinoma (HR=0.46, 95% CI=0.22-0.99). We found no evidence that surgical cytoreduction was of greater prognostic importance in high-grade serous carcinomas than in histologies that are less responsive to chemotherapy. Copyright © 2017 Elsevier Inc. All rights reserved.

Selumetinib Sulfate in Treating Woman With Recurrent Low-Grade Ovarian Cancer or Peritoneum Cancer

ClinicalTrials.gov

2018-03-30

Borderline Ovarian Epithelial Tumor; Low Grade Ovarian Serous Adenocarcinoma; Primary Peritoneal Carcinoma; Primary Peritoneal Low Grade Serous Adenocarcinoma; Recurrent Borderline Ovarian Surface Epithelial-Stromal Tumor

Genome-wide profiling of the PIWI-interacting RNA-mRNA regulatory networks in epithelial ovarian cancers.

PubMed

Singh, Garima; Roy, Jyoti; Rout, Pratiti; Mallick, Bibekanand

2018-01-01

PIWI-interacting (piRNAs), ~23-36 nucleotide-long small non-coding RNAs (sncRNAs), earlier believed to be germline-specific, have now been identified in somatic cells, including cancer cells. These sncRNAs impact critical biological processes by fine-tuning gene expression at post-transcriptional and epigenetic levels. The expression of piRNAs in ovarian cancer, the most lethal gynecologic cancer is largely uncharted. In this study, we investigated the expression of PIWILs by qRT-PCR and western blotting and then identified piRNA transcriptomes in tissues of normal ovary and two most prevalent epithelial ovarian cancer subtypes, serous and endometrioid by small RNA sequencing. We detected 219, 256 and 234 piRNAs in normal ovary, endometrioid and serous ovarian cancer samples respectively. We observed piRNAs are encoded from various genomic regions, among which introns harbor the majority of them. Surprisingly, piRNAs originated from different genomic contexts showed the varied level of conservations across vertebrates. The functional analysis of predicted targets of differentially expressed piRNAs revealed these could modulate key processes and pathways involved in ovarian oncogenesis. Our study provides the first comprehensive piRNA landscape in these samples and a useful resource for further functional studies to decipher new mechanistic views of piRNA-mediated gene regulatory networks affecting ovarian oncogenesis. The RNA-seq data is submitted to GEO database (GSE83794).

Preserved foods associated with increased risk of ovarian cancer.

PubMed

Lee, Andy H; Su, Dada; Pasalich, Maria; Binns, Colin W

2013-06-01

To investigate the association between consumption of preserved foods and risk of epithelial ovarian cancer in southern Chinese women. A hospital-based case-control study was undertaken in Guangzhou, Guangdong Province, from 2006 to 2008. Participants were 500 incident epithelial ovarian cancer patients and 500 controls, with a mean age 59 years. Information on habitual food consumption was obtained by face-to-face interview using a validated and reliable food frequency questionnaire. Logistic regression analyses were performed to assess the association between preserved foods intake and the ovarian cancer risk. The ovarian cancer patients consumed more preserved foods (median 15.5, interquartile range (IQR) 18.2g/day) than controls (median 13.8, IQR 20.5 g/day), p<0.001. The adjusted odds ratios of ovarian cancer was 1.78 (95% confidence interval 1.35 to 2.34) for women consuming more than 13.5 g of preserved vegetables and preserved meats per day relative to those below. Similar two-fold increases in risk at high level of intake were also evident for serous and mucinous subtypes of epithelial ovarian tumours. Intake of preserved foods was positively associated with the incidence of epithelial ovarian cancer in southern Chinese women. Copyright © 2013 Elsevier Inc. All rights reserved.

[Expression of MiR-130a in Serum Samples of Patients with Epithelial Ovarian Cancer and Its Association with Platinum Resistance].

PubMed

Chen, Cen; Wang, Hong-jing; Yang, Ling-Yun; Jia, Xi-biao; Xu, Pan; Chen, Jing; Liu, Ya

2016-01-01

To determine the expression of miR-130a in patients with epithelial ovarian cancer and its association with platinum resistance. 32 patients with platinum resistance and 30 patients without platinum resistance were recruited in this study. Real-time PCR was performed to detect the expression of miR-130a in the serum samples of the patients. ELISA was used to measure the expression level of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and B-cell lymphoma-2 (BCL-2). Platinum-resistant patients had significantly higher levels of expression of miR-130a and BCL-2, and lower level of PTEN than platinum-sensitive patients (P < 0.05). The expression level of miR-130a increased with increased severity in histological classification and appearance of lymph node metastasis in the platinum-resistant patients (P < 0.05). MiR-130a may mediate the generation of platinum resistance in epithelial ovarian cancer through inhibiting PTEN to activate PI3K/AKT signaling pathway and increasing BCL-2 to inhibit tumor cell apoptosis. MiR-130a may be a new potential target of gene therapy in platinum-resistant ovarian cancers.

Dietary fat intake and risk of epithelial ovarian cancer: a meta-analysis of 6,689 subjects from 8 observational studies.

PubMed

Huncharek, M; Kupelnick, B

2001-01-01

The etiology of epithelial ovarian cancer is unknown. Prior work suggests that high dietary fat intake is associated with an increased risk of this tumor, although this association remains speculative. A meta-analysis was performed to evaluate this suspected relationship. Using previously described methods, a protocol was developed for a meta-analysis examining the association between high vs. low dietary fat intake and the risk of epithelial ovarian cancer. Literature search techniques, study inclusion criteria, and statistical procedures were prospectively defined. Data from observational studies were pooled using a general variance-based meta-analytic method employing confidence intervals (CI) previously described by Greenland. The outcome of interest was a summary relative risk (RRs) reflecting the risk of ovarian cancer associated with high vs. low dietary fat intake. Sensitivity analyses were performed when necessary to evaluate any observed statistical heterogeneity. The literature search yielded 8 observational studies enrolling 6,689 subjects. Data were stratified into three dietary fat intake categories: total fat, animal fat, and saturated fat. Initial tests for statistical homogeneity demonstrated that hospital-based studies accounted for observed heterogeneity possibly because of selection bias. Accounting for this, an RRs was calculated for high vs. low total fat intake, yielding a value of 1.24 (95% CI = 1.07-1.43), a statistically significant result. That is, high total fat intake is associated with a 24% increased risk of ovarian cancer development. The RRs for high saturated fat intake was 1.20 (95% CI = 1.04-1.39), suggesting a 20% increased risk of ovarian cancer among subjects with these dietary habits. High vs. low animal fat diet gave an RRs of 1.70 (95% CI = 1.43-2.03), consistent with a statistically significant 70% increased ovarian cancer risk. High dietary fat intake appears to represent a significant risk factor for the development of

Body weight, hemoglobin, and absolute neutrophil count in patients with advanced-stage epithelial ovarian cancer who received chemotherapy: A single-center study

NASA Astrophysics Data System (ADS)

Gunawan, Y.; Winarto, H.

2017-08-01

The side effects of chemotherapy, a treatment modality of ovarian cancer, can disrupt overall treatment. To date, the clinical and laboratory profiles of ovarian cancer patients during chemotherapy have not been investigated. This study aimed to elucidate the clinical and laboratory profiles of patients with advanced-stage epithelial ovarian cancer who received chemotherapy in Dr. Cipto Mangunkusumo Hospital, including body mass index (BMI), hemoglobin (Hb), and absolute neutrophil count (ANC). To generate these clinical and laboratory profiles, we collected secondary data from the medical records of advanced-stage epithelial ovarian cancer patients who received six cycles of carboplatin and paclitaxel chemotherapy. We enrolled 23 patients with advanced-stage epithelial ovarian cancer patients who received six cycles of chemotherapy. Mean patient BMI before and after chemotherapy was 22.86 kg/m2 and 21.78 kg/m2, respectively. Hb levels before chemotherapy were 8-13 g/dl, with Hb < 10 g/dl in one patient (4.35%) and Hb ≥ 10 g/dl in 22 patients (95.65%). Mean ANC was 5845.6 ± 3325.0. An average of 24.65% of patients experienced anemia after each cycle of chemotherapy. Mean ANC before chemotherapy was 3.5582 ± 3.3250. An average of 26.81% of patients had ANC <1500 after each cycle of chemotherapy; no patients had ANC <1500 before chemotherapy initiation. After six cycles of chemotherapy, three patients (13.04%) had mild neutropenia, four patients (17.39%) had moderate neutropenia, and one patient (4.35%) had severe neutropenia. Of the 22 patients with Hb ≥ 10 g/dl before chemotherapy, 16 (72.72%) experienced a decrease in ANC during chemotherapy. Of the 20 patients (60.87%) with normal BMI or higher, 14 experienced a decrease in ANC during chemotherapy. The mean patient body weight decreased after six cycles of chemotherapy. Hb and ANC were persistently decreased in approximately a quarter of the 23 subjects. The decrease in ANC was not influenced by initial Hb

Sargramostim and Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Patients With Advanced Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer That Did Not Respond to Previous Chemotherapy

ClinicalTrials.gov

2017-07-24

Brenner Tumor; Fallopian Tube Cancer; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Peritoneal Cavity Cancer; Recurrent Ovarian Epithelial Cancer; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

The emerging roles and therapeutic potential of exosomes in epithelial ovarian cancer.

PubMed

Li, Xiaoduan; Wang, Xipeng

2017-05-15

Ovarian cancer (OC) is one of the three types of malignant tumors in the female reproductive system, and epithelial ovarian cancer (EOC) is its most typical form. Due to the asymptomatic nature of the early stages and resistance to chemotherapy, EOC has both a poor prognosis and a high fatality rate. Current treatments for OC are very limited, and the 5-years survival rate is approximately 30%. Exosomes, which are microvesicles ranging from approximately 30-100 nm in size that are secreted by living cells, can be produced from different cell types and detected in various body fluids. Cancer cells can secrete more exosomes than healthy cells, and more importantly, the content of cancer cell-derived exosomes is distinct. The exosomes shedding from tumor cells are considered to be involved in tumor progression and metastasis. As such, exosomes are expected to be potential tools for tumor diagnosis and treatment. In this review, we briefly present the emerging roles of exosomes in OC and summarize related articles about their roles as diagnostic or prognostic biomarkers and in the treatment and drug resistance of OC.

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

PubMed

Phelan, Catherine M; Kuchenbaecker, Karoline B; Tyrer, Jonathan P; Kar, Siddhartha P; Lawrenson, Kate; Winham, Stacey J; Dennis, Joe; Pirie, Ailith; Riggan, Marjorie J; Chornokur, Ganna; Earp, Madalene A; Lyra, Paulo C; Lee, Janet M; Coetzee, Simon; Beesley, Jonathan; McGuffog, Lesley; Soucy, Penny; Dicks, Ed; Lee, Andrew; Barrowdale, Daniel; Lecarpentier, Julie; Leslie, Goska; Aalfs, Cora M; Aben, Katja K H; Adams, Marcia; Adlard, Julian; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia; Aravantinos, Gerasimos; Arnold, Norbert; Arun, Banu K; Arver, Brita; Azzollini, Jacopo; Balmaña, Judith; Banerjee, Susana N; Barjhoux, Laure; Barkardottir, Rosa B; Bean, Yukie; Beckmann, Matthias W; Beeghly-Fadiel, Alicia; Benitez, Javier; Bermisheva, Marina; Bernardini, Marcus Q; Birrer, Michael J; Bjorge, Line; Black, Amanda; Blankstein, Kenneth; Blok, Marinus J; Bodelon, Clara; Bogdanova, Natalia; Bojesen, Anders; Bonanni, Bernardo; Borg, Åke; Bradbury, Angela R; Brenton, James D; Brewer, Carole; Brinton, Louise; Broberg, Per; Brooks-Wilson, Angela; Bruinsma, Fiona; Brunet, Joan; Buecher, Bruno; Butzow, Ralf; Buys, Saundra S; Caldes, Trinidad; Caligo, Maria A; Campbell, Ian; Cannioto, Rikki; Carney, Michael E; Cescon, Terence; Chan, Salina B; Chang-Claude, Jenny; Chanock, Stephen; Chen, Xiao Qing; Chiew, Yoke-Eng; Chiquette, Jocelyne; Chung, Wendy K; Claes, Kathleen B M; Conner, Thomas; Cook, Linda S; Cook, Jackie; Cramer, Daniel W; Cunningham, Julie M; D'Aloisio, Aimee A; Daly, Mary B; Damiola, Francesca; Damirovna, Sakaeva Dina; Dansonka-Mieszkowska, Agnieszka; Dao, Fanny; Davidson, Rosemarie; DeFazio, Anna; Delnatte, Capucine; Doheny, Kimberly F; Diez, Orland; Ding, Yuan Chun; Doherty, Jennifer Anne; Domchek, Susan M; Dorfling, Cecilia M; Dörk, Thilo; Dossus, Laure; Duran, Mercedes; Dürst, Matthias; Dworniczak, Bernd; Eccles, Diana; Edwards, Todd; Eeles, Ros; Eilber, Ursula; Ejlertsen, Bent; Ekici, Arif B; Ellis, Steve; Elvira, Mingajeva; Eng, Kevin H; Engel, Christoph; Evans, D Gareth; Fasching, Peter A; Ferguson, Sarah; Ferrer, Sandra Fert; Flanagan, James M; Fogarty, Zachary C; Fortner, Renée T; Fostira, Florentia; Foulkes, William D; Fountzilas, George; Fridley, Brooke L; Friebel, Tara M; Friedman, Eitan; Frost, Debra; Ganz, Patricia A; Garber, Judy; García, María J; Garcia-Barberan, Vanesa; Gehrig, Andrea; Gentry-Maharaj, Aleksandra; Gerdes, Anne-Marie; Giles, Graham G; Glasspool, Rosalind; Glendon, Gord; Godwin, Andrew K; Goldgar, David E; Goranova, Teodora; Gore, Martin; Greene, Mark H; Gronwald, Jacek; Gruber, Stephen; Hahnen, Eric; Haiman, Christopher A; Håkansson, Niclas; Hamann, Ute; Hansen, Thomas V O; Harrington, Patricia A; Harris, Holly R; Hauke, Jan; Hein, Alexander; Henderson, Alex; Hildebrandt, Michelle A T; Hillemanns, Peter; Hodgson, Shirley; Høgdall, Claus K; Høgdall, Estrid; Hogervorst, Frans B L; Holland, Helene; Hooning, Maartje J; Hosking, Karen; Huang, Ruea-Yea; Hulick, Peter J; Hung, Jillian; Hunter, David J; Huntsman, David G; Huzarski, Tomasz; Imyanitov, Evgeny N; Isaacs, Claudine; Iversen, Edwin S; Izatt, Louise; Izquierdo, Angel; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jernetz, Mats; Jensen, Allan; Jensen, Uffe Birk; John, Esther M; Johnatty, Sharon; Jones, Michael E; Kannisto, Päivi; Karlan, Beth Y; Karnezis, Anthony; Kast, Karin; Kennedy, Catherine J; Khusnutdinova, Elza; Kiemeney, Lambertus A; Kiiski, Johanna I; Kim, Sung-Won; Kjaer, Susanne K; Köbel, Martin; Kopperud, Reidun K; Kruse, Torben A; Kupryjanczyk, Jolanta; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Larrañaga, Nerea; Larson, Melissa C; Lazaro, Conxi; Le, Nhu D; Le Marchand, Loic; Lee, Jong Won; Lele, Shashikant B; Leminen, Arto; Leroux, Dominique; Lester, Jenny; Lesueur, Fabienne; Levine, Douglas A; Liang, Dong; Liebrich, Clemens; Lilyquist, Jenna; Lipworth, Loren; Lissowska, Jolanta; Lu, Karen H; Lubinński, Jan; Luccarini, Craig; Lundvall, Lene; Mai, Phuong L; Mendoza-Fandiño, Gustavo; Manoukian, Siranoush; Massuger, Leon F A G; May, Taymaa; Mazoyer, Sylvie; McAlpine, Jessica N; McGuire, Valerie; McLaughlin, John R; McNeish, Iain; Meijers-Heijboer, Hanne; Meindl, Alfons; Menon, Usha; Mensenkamp, Arjen R; Merritt, Melissa A; Milne, Roger L; Mitchell, Gillian; Modugno, Francesmary; Moes-Sosnowska, Joanna; Moffitt, Melissa; Montagna, Marco; Moysich, Kirsten B; Mulligan, Anna Marie; Musinsky, Jacob; Nathanson, Katherine L; Nedergaard, Lotte; Ness, Roberta B; Neuhausen, Susan L; Nevanlinna, Heli; Niederacher, Dieter; Nussbaum, Robert L; Odunsi, Kunle; Olah, Edith; Olopade, Olufunmilayo I; Olsson, Håkan; Olswold, Curtis; O'Malley, David M; Ong, Kai-Ren; Onland-Moret, N Charlotte; Orr, Nicholas; Orsulic, Sandra; Osorio, Ana; Palli, Domenico; Papi, Laura; Park-Simon, Tjoung-Won; Paul, James; Pearce, Celeste L; Pedersen, Inge Søkilde; Peeters, Petra H M; Peissel, Bernard; Peixoto, Ana; Pejovic, Tanja; Pelttari, Liisa M; Permuth, Jennifer B; Peterlongo, Paolo; Pezzani, Lidia; Pfeiler, Georg; Phillips, Kelly-Anne; Piedmonte, Marion; Pike, Malcolm C; Piskorz, Anna M; Poblete, Samantha R; Pocza, Timea; Poole, Elizabeth M; Poppe, Bruce; Porteous, Mary E; Prieur, Fabienne; Prokofyeva, Darya; Pugh, Elizabeth; Pujana, Miquel Angel; Pujol, Pascal; Radice, Paolo; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Rhiem, Kerstin; Rice, Patricia; Richardson, Andrea; Robson, Mark; Rodriguez, Gustavo C; Rodríguez-Antona, Cristina; Romm, Jane; Rookus, Matti A; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Salvesen, Helga B; Sandler, Dale P; Schoemaker, Minouk J; Senter, Leigha; Setiawan, V Wendy; Severi, Gianluca; Sharma, Priyanka; Shelford, Tameka; Siddiqui, Nadeem; Side, Lucy E; Sieh, Weiva; Singer, Christian F; Sobol, Hagay; Song, Honglin; Southey, Melissa C; Spurdle, Amanda B; Stadler, Zsofia; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sucheston-Campbell, Lara E; Sukiennicki, Grzegorz; Sutphen, Rebecca; Sutter, Christian; Swerdlow, Anthony J; Szabo, Csilla I; Szafron, Lukasz; Tan, Yen Y; Taylor, Jack A; Tea, Muy-Kheng; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Thomsen, Liv Cecilie Vestrheim; Thull, Darcy L; Tihomirova, Laima; Tinker, Anna V; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Tone, Alicia; Trabert, Britton; Travis, Ruth C; Trichopoulou, Antonia; Tung, Nadine; Tworoger, Shelley S; van Altena, Anne M; Van Den Berg, David; van der Hout, Annemarie H; van der Luijt, Rob B; Van Heetvelde, Mattias; Van Nieuwenhuysen, Els; van Rensburg, Elizabeth J; Vanderstichele, Adriaan; Varon-Mateeva, Raymonda; Vega, Ana; Edwards, Digna Velez; Vergote, Ignace; Vierkant, Robert A; Vijai, Joseph; Vratimos, Athanassios; Walker, Lisa; Walsh, Christine; Wand, Dorothea; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Webb, Penelope M; Weinberg, Clarice R; Weitzel, Jeffrey N; Wentzensen, Nicolas; Whittemore, Alice S; Wijnen, Juul T; Wilkens, Lynne R; Wolk, Alicja; Woo, Michelle; Wu, Xifeng; Wu, Anna H; Yang, Hannah; Yannoukakos, Drakoulis; Ziogas, Argyrios; Zorn, Kristin K; Narod, Steven A; Easton, Douglas F; Amos, Christopher I; Schildkraut, Joellen M; Ramus, Susan J; Ottini, Laura; Goodman, Marc T; Park, Sue K; Kelemen, Linda E; Risch, Harvey A; Thomassen, Mads; Offit, Kenneth; Simard, Jacques; Schmutzler, Rita Katharina; Hazelett, Dennis; Monteiro, Alvaro N; Couch, Fergus J; Berchuck, Andrew; Chenevix-Trench, Georgia; Goode, Ellen L; Sellers, Thomas A; Gayther, Simon A; Antoniou, Antonis C; Pharoah, Paul D P

2017-05-01

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

Clinical outcomes of fertility-sparing treatments in young patients with epithelial ovarian carcinoma.

PubMed

Hu, Jun; Zhu, Li-rong; Liang, Zhi-qing; Meng, Yuan-guang; Guo, Hong-yan; Qu, Peng-peng; Ma, Cai-ling; Xu, Cong-jian; Yuan, Bi-bo

2011-10-01

To assess the clinical outcomes of fertility-sparing treatments in young patients with epithelial ovarian carcinoma (EOC). A retrospective study of young EOC inpatients (≤40 years old) was performed during January 1994 and December 2010 in eight institutions. Data were analyzed from 94 patients treated with fertility-sparing surgery with a median follow-up time of 58.7 months. As histologic grade increased, overall survival (OS) and disease-free survival (DFS) of patients receiving fertility-sparing surgery declined. Neither staging surgery nor laparoscopy of early stage EOC with conservative surgery had a significant effect on OS or DFS. Normal menstruation recommenced after chemotherapy in 89% of the fertility-sparing group. Seventeen pregnancies among twelve patients were achieved by the end of the follow-ups. Fertility-sparing treatment for patients with EOC Stage I Grade 1 could be cautiously considered for young patients. The surgical procedure and surgical route might not significantly influence the prognosis. Standard chemotherapy is not likely to have an evident impact on ovarian function or fertility in young patients.

Identification of twelve new susceptibility loci for different histotypes of epithelial ovarian cancer

PubMed Central

Phelan, Catherine M.; Kuchenbaecker, Karoline B.; Tyrer, Jonathan P.; Kar, Siddhartha P.; Lawrenson, Kate; Winham, Stacey J.; Dennis, Joe; Pirie, Ailith; Riggan, Marjorie; Chornokur, Ganna; Earp, Madalene A.; Lyra, Paulo C.; Lee, Janet M.; Coetzee, Simon; Beesley, Jonathan; McGuffog, Lesley; Soucy, Penny; Dicks, Ed; Lee, Andrew; Barrowdale, Daniel; Lecarpentier, Julie; Leslie, Goska; Aalfs, Cora M.; Aben, Katja K.H.; Adams, Marcia; Adlard, Julian; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia; Aravantinos, Gerasimos; Arnold, Norbert; Arun, Banu K.; Arver, Brita; Azzollini, Jacopo; Balmaña, Judith; Banerjee, Susana N.; Barjhoux, Laure; Barkardottir, Rosa B.; Bean, Yukie; Beckmann, Matthias W.; Beeghly-Fadiel, Alicia; Benitez, Javier; Bermisheva, Marina; Bernardini, Marcus Q.; Birrer, Michael J.; Bjorge, Line; Black, Amanda; Blankstein, Kenneth; Blok, Marinus J.; Bodelon, Clara; Bogdanova, Natalia; Bojesen, Anders; Bonanni, Bernardo; Borg, Åke; Bradbury, Angela R.; Brenton, James D.; Brewer, Carole; Brinton, Louise; Broberg, Per; Brooks-Wilson, Angela; Bruinsma, Fiona; Brunet, Joan; Buecher, Bruno; Butzow, Ralf; Buys, Saundra S.; Caldes, Trinidad; Caligo, Maria A.; Campbell, Ian; Cannioto, Rikki; Carney, Michael E.; Cescon, Terence; Chan, Salina B.; Chang-Claude, Jenny; Chanock, Stephen; Chen, Xiao Qing; Chiew, Yoke-Eng; Chiquette, Jocelyne; Chung, Wendy K.; Claes, Kathleen B.M.; Conner, Thomas; Cook, Linda S.; Cook, Jackie; Cramer, Daniel W.; Cunningham, Julie M.; D’Aloisio, Aimee A.; Daly, Mary B.; Damiola, Francesca; Damirovna, Sakaeva Dina; Dansonka-Mieszkowska, Agnieszka; Dao, Fanny; Davidson, Rosemarie; DeFazio, Anna; Delnatte, Capucine; Doheny, Kimberly F.; Diez, Orland; Ding, Yuan Chun; Doherty, Jennifer Anne; Domchek, Susan M.; Dorfling, Cecilia M.; Dörk, Thilo; Dossus, Laure; Duran, Mercedes; Dürst, Matthias; Dworniczak, Bernd; Eccles, Diana; Edwards, Todd; Eeles, Ros; Eilber, Ursula; Ejlertsen, Bent; Ekici, Arif B.; Ellis, Steve; Elvira, Mingajeva; Eng, Kevin H.; Engel, Christoph; Evans, D. Gareth; Fasching, Peter A.; Ferguson, Sarah; Ferrer, Sandra Fert; Flanagan, James M.; Fogarty, Zachary C.; Fortner, Renée T.; Fostira, Florentia; Foulkes, William D.; Fountzilas, George; Fridley, Brooke L.; Friebel, Tara M.; Friedman, Eitan; Frost, Debra; Ganz, Patricia A.; Garber, Judy; García, María J.; Garcia-Barberan, Vanesa; Gehrig, Andrea; Gentry-Maharaj, Aleksandra; Gerdes, Anne-Marie; Giles, Graham G.; Glasspool, Rosalind; Glendon, Gord; Godwin, Andrew K.; Goldgar, David E.; Goranova, Teodora; Gore, Martin; Greene, Mark H.; Gronwald, Jacek; Gruber, Stephen; Hahnen, Eric; Haiman, Christopher A.; Håkansson, Niclas; Hamann, Ute; Hansen, Thomas V.O.; Harrington, Patricia A.; Harris, Holly R; Hauke, Jan; Hein, Alexander; Henderson, Alex; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hodgson, Shirley; Høgdall, Claus K.; Høgdall, Estrid; Hogervorst, Frans B.L.; Holland, Helene; Hooning, Maartje J.; Hosking, Karen; Huang, Ruea-Yea; Hulick, Peter J.; Hung, Jillian; Hunter, David J.; Huntsman, David G.; Huzarski, Tomasz; Imyanitov, Evgeny N.; Isaacs, Claudine; Iversen, Edwin S.; Izatt, Louise; Izquierdo, Angel; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jernetz, Mats; Jensen, Allan; Jensen, Uffe Birk; John, Esther M.; Johnatty, Sharon; Jones, Michael E.; Kannisto, Päivi; Karlan, Beth Y.; Karnezis, Anthony; Kast, Karin; Kennedy, Catherine J.; Khusnutdinova, Elza; Kiemeney, Lambertus A.; Kiiski, Johanna I.; Kim, Sung-Won; Kjaer, Susanne K.; Köbel, Martin; Kopperud, Reidun K.; Kruse, Torben A.; Kupryjanczyk, Jolanta; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Larrañaga, Nerea; Larson, Melissa C.; Lazaro, Conxi; Le, Nhu D.; Le Marchand, Loic; Lee, Jong Won; Lele, Shashikant B.; Leminen, Arto; Leroux, Dominique; Lester, Jenny; Lesueur, Fabienne; Levine, Douglas A.; Liang, Dong; Liebrich, Clemens; Lilyquist, Jenna; Lipworth, Loren; Lissowska, Jolanta; Lu, Karen H.; Lubiński, Jan; Luccarini, Craig; Lundvall, Lene; Mai, Phuong L.; Mendoza-Fandiño, Gustavo; Manoukian, Siranoush; Massuger, Leon F.A.G.; May, Taymaa; Mazoyer, Sylvie; McAlpine, Jessica N.; McGuire, Valerie; McLaughlin, John R.; McNeish, Iain; Meijers-Heijboer, Hanne; Meindl, Alfons; Menon, Usha; Mensenkamp, Arjen R.; Merritt, Melissa A.; Milne, Roger L.; Mitchell, Gillian; Modugno, Francesmary; Moes-Sosnowska, Joanna; Moffitt, Melissa; Montagna, Marco; Moysich, Kirsten B.; Mulligan, Anna Marie; Musinsky, Jacob; Nathanson, Katherine L.; Nedergaard, Lotte; Ness, Roberta B.; Neuhausen, Susan L.; Nevanlinna, Heli; Niederacher, Dieter; Nussbaum, Robert L.; Odunsi, Kunle; Olah, Edith; Olopade, Olufunmilayo I.; Olsson, Håkan; Olswold, Curtis; O’Malley, David M.; Ong, Kai-ren; Onland-Moret, N. Charlotte; Orr, Nicholas; Orsulic, Sandra; Osorio, Ana; Palli, Domenico; Papi, Laura; Park-Simon, Tjoung-Won; Paul, James; Pearce, Celeste L.; Pedersen, Inge Søkilde; Peeters, Petra H.M.; Peissel, Bernard; Peixoto, Ana; Pejovic, Tanja; Pelttari, Liisa M.; Permuth, Jennifer B.; Peterlongo, Paolo; Pezzani, Lidia; Pfeiler, Georg; Phillips, Kelly-Anne; Piedmonte, Marion; Pike, Malcolm C.; Piskorz, Anna M.; Poblete, Samantha R.; Pocza, Timea; Poole, Elizabeth M.; Poppe, Bruce; Porteous, Mary E.; Prieur, Fabienne; Prokofyeva, Darya; Pugh, Elizabeth; Pujana, Miquel Angel; Pujol, Pascal; Radice, Paolo; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Rhiem, Kerstin; Rice, Patricia; Richardson, Andrea; Robson, Mark; Rodriguez, Gustavo C.; Rodríguez-Antona, Cristina; Romm, Jane; Rookus, Matti A.; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Salvesen, Helga B.; Sandler, Dale P.; Schoemaker, Minouk J.; Senter, Leigha; Setiawan, V. Wendy; Severi, Gianluca; Sharma, Priyanka; Shelford, Tameka; Siddiqui, Nadeem; Side, Lucy E.; Sieh, Weiva; Singer, Christian F.; Sobol, Hagay; Song, Honglin; Southey, Melissa C.; Spurdle, Amanda B.; Stadler, Zsofia; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sucheston-Campbell, Lara E.; Sukiennicki, Grzegorz; Sutphen, Rebecca; Sutter, Christian; Swerdlow, Anthony J.; Szabo, Csilla I.; Szafron, Lukasz; Tan, Yen Y.; Taylor, Jack A.; Tea, Muy-Kheng; Teixeira, Manuel R.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Thomsen, Liv Cecilie Vestrheim; Thull, Darcy L.; Tihomirova, Laima; Tinker, Anna V.; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Tone, Alicia; Trabert, Britton; Travis, Ruth C.; Trichopoulou, Antonia; Tung, Nadine; Tworoger, Shelley S.; van Altena, Anne M.; Van Den Berg, David; van der Hout, Annemarie H.; van der Luijt, Rob B.; Van Heetvelde, Mattias; Van Nieuwenhuysen, Els; van Rensburg, Elizabeth J.; Vanderstichele, Adriaan; Varon-Mateeva, Raymonda; Ana, Vega; Edwards, Digna Velez; Vergote, Ignace; Vierkant, Robert A.; Vijai, Joseph; Vratimos, Athanassios; Walker, Lisa; Walsh, Christine; Wand, Dorothea; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Webb, Penelope M.; Weinberg, Clarice R.; Weitzel, Jeffrey N.; Wentzensen, Nicolas; Whittemore, Alice S.; Wijnen, Juul T.; Wilkens, Lynne R.; Wolk, Alicja; Woo, Michelle; Wu, Xifeng; Wu, Anna H.; Yang, Hannah; Yannoukakos, Drakoulis; Ziogas, Argyrios; Zorn, Kristin K.; Narod, Steven A.; Easton, Douglas F.; Amos, Christopher I.; Schildkraut, Joellen M.; Ramus, Susan J.; Ottini, Laura; Goodman, Marc T.; Park, Sue K.; Kelemen, Linda E.; Risch, Harvey A.; Thomassen, Mads; Offit, Kenneth; Simard, Jacques; Schmutzler, Rita Katharina; Hazelett, Dennis; Monteiro, Alvaro N.; Couch, Fergus J.; Berchuck, Andrew; Chenevix-Trench, Georgia; Goode, Ellen L.; Sellers, Thomas A.; Gayther, Simon A.; Antoniou, Antonis C.; Pharoah, Paul D.P.

2017-01-01

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3, 9q31.1) and one for endometrioid EOC (5q12.3). We then meta-analysed the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified an additional three loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a novel susceptibility gene for low grade/borderline serous EOC. PMID:28346442

Development of a Mouse Model of Menopausal Ovarian Cancer

PubMed Central

Smith, Elizabeth R.; Wang, Ying; Xu, Xiang-Xi

2014-01-01

Despite significant understanding of the genetic mutations involved in ovarian epithelial cancer and advances in genomic approaches for expression and mutation profiling of tumor tissues, several key questions in ovarian cancer biology remain enigmatic: the mechanism for the well-established impact of reproductive factors on ovarian cancer risk remains obscure; cell of origin of ovarian cancer continue to be debated; and the precursor lesion, sequence, or events in progression remain to be defined. Suitable mouse models should complement the analysis of human tumor tissues and may provide clues to these questions currently perplexing ovarian cancer biology. A potentially useful model is the germ cell-deficient Wv (white spotting variant) mutant mouse line, which may be used to study the impact of menopausal physiology on the increased risk of ovarian cancer. The Wv mice harbor a point mutation in c-Kit that reduces the receptor tyrosine kinase activity to about 1–5% (it is not a null mutation). Homozygous Wv mutant females have a reduced ovarian germ cell reservoir at birth and the follicles are rapidly depleted upon reaching reproductive maturity, but other biological phenotypes are minimal and the mice have a normal life span. The loss of ovarian function precipitates changes in hormonal and metabolic activity that model features of menopause in humans. As a consequence of follicle depletion, the Wv ovaries develop ovarian tubular adenomas, a benign epithelial tumor corresponding to surface epithelial invaginations and papillomatosis that mark human ovarian aging. Ongoing work will test the possibility of converting the benign epithelial tubular adenomas into neoplastic tumors by addition of an oncogenic mutation, such as of Tp53, to model the genotype and biology of serous ovarian cancer. Model based on the Wv mice may have the potential to gain biological and etiological insights into ovarian cancer development and prevention. PMID:24616881

Risk factors for ovarian cancers with and without microsatellite instability.

PubMed

Segev, Yakir; Pal, Tuya; Rosen, Barry; McLaughlin, John R; Sellers, Thomas A; Risch, Harvey A; Zhang, Shiyu; Ping, Sun; Narod, Steven A; Schildkraut, Joellen

2013-07-01

The objective of this study was to evaluate the association between microsatellite instability (MSI) status and (1) ovarian cancer risk factors and (2) the distribution of the specific histologic subtypes in a population-based sample of epithelial ovarian cancers. Participants were drawn from 3 population-based studies of primary epithelial ovarian cancer. Tumor DNA was analyzed using 5 standardized microsatellite markers to assess MSI status. Patients were divided into 3 groups (MSI-high, MSI-low, and MSI-stable) according to National Cancer Institute criteria. We compared the prevalence of specific known risk and protective factors among the 3 subgroups, including body mass index, smoking history, parity, BRCA1 and BRCA2 mutation status, past oral contraceptive use, and tubal ligation. Similarly, we compared the distribution of the histologic subtypes among the 3 subgroups. A total of 917 ovarian cancer patients were included. One hundred twenty-seven (13.8%) cancers were MSI-high. Subgroup analyses according to smoking, body mass index, parity, past oral contraceptive use, and past tubal ligation did not reveal any statistically significant differences among the groups. Among the 29 patients with BRCA1 mutations, 20.7% had MSI-high cancers compared with 5.9% among 17 BRCA2-mutation patients. The proportions of different ovarian cancer histologic findings among the various MSI subgroups were similar. The prevalence of risk and protective factors among ovarian cancer patients is similar for cancers with and without MSI. The distributions of MSI do not differ significantly among ovarian cancers with different histologic findings. Ovarian cancer patients with BRCA1 mutations had a 21% rate of MSI-high tumors, compared with 6% among patients with BRCA2 mutations, but this difference was not statistically significant.

Biological Basis for Chemoprevention of Ovarian Cancer

DTIC Science & Technology

2005-10-01

epithelial cells treated with the progestin levonorgestrel . Progestin mediated apoptotic effects may be a major mechanism underlying the protection...epithelial ovarian cancer. Initial studies to test the progestin levonorgestrel in an avian model of ovarian cancer have been undertaken and...is receiving 0.05 mg/day Levonorgestrel equivalent (same as first chicken trial demonstrating a chemopreventive effect), and the high progestin dose

Oral Contraceptive Use and Reproductive Characteristics Affect Survival in Patients With Epithelial Ovarian Cancer

PubMed Central

Kolomeyevskaya, Nonna V.; Szender, J. Brian; Zirpoli, Gary; Minlikeeva, Albina; Friel, Grace; Cannioto, Rikki A.; Brightwell, Rachel M.; Grzankowski, Kassondra S.; Moysich, Kirsten B.

2015-01-01

Objectives Prognostic risk factors influencing survival in patients with epithelial ovarian cancer (EOC) include tumor stage, grade, histologic subtype, debulking, and platinum status. Little is known about the impact of hormonal milieu and reproductive factors before cancer diagnosis on clinical outcome. We sought to evaluate whether oral contraceptive (OC) use carries any prognostic significance on overall survival (OS) in patients with EOC. Methods Newly diagnosed patients with EOC, fallopian tube, and primary peritoneal cancers between 1982 and 1998 were prospectively evaluated with a comprehensive epidemiologic questionnaire. A retrospective chart review was performed to abstract clinicopathologic data, including OS. A Kaplan-Meier analysis was performed to compare survival across various exposures. A Cox regression model was used to compute adjusted hazards ratios (aHRs) and 95% confidence intervals (CIs). Results We identified 387 newly diagnosed cancers with evaluable information in this cohort. Decreased risk of death was observed in women who reported prior use of OC (aHR, 0.79; 95% CI, 0.58–1.09), previous pregnancy (aHR, 0.77; 95% CI, 0.57–1.04), or a live birth (aHR, 0.81; 95% CI, 0.60–1.08) after adjusting for age at diagnosis, stage, and histologic subtype. Oral contraceptive use was associated with a crude reduced risk of death (HR, 0.55; 95% CI, 0.42–0.72), with reported median OS of 81 months in OC users versus 46 months in nonusers. Patients who reported a single live birth experienced the largest potential survival advantage (aHR, 0.61; 95% CI, 0.39–0.94). Oral contraceptive use and prior pregnancy were associated with improved survival across all strata. Conclusions Oral contraceptive use may have lasting effects on epithelial ovarian tumor characteristics conferring favorable prognosis. Putative mechanisms that affect tumor biology include complex interactions between ovarian cells, host immune cells, and hormonal microenvironment

Association of a PARK2 Germline Variant and Epithelial Ovarian Cancer in a Southern Brazilian Population.

PubMed

Klimczak, Phamela Ferreira; Ventury, Danielle Hornung; Faucz, Fabio Rueda; Settas, Nikolaos; Machado de Souza, Cleber; Sotomaior, Vanessa Santos

2016-01-01

Ovarian cancer (OC) is the eighth most common cancer among women in Brazil and seventh in the world population. OC has a high mortality rate and is difficult to diagnose. Currently, OC detection most often occurs at an advanced stage of the disease due to its silent progression, which contributes to the high mortality rate. Available genetic markers are not considered specifically enough for an initial and definite diagnosis. The association with new genes involved with OC can provide a better understanding of this pathology as well as contribute to the development of a marker scenario, providing an improvement in the treatment and survival of patients. The aim of this study was to examine the potential association between the PARK2 gene and epithelial ovarian cancer (EOC). Accordingly, we conducted a study for which 25 patients and 87 controls were recruited. Linkage disequilibrium analysis showed that the four studied tag SNPs (rs2803073, rs6930532, rs1040079, and rs2276201) were independent. Our results using the multivariate analysis between the additive and dominant model demonstrated that tag SNP rs2803073 of PARK2 is associated with susceptibility to EOC (p = 0.018, OR = 0.42). These findings suggest that hereditary variation in the PARK2 gene could influence EOC development mechanisms. © 2016 S. Karger AG, Basel.

[Clinical validation of multiple biomarkers suspension array technology for ovarian cancer].

PubMed

Zhao, B B; Yang, Z J; Wang, Q; Pan, Z M; Zhang, W; Li, L

2017-01-25

Objective: To investigates the diagnostic value of combined detection serum CCL18, CXCL1 antigen, C1D, TM4SF1, FXR1, TIZ IgG autoantibody by suspension array for ovarian cancer. Methods: Suspension array was used to detect CCL18, CXCL1 antigen, C1D, TM4SF1, FXR1, TIZ IgG autoantibody in 120 cases of healthy women, 204 cases of patients with benign pelvic tumors, 119 cases of pelvic malignant tumor patients, and 40 cases with breast cancer, lung cancer oroliver cancer, respectively. Constructed diagnosis model of combined detection six biomarkers for diagnosis of ovarian malignant tumor. Constructed diagnosis model of combined detection autoantibodies to diagnose epithelial ovarian cancer. Analysed the value of detecting six biomarkers for diagnosis of ovarian malignant tumor and detecting autoantibodies for diagnosis of epithelial ovarian cancer. Analysed diagnostic value of detecting six biomarkers to diagnose stage Ⅰ and Ⅱepithelial ovarian cancer. Compared diagnostic value of detecting six biomarkers in diagnosis of tissue types and pathologic grading with that of CA(125). Results: Model of combined detecting six biomarkers to diagnose ovarian malignant tumor was logit ( P ) =-11.151+0.008×C1D+0.011×TM4SF1+0.011×TIZ-0.008×FXR1+0.021×CCL18+0.200×CXCL1. Model of combined detection autoantibodies to diagnose epithelial ovarian cancer was logit ( P ) =-5.137+0.013×C1D+0.014×TM4SF1+0.060×TIZ-0.060×FXR1. Sensitivity and specificity of detecting six biomarker to diagnose ovarian malignant tumor was 90.6% and 98.7%. Sensitivity and specificity of detecting autoantibodies to diagnose epithelial ovarian cancer was 75.8% and 96.7%. Combined detection for six biomarkers to diagnose serous and mucinous ovarian cancer was statistically no better than those of CA(125) ( P =0.196 and P =0.602, respectively); there was significantly difference in diagnosis of ovarian cancer ( P =0.023), and there was no significantly difference in diagnosis of different

Germline Mutations of BRCA1 and BRCA2 in Korean Ovarian Cancer Patients: Finding Founder Mutations.

PubMed

Choi, Min Chul; Heo, Jin-Hyung; Jang, Ja-Hyun; Jung, Sang Geun; Park, Hyun; Joo, Won Duk; Lee, Chan; Lee, Je Ho; Lee, Jun Mo; Hwang, Yoon Young; Kim, Seung Jo

2015-10-01

To investigate and analyze the BRCA mutations in Korean ovarian cancer patients with or without family history and to find founder mutations in this group. One hundred two patients who underwent a staging operation for pathologically proven epithelial cancer between January 2013 and December 2014 were enrolled. Thirty-two patients declined to analyze BRCA1/2 gene alterations after genetic counseling and pedigree analysis. Lymphocyte specimens from peripheral blood were assessed for BRCA1/2 by direct sequencing. BRCA genetic test results of 70 patients were available. Eighteen BRCA1/2 mutations and 17 unclassified variations (UVs) were found. Five of the BRCA1/2 mutations and 4 of the UVs were not reported in the Breast Cancer Information Core database. One BRCA2 UV (8665_8667delGGA) was strongly suspicious to be a deleterious mutation. BRCA1/2 mutations were identified in 11 (61.1%) of 18 patients with a family history and in 7 (13.5%) of 52 patients without a family history.Candidates for founder mutations in Korean ovarian cancer patients were assessed among 39 BRCA1/2 mutations from the present study and from literature reviews. The analysis showed that 1041_1043delAGCinsT (n = 4; 10.2%) and 3746insA (n = 4; 10.2%) were possible BRCA1 founder mutations. Only one of the BRCA2 mutations (5804_5807delTTAA) was repeated twice (n = 2; 5.1%). The prevalence of BRCA1/2 mutations in Korean ovarian cancer patients irrespective of the family history was significantly higher than previously reported. Possible founder mutations in Korean ovarian cancer patients were identified.

Optical Biomarkers of Serous and Mucinous Human Ovarian Tumor Assessed with Nonlinear Optics Microscopies

PubMed Central

Adur, Javier; Pelegati, Vitor B.; de Thomaz, Andre A.; Baratti, Mariana O.; Almeida, Diogo B.; Andrade, L. A. L. A.; Bottcher-Luiz, Fátima; Carvalho, Hernandes F.; Cesar, Carlos L.

2012-01-01

Background Nonlinear optical (NLO) microscopy techniques have potential to improve the early detection of epithelial ovarian cancer. In this study we showed that multimodal NLO microscopies, including two-photon excitation fluorescence (TPEF), second-harmonic generation (SHG), third-harmonic generation (THG) and fluorescence lifetime imaging microscopy (FLIM) can detect morphological and metabolic changes associated with ovarian cancer progression. Methodology/Principal Findings We obtained strong TPEF + SHG + THG signals from fixed samples stained with Hematoxylin & Eosin (H&E) and robust FLIM signal from fixed unstained samples. Particularly, we imaged 34 ovarian biopsies from different patients (median age, 49 years) including 5 normal ovarian tissue, 18 serous tumors and 11 mucinous tumors with the multimodal NLO platform developed in our laboratory. We have been able to distinguish adenomas, borderline, and adenocarcinomas specimens. Using a complete set of scoring methods we found significant differences in the content, distribution and organization of collagen fibrils in the stroma as well as in the morphology and fluorescence lifetime from epithelial ovarian cells. Conclusions/Significance NLO microscopes provide complementary information about tissue microstructure, showing distinctive patterns for serous and mucinous ovarian tumors. The results provide a basis to interpret future NLO images of ovarian tissue and lay the foundation for future in vivo optical evaluation of premature ovarian lesions. PMID:23056557

Cytogenetic and molecular genetic characterization of immortalized human ovarian surface epithelial cell lines: consistent loss of chromosome 13 and amplification of chromosome 20.

PubMed

Jin, Yuesheng; Zhang, Hao; Tsao, Sai Wah; Jin, Charlotte; Lv, Mei; Strömbeck, Bodil; Wiegant, Joop; Wan, Thomas Shek Kong; Yuen, Po Wing; Kwong, Yok-Lam

2004-01-01

This study aimed at identifying the genetic events involved in immortalization of ovarian epithelial cells, which might be important steps in ovarian carcinogenesis. The genetic profiles of five human ovarian surface epithelial (HOSE) cell lines immortalized by retroviral transfection of the human papillomavirus (HPV) E6/E7 genes were thoroughly characterized by chromosome banding and fluorescence in situ hybridization (FISH), at various passages pre- and post-crisis. In pre-crisis, most cells had simple, non-clonal karyotypic changes. Telomere association was the commonest aberration, suggesting that tolermase dysfunction might be an important genetic event leading to cellular crisis. After immortalization post-crisis, however, the karyotypic patterns were non-random. Loss of genetic materials was a characteristic feature. The commonest numerical aberrations were -13, -14, -16, -17, -18, and +5. Among them, loss of chromosome 13 was common change observed in all lines. The only recurrent structural aberration was homogeneously staining regions (hsr) observed in three lines. FISH and combined binary ratio labeling (COBRA)-FISH showed in two cases that the hsrs were derived from chromosome 20. Clonal evolution was observed in four of the lines. In one line, hsr was the only change shared by all subclones, suggesting that it might be a primary event in cell immortalization. The results of the present study suggested that loss of chromosome 13 and the amplification of chromosome 20 might be early genetic events involved in ovarian cell immortalization, and might be useful targets for the study of genomic aberrations in ovarian carcinogenesis.

Altered expression pattern of circular RNAs in primary and metastatic sites of epithelial ovarian carcinoma.

PubMed

Ahmed, Ikhlak; Karedath, Thasni; Andrews, Simeon S; Al-Azwani, Iman K; Mohamoud, Yasmin Ali; Querleu, Denis; Rafii, Arash; Malek, Joel A

2016-06-14

Recently, a class of endogenous species of RNA called circular RNA (circRNA) has been shown to regulate gene expression in mammals and their role in cellular function is just beginning to be understood. To investigate the role of circRNAs in ovarian cancer, we performed paired-end RNA sequencing of primary sites, peritoneal and lymph node metastases from three patients with stage IIIC ovarian cancer. We developed an in-house computational pipeline to identify and characterize the circRNA expression from paired-end RNA-Seq libraries. This pipeline revealed thousands of circular isoforms in Epithelial Ovarian Carcinoma (EOC). These circRNAs are enriched for potentially effective miRNA seed matches. A significantly larger number of circRNAs are differentially expressed between tumor sites than mRNAs. Circular and linear expression exhibits an inverse trend for many cancer related pathways and signaling pathways like NFkB, PI3k/AKT and TGF-β typically activated for mRNA in metastases are inhibited for circRNA expression. Further, circRNAs show a more robust expression pattern across patients than mRNA forms indicating their suitability as biomarkers in highly heterogeneous cancer transcriptomes. The consistency of circular RNA expression may offer new candidates for cancer treatment and prognosis.

Altered expression pattern of circular RNAs in primary and metastatic sites of epithelial ovarian carcinoma

PubMed Central

Ahmed, Ikhlak; Karedath, Thasni; Andrews, Simeon S.; Al, Iman K.; Mohamoud, Yasmin Ali; Querleu, Denis; Rafii, Arash; Malek, Joel A.

2016-01-01

Recently, a class of endogenous species of RNA called circular RNA (circRNA) has been shown to regulate gene expression in mammals and their role in cellular function is just beginning to be understood. To investigate the role of circRNAs in ovarian cancer, we performed paired-end RNA sequencing of primary sites, peritoneal and lymph node metastases from three patients with stage IIIC ovarian cancer. We developed an in-house computational pipeline to identify and characterize the circRNA expression from paired-end RNA-Seq libraries. This pipeline revealed thousands of circular isoforms in Epithelial Ovarian Carcinoma (EOC). These circRNAs are enriched for potentially effective miRNA seed matches. A significantly larger number of circRNAs are differentially expressed between tumor sites than mRNAs. Circular and linear expression exhibits an inverse trend for many cancer related pathways and signaling pathways like NFkB, PI3k/AKT and TGF-β typically activated for mRNA in metastases are inhibited for circRNA expression. Further, circRNAs show a more robust expression pattern across patients than mRNA forms indicating their suitability as biomarkers in highly heterogeneous cancer transcriptomes. The consistency of circular RNA expression may offer new candidates for cancer treatment and prognosis. PMID:27119352

High prevalence of atypical hyperplasia in the endometrium of patients with epithelial ovarian cancer.

PubMed

Mingels, Marjanka J J M; Masadah, Rina; Geels, Yvette P; Otte-Höller, Irene; de Kievit, Ineke M; van der Laak, Jeroen A W M; van Ham, Maaike A P C; Bulten, Johan; Massuger, Leon F A G

2014-08-01

The aim of the present study is to determine the prevalence of endometrial premalignancies in women diagnosed with epithelial ovarian cancer (EOC). Endometrial and ovarian specimens of 186 patients with EOC were retrospectively selected using the nationwide pathology network and registry, and sections were comprehensively reviewed: 136 (73%) serous, 19 (10%) endometrioid, 15 (8%) mucinous, seven (4%) clear cell, and nine (5%) undifferentiated. Immunohistochemical phenotypes were compared for patients with serous EOC with concurrent endometrial pathology. In 31%, endometrial (pre)malignancy was found: carcinoma in 3%, endometrial intraepithelial carcinoma (EIC) in 4%, and atypical hyperplasia in 24%. Atypical hyperplasia was found in 47% of endometrioid EOCs but in 7% to 33% of other subtypes. Body mass index was higher concurrent to atypical hyperplasia (P=.001). Serous EOC and EIC immunophenotypes were comparable, whereas atypical hyperplasia was expressed differently. Apart from synchronous endometrial carcinoma, endometrial premalignancies should be taken into account when determining optimal treatment for women diagnosed with EOC. Copyright© by the American Society for Clinical Pathology.

Chronic Recreational Physical Inactivity and Epithelial Ovarian Cancer Risk: Evidence from the Ovarian Cancer Association Consortium

PubMed Central

Cannioto, Rikki; LaMonte, Michael J.; Risch, Harvey A.; Hong, Chi-Chen; Sucheston-Campbell, Lara E.; Eng, Kevin H.; Szender, J. Brian; Chang-Claude, Jenny; Schmalfeldt, Barbara; Klapdor, Ruediger; Gower, Emily; Minlikeeva, Albina N.; Zirpoli, Gary; Bandera, Elisa V.; Berchuck, Andrew; Cramer, Daniel; Doherty, Jennifer A.; Edwards, Robert P.; Fridley, Brooke L.; Goode, Ellen L.; Goodman, Marc T.; Hogdall, Estrid; Hosono, Satoyo; Jensen, Allan; Jordan, Susan; Kjaer, Susanne K.; Matsuo, Keitaro; Ness, Roberta B.; Olsen, Catherine M.; Olson, Sara H.; Pearce, Celeste Leigh; Pike, Malcolm C.; Rossing, Mary Anne; Szamreta, Elizabeth A.; Thompson, Pamela J.; Tseng, Chiu-Chen; Vierkant, Robert A.; Webb, Penelope M.; Wentzensen, Nicolas; Wicklund, Kristine G.; Winham, Stacey J.; Wu, Anna H.; Modugno, Francesmary; Schildkraut, Joellen M.; Terry, Kathryn L.; Kelemen, Linda E.; Moysich, Kirsten B.

2016-01-01

Background Despite a large body of literature evaluating the association between recreational physical activity and epithelial ovarian cancer (EOC) risk, the extant evidence is inconclusive and little is known about the independent association between recreational physical inactivity and EOC risk. We conducted a pooled analysis of nine studies from the Ovarian Cancer Association Consortium (OCAC) to investigate the association between chronic recreational physical inactivity and EOC risk. Methods In accordance with the 2008 Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. Multivariable logistic regression was utilized to estimate the odds ratios (OR) and 95% confidence intervals (CI) for the association between inactivity and EOC risk overall and by subgroups based upon histotype, menopausal status, race and body mass index (BMI). Results The current analysis included data from 8,309 EOC patients and 12,612 controls. We observed a significant positive association between inactivity and EOC risk (OR=1.34, 95% CI: 1.14-1.57) and similar associations were observed for each histotype. Conclusions In this large pooled analysis examining the association between recreational physical inactivity and EOC risk, we observed consistent evidence of an association between chronic inactivity and all EOC histotypes. Impact These data add to the growing body of evidence suggesting that inactivity is an independent risk factor for cancer. If the apparent association between inactivity and EOC risk is substantiated, additional work via targeted interventions should be pursued to characterize the dose of activity required to mitigate the risk of this highly fatal disease. PMID:27197285

Epigenetic alteration of p16 and retinoic acid receptor beta genes in the development of epithelial ovarian carcinoma.

PubMed

Bhagat, Rahul; Kumar, Sandeep Sriram; Vaderhobli, Shilpa; Premalata, Chennagiri S; Pallavi, Venkateshaiah Reddihalli; Ramesh, Gawari; Krishnamoorthy, Lakshmi

2014-09-01

Silencing of tumor suppressor and tumor-related genes by promoter hypermethylation is one of the major events in ovarian carcinogenesis. In this study, we analyzed aberrant promoter methylation of p16 and RAR-β genes in 134 epithelial ovarian carcinomas (EOCs), 23 low malignant potential (LMP) tumors, 26 benign cystadenomas, and 15 normal ovarian tissues. Methylation was investigated by methylation-specific PCR (MSP), and the results were confirmed by bisulfite DNA sequencing. Relative gene expression of p16 and RAR-β was done using quantitative reverse transcriptase PCR (qRT-PCR) on 51 EOC cases, 9 LMP tumors, and 7 benign cystadenomas with 5 normal ovarian tissues. Aberrant methylation for p16 and RAR-β was present in 43 % (58/134) and 31 % (41/134) in carcinoma cases, 22 % (05/23) and 52 % (12/23) in LMP tumors, and 42 % (11/26) and 69 % (18/26) in benign cystadenomas. No methylation was observed in any of the normal ovarian tissues. The mRNA expression level of p16 and RAR-β was significantly downregulated in EOC and LMP tumors than the corresponding normal tissues whereas the expression level was normal in benign cystadenomas for p16 and slightly reduced for RAR-β. A significant correlation of p16 promoter methylation was observed with reduced gene expression in EOC. For RAR-β, no significant correlation was observed between promoter methylation and gene expression. Our results suggest that epigenetic alterations of p16 and RAR-β have an important role in ovarian carcinogenesis and that mechanism along with methylation plays a significant role in downregulation of RAR-β gene in ovarian cancer.

The role of KRAS rs61764370 in invasive epithelial ovarian cancer: implications for clinical testing

PubMed Central

Pharoah, Paul D. P.; Palmieri, Rachel T.; Ramus, Susan J.; Gayther, Simon A.; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia; Antoniou, Antonis C.; Beattie, Mary S.; Beckmann, Matthias W.; Birrer, Michael J.; Bogdanova, Natalia; Bolton, Kelly L.; Brewster, Wendy; Brooks-Wilson, Angela; Brown, Robert; Butzow, Ralf; Caldes, Trinidad; Caligo, Maria Adelaide; Campbell, Ian; Chang-Claude, Jenny; Chen, Y. Ann; Chenevix-Trench, Georgia; Cook, Linda S.; Couch, Fergus J.; Cramer, Daniel W.; Cunningham, Julie M.; Despierre, Evelyn; Doherty, Jennifer A.; Dörk, Thilo; Dürst, Matthias; Eccles, Diana M.; Ekici, Arif B.; Fasching, Peter A.; de Fazio, Anna; Fenstermacher, David A.; Flanagan, James M.; Fridley, Brooke L.; Friedman, Eitan; Gao, Bo; Gentry-Maharaj, Aleksandra; Godwin, Andrew K.; Goode, Ellen L.; Goodman, Marc T.; Gross, Jenny; Hansen, Thomas V. O.; Harnett, Paul; Heikkinen, Tuomas; Hein, Rebecca; Høgdall, Claus; Høgdall, Estrid; Iversen, Edwin S.; Jakubowska, Anna; Johnatty, Sharon E.; Karlan, Beth Y.; Kauff, Noah D.; Kaye, Stanley B.; Kelemen, Linda E.; Kiemeney, Lambertus A.; Kjaer, Susanne Krüger; Lambrechts, Diether; LaPolla, James P.; Lázaro, Conxi; Le, Nhu D.; Leminen, Arto; Leunen, Karin; Levine, Douglas A.; Lu, Yi; Lundvall, Lene; Macgregor, Stuart; Marees, Tamara; Massuger, Leon F.; McLaughlin, John R.; Menon, Usha; Montagna, Marco; Moysich, Kirsten B.; Narod, Steven A.; Nathanson, Katherine L.; Nedergaard, Lotte; Ness, Roberta B.; Nevanlinna, Heli; Nickels, Stefan; Osorio, Ana; Paul, Jim; Pearce, Celeste Leigh; Phelan, Catherine M.; Pike, Malcolm C.; Radice, Paolo; Rossing, Mary Anne; Schildkraut, Joellen M.; Sellers, Thomas A.; Singer, Christian F.; Song, Honglin; Stram, Daniel O.; Sutphen, Rebecca; Terry, Kathryn L.; Tsai, Ya-Yu; van Altena, Anne M.; Vergote, Ignace; Vierkant, Robert A.; Vitonis, Allison F.; Walsh, Christine; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Wu, Anna H.; Ziogas, Argyrios; Berchuck, Andrew; Risch, Harvey A.

2011-01-01

Purpose An assay for the single nucleotide polymorphism (SNP) rs61764370 has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3′UTR miRNA binding site of the KRAS oncogene, and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published paper, analyzing fewer than 1,000 subjects in total, has examined this association. Experimental Design Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from nineteen studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival data and eighteen studies with all-cause mortality data. Results No evidence of association was observed between genotype and risk of unselected EOC (odds ratio (OR)=1.02, 95% confidence interval (CI)=0.95-1.10), serous EOC (OR=1.08, 95%CI=0.98-1.18), familial EOC (OR=1.09, 95%CI=0.78-1.54), or among women carrying deleterious mutations in BRCA1 (OR=1.09, 95%CI=0.88-1.36). There was little evidence for association with survival time among unselected cases (hazard ratio (HR)=1.10, 95%CI=0.99-1.22), among serous cases (HR=1.12, 95%CI=0.99-1.28), or with progression-free survival in 540 cases treated with carboplatin and paclitaxel (HR=1.18, 95%CI=0.93-1.52). Conclusions These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction therefore appears unwarranted. PMID:21385923

Biological Basis for Chemoprevention of Ovarian Cancer

DTIC Science & Technology

2000-10-01

potent apoptotic effect on ovarian epithelial cells, the use of levonorgestrel in chemoprevention of ovarian cancer is being explored in chickens and women...A chemoprevention trial is ongoing in chickens and we will begin a trial to determine whether levonorgestrel induces apoptosis in the ovarian epithelium of women undergoing oophorectomy.

MiR-212 exerts suppressive effect on SKOV3 ovarian cancer cells through targeting HBEGF.

PubMed

Wei, Li-Qiang; Liang, Hui-Tao; Qin, Dong-Chun; Jin, Hui-Fang; Zhao, Yong; She, Ming-Cong

2014-12-01

MicroRNAs (miRNAs) play critical roles in the development and progression of ovarian cancer. We found that miR-212 was significantly downregulated in serum and tissues from epithelial ovarian cancer (EOC) patients. Overexpression of miR-212 in ovarian cancer cells inhibited cell proliferation, migration, and invasion. Luciferase reporter assay confirmed HBEGF as a direct target of miR-212. Overexpression of miR-212 decreased HBEGF expression at both the protein and messenger RNA (mRNA) levels. Knockdown of HBEGF expression in SKOV3 cell line significantly inhibited cell growth, migration, and invasion. HBEGF mRNA level was upregulated in EOC tissues and inversely correlated with miR-212 expression in tissues. Upregulation of HBEGF could attenuate the effect induced by miR-212. These findings indicate that miR-212 displays a tumor-suppressive effect in human ovarian cancer. And miR-212 suppresses cell proliferation, migration, and invasion by targeting the HBEGF transcript, highlighting the therapeutic potential of miR-212 and HBEGF in epithelial ovarian cancer treatment.

Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Stage III Ovarian Cancer

ClinicalTrials.gov

2017-08-08

Malignant Ovarian Mixed Epithelial Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Primary Peritoneal Carcinoma; Stage III Ovarian Cancer; Undifferentiated Ovarian Carcinoma

Cell membrane-anchored MUC4 promotes tumorigenicity in epithelial carcinomas

PubMed Central

Xia, Pengpeng; Choi, Agnes Hakyung; Deng, Zengping; Yang, Yuqian; Zhao, Jing; Wang, Yiting; Hardwidge, Philip R.; Zhu, Guoqiang

2017-01-01

The cell surface membrane-bound mucin protein MUC4 promotes tumorigenicity, aggressive behavior, and poor outcomes in various types of epithelial carcinomas, including pancreatic, breast, colon, ovarian, and prostate cancer. This review summarizes the theories and findings regarding MUC4 function, and its role in epithelial carcinogenesis. Based on these insights, we developed an outline of the processes and mechanisms by which MUC4 critically supports the propagation and survival of cancer cells in various epithelial organs. MUC4 may therefore be a useful prognostic and diagnostic tool that improves our ability to eradicate various forms of cancer. PMID:27829225

Cell membrane-anchored MUC4 promotes tumorigenicity in epithelial carcinomas.

PubMed

Xia, Pengpeng; Choi, Agnes Hakyung; Deng, Zengping; Yang, Yuqian; Zhao, Jing; Wang, Yiting; Hardwidge, Philip R; Zhu, Guoqiang

2017-02-21

The cell surface membrane-bound mucin protein MUC4 promotes tumorigenicity, aggressive behavior, and poor outcomes in various types of epithelial carcinomas, including pancreatic, breast, colon, ovarian, and prostate cancer. This review summarizes the theories and findings regarding MUC4 function, and its role in epithelial carcinogenesis. Based on these insights, we developed an outline of the processes and mechanisms by which MUC4 critically supports the propagation and survival of cancer cells in various epithelial organs. MUC4 may therefore be a useful prognostic and diagnostic tool that improves our ability to eradicate various forms of cancer.

18β-glycyrrhetinic acid potentiates Hsp90 inhibition-induced apoptosis in human epithelial ovarian carcinoma cells via activation of death receptor and mitochondrial pathway.

PubMed

Yang, Jae Chon; Myung, Soon Chul; Kim, Wonyong; Lee, Chung Soo

2012-11-01

The Hsp90 inhibition has been shown to induce apoptosis in various cancer cells. The licorice compounds may enhance the anti-cancer drug effect. However, effect of the licorice compounds on the Hsp90 inhibition-induced apoptosis in ovarian cancer cells has not been studied. To assess the ability of 18β-glycyrrhetinic acid to promote apoptosis, we examined whether 18β-glycyrrhetinic acid potentiated the Hsp90 inhibitor-induced apoptosis in the human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3. Radicicol and geldanamycin induced a decrease in Bid, Bcl-2, Bcl-xL and survivin protein levels, an increase in Bax levels, the mitochondrial transmembrane potential loss, cytochrome c release, activation of caspases (-8, -9, and -3), cleavage of PARP-1, and an increase in the tumor suppressor p53 levels. 18β-Glycyrrhetinic acid enhanced Hsp90 inhibitor-induced apoptosis-related protein activation, nuclear damage, and cell death. The results suggest that 18β-glycyrrhetinic acid may potentiate the Hsp90 inhibition-induced apoptosis in ovarian carcinoma cell lines via the activation of the caspase-8- and Bid-dependent pathways and the mitochondria-mediated cell death pathway, leading to activation of caspases. Combination of Hsp90 inhibitors and 18β-glycyrrhetinic acid may confer a benefit in the treatment of epithelial ovarian adenocarcinoma.

Stages of Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer

MedlinePlus

... of Ovarian Germ Cell Tumors Ovarian Low Malignant Potential Tumors Symptoms, Tests, Prognosis, & Stages Treatment of Ovarian Low Malignant Potential Tumors Prevention of Ovarian, Fallopian Tube, & Primary Peritoneal ...

Diagnosis of neonatal ovarian torsion: Emphasis on prenatal and postnatal sonographic findings.

PubMed

Kim, Hyun Su; Yoo, So-Young; Cha, Min Jae; Kim, Ji Hye; Jeon, Tae Yeon; Kim, Wee Kyoung

2016-06-01

Our aim was to retrospectively review the imaging findings of patients with neonatal ovarian torsion, emphasizing prenatal and postnatal sonographic findings. Eleven patients who had had neonatal ovarian torsion diagnosed surgically (n = 9) or clinicoradiologically (n = 2) were enrolled. Prenatal and postnatal sonographic features, including sequential postnatal change, were reviewed. Clinical and pathologic features were also investigated. All patients except one had a fetal ovarian cyst (mean, 5.3 cm) detected on third-trimester sonography, either simple (n = 6) or complex (n = 4). In all 11 patients, initial postnatal sonography had revealed a complex cyst (mean, 4.7 cm) with intracystic clot or debris, the double-wall sign, a fluid-fluid level, and multiple septation. None of the patients had had symptoms or signs related to the ovarian torsion. Follow-up sonography in seven patients had revealed increased echogenicity of the cyst wall with frequent calcification and a decrease in size of the cyst. In two patients, the interval of the change in cyst position was noted, and autoamputation of the torsed ovary had been surgically confirmed. Serous cystadenoma had been identified in one patient. Neonatal ovarian torsion most commonly manifests as an asymptomatic complex cyst on sonography due to torsion of a fetal ovarian cyst. Serial monitoring of a fetal ovarian cyst for its resolution or changes in its appearance is mandatory for making an early diagnosis of torsion. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:290-297, 2016. © 2016 Wiley Periodicals, Inc.

Management of epithelial ovarian cancer from diagnosis to restaging: an overview of the role of imaging techniques with particular regard to the contribution of 18F-FDG PET/CT.

PubMed

Musto, Alessandra; Grassetto, Gaia; Marzola, Maria Cristina; Rampin, Lucia; Chondrogiannis, Sotirios; Maffione, Anna Margherita; Colletti, Patrick M; Perkins, Alan C; Fagioli, Giorgio; Rubello, Domenico

2014-06-01

Epithelial ovarian carcinoma is a major form of cancer affecting women in the western world. The silent nature of this disease results in late presentation at an advanced stage in many patients. It is therefore important to assess the role of imaging techniques in the management of these patients. This article presents a review of the literature on the role of (18)F-FDG-PET/CT in the different stages of management of epithelial ovarian cancer. Moreover, a comparison with other imaging techniques has been made and the relationship between (18)F-PET/CT and the assay of serum CA-125 levels has been discussed.

Enhanced expression of peroxisome proliferator-activated receptor gamma in epithelial ovarian carcinoma.

PubMed

Zhang, G Y; Ahmed, N; Riley, C; Oliva, K; Barker, G; Quinn, M A; Rice, G E

2005-01-17

The peroxisome proliferator-activated receptors (PPARs) belong to a subclass of nuclear hormone receptor that executes important cellular transcriptional functions. Previous studies have demonstrated the expression of PPARgamma in several tumours including colon, breast, bladder, prostate, lung and stomach. This study demonstrates the relative expression of PPARgamma in normal ovaries and different pathological grades of ovarian tumours of serous, mucinous, endometrioid, clear cell and mixed subtypes. A total of 56 ovarian specimens including 10 normal, eight benign, 10 borderline, seven grade 1, nine grade 2 and 12 grade 3 were analysed using immunohistochemistry. Immunoreactive PPARgamma was not expressed in normal ovaries. Out of eight benign and 10 borderline tumours, only one tumour in each group showed weak cytoplasmic PPARgamma expression. In contrast, 26 out of 28 carcinomas studied were positive for PPARgamma expression with staining confined to cytoplasmic and nuclear regions. An altered staining pattern of PPARgamma was observed in high-grade ovarian tumours with PPARgamma being mostly localized in the nuclei with little cytoplasmic immunoreactivity. On the other hand, predominant cytoplasmic staining was observed in lower-grade tumours. Significantly increased PPARgamma immunoreactivity was observed in malignant ovarian tumours (grade 1, 2 and 3) compared to benign and borderline tumours (chi2 = 48.80, P < 0.001). Western blot analyses showed significant elevation in the expression of immunoreactive PPARgamma in grade 3 ovarian tumours compared with that of normal ovaries and benign ovarian tumours (P < 0.01). These findings suggest an involvement of PPARgamma in the onset and development of ovarian carcinoma and provide an insight into the regulation of this molecule in the progression of the disease.

Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study.

PubMed

Ong, Jue-Sheng; Cuellar-Partida, Gabriel; Lu, Yi; Fasching, Peter A; Hein, Alexander; Burghaus, Stefanie; Beckmann, Matthias W; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Vanderstichele, Adriaan; Anne Doherty, Jennifer; Anne Rossing, Mary; Chang-Claude, Jenny; Eilber, Ursula; Rudolph, Anja; Wang-Gohrke, Shan; Goodman, Marc T; Bogdanova, Natalia; Dörk, Thilo; Dürst, Matthias; Hillemanns, Peter; Runnebaum, Ingo B; Antonenkova, Natalia; Butzow, Ralf; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M; Edwards, Robert P; Kelley, Joseph L; Modugno, Francesmary; Moysich, Kirsten B; Ness, Roberta B; Cannioto, Rikki; Høgdall, Estrid; Høgdall, Claus K; Jensen, Allan; Giles, Graham G; Bruinsma, Fiona; Kjaer, Susanne K; Hildebrandt, Michelle At; Liang, Dong; Lu, Karen H; Wu, Xifeng; Bisogna, Maria; Dao, Fanny; Levine, Douglas A; Cramer, Daniel W; Terry, Kathryn L; Tworoger, Shelley S; Stampfer, Meir; Missmer, Stacey; Bjorge, Line; Salvesen, Helga B; Kopperud, Reidun K; Bischof, Katharina; Aben, Katja Kh; Kiemeney, Lambertus A; Massuger, Leon Fag; Brooks-Wilson, Angela; Olson, Sara H; McGuire, Valerie; Rothstein, Joseph H; Sieh, Weiva; Whittemore, Alice S; Cook, Linda S; Le, Nhu D; Gilks, C Blake; Gronwald, Jacek; Jakubowska, Anna; Lubiński, Jan; Kluz, Tomasz; Song, Honglin; Tyrer, Jonathan P; Wentzensen, Nicolas; Brinton, Louise; Trabert, Britton; Lissowska, Jolanta; McLaughlin, John R; Narod, Steven A; Phelan, Catherine; Anton-Culver, Hoda; Ziogas, Argyrios; Eccles, Diana; Campbell, Ian; Gayther, Simon A; Gentry-Maharaj, Aleksandra; Menon, Usha; Ramus, Susan J; Wu, Anna H; Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Timorek, Agnieszka; Szafron, Lukasz; Cunningham, Julie M; Fridley, Brooke L; Winham, Stacey J; Bandera, Elisa V; Poole, Elizabeth M; Morgan, Terry K; Risch, Harvey A; Goode, Ellen L; Schildkraut, Joellen M; Pearce, Celeste L; Berchuck, Andrew; Pharoah, Paul Dp; Chenevix-Trench, Georgia; Gharahkhani, Puya; Neale, Rachel E; Webb, Penelope M; MacGregor, Stuart

2016-10-01

In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer. We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases). The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01). Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer. © The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Ovarian cancer stem cells more questions than answers.

PubMed

Ottevanger, Petronella Beatrix

2017-06-01

Epithelial ovarian cancer is a highly lethal disease, which is usually diagnosed at a late stage with extensive metastases in the abdominal cavity. Ovarian cancer either develops from the ovarian surface epithelium (OSE) or from serous intra-epithelial carcinoma (STIC). Primary therapy consists of debulking surgery and platinum based chemotherapy. The success of debulking surgery depends on surgical skills but also on the gene signature of the tumour. Debulking surgery combined with first line platinum based chemotherapy, frequently leads to complete remission. However, most ovarian cancers relapse. Once the disease has relapsed, the interval between subsequent therapies decreases steadily due to rapid progression and therapy resistance. Research on therapy resistance of ovarian cancer is frequently devoted to genetic alterations in cancer cells, leading to drug inactivation, enhanced DNA repair mechanisms and intracellular pathway derangements. However the knowledge of ovarian cancer stem cells (OCSC) and the role they play in the development of cancer and therapy resistance is sparse. In this review current knowledge on the characteristics of OCSCs and the micro environmental mechanisms leading to the development or activation of OCSCs resulting in ovarian cancer is reviewed. Moreover the role of OCSC in both surgical and systemic therapy resistance and the relation with epithelial mesenchymal transformation (EMT) is discussed, as are micro-environmental signals leading to OCSC or EMT activation. Copyright © 2017 The Author. Published by Elsevier Ltd.. All rights reserved.

Anthropometric measurements and epithelial ovarian cancer risk in African-American and White women.

PubMed

Hoyo, Cathrine; Berchuck, Andrew; Halabi, Susan; Bentley, Rex C; Moorman, Patricia; Calingaert, Brian; Schildkraut, Joellen M

2005-10-01

Previous studies of anthropometric factors and ovarian cancer risk have been inconsistent and none have evaluated the association among African-American women. Data from a population-based, case-control study of 593 cases and 628 controls were used to evaluate ovarian cancer risk in relation to weight, height, body mass index (BMI) and waist-to-hip ratio (WHR). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed and established risk factors were adjusted for using logistic regression models, stratified by race. Among all races, weight at age 18, WHR, weight and BMI one year prior to interview were associated with elevated ovarian cancer risk. When stratified by race, the association between WHR and ovarian was similar among Whites and among African Americans. However, African-American women in the fourth quartile of height had an elevated risk of ovarian cancer (OR = 3.2; 95% CI = 1.3-7.8), but this risk was not apparent in Whites (OR = 1.0; 95% CI = 0.7-1.4). These findings support the hypothesis that obesity is an important risk factor of ovarian cancer among African-Americans and Whites and also suggest that height may be a risk factor specific to African-Americans.

Long-term follow-up of patients with an isolated ovarian recurrence after conservative treatment of epithelial ovarian cancer: review of the results of an international multicenter study comprising 545 patients.

PubMed

Bentivegna, Enrica; Fruscio, Robert; Roussin, Stephanie; Ceppi, Lorenzo; Satoh, Toyomi; Kajiyama, Hiroaki; Uzan, Catherine; Colombo, Nicoletta; Gouy, Sebastien; Morice, Philippe

2015-11-01

To determine the long-term outcomes of patients with an isolated ovarian recurrence after fertility sparing surgery (FSS) for epithelial ovarian cancer (EOC) and to evaluate the recurrence rates (and location) according to the new 2014 International Federation of Gynecology and Obstetrics (FIGO) staging system. Retrospective multicenter study. Teams having reported recurrence after FSS for EOC. Four series comprising 545 patients undergoing FSS and 63 (12%) recurrences. FSS (salpingo-oophorectomy for a majority of cases) for EOC. Recurrences rates and characteristics of recurrent disease. Among 63 recurrent patients, 24 (38%) recurrences were isolated on the spared ovary, and 39 (62%) arose at an extraovarian site. Among the patients with an isolated ovarian recurrence, three patients died after a median follow-up period of 186 months (range: 28-294 months). Among the patients with recurrent extraovarian disease, 24 died and 7 were alive with persistent disease after a median follow-up period of 34 months (range: 3-231 months). The overall rate of isolated ovarian and extrapelvic recurrences was higher for grade 3 tumors (compared with grades 1/2). The long-term survival of patients with an isolated ovarian recurrence after FSS for EOC remains favorable. The prognosis of patients with an extraovarian recurrence is poor compared with those who have an isolated recurrent ovarian tumor. Grade 3 tumors (compared to grades 1/2) give rise to a higher rate of extraovarian recurrences. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Chronic Recreational Physical Inactivity and Epithelial Ovarian Cancer Risk: Evidence from the Ovarian Cancer Association Consortium.

PubMed

Cannioto, Rikki; LaMonte, Michael J; Risch, Harvey A; Hong, Chi-Chen; Sucheston-Campbell, Lara E; Eng, Kevin H; Brian Szender, J; Chang-Claude, Jenny; Schmalfeldt, Barbara; Klapdor, Ruediger; Gower, Emily; Minlikeeva, Albina N; Zirpoli, Gary R; Bandera, Elisa V; Berchuck, Andrew; Cramer, Daniel; Doherty, Jennifer A; Edwards, Robert P; Fridley, Brooke L; Goode, Ellen L; Goodman, Marc T; Hogdall, Estrid; Hosono, Satoyo; Jensen, Allan; Jordan, Susan; Kjaer, Susanne K; Matsuo, Keitaro; Ness, Roberta B; Olsen, Catherine M; Olson, Sara H; Leigh Pearce, Celeste; Pike, Malcolm C; Anne Rossing, Mary; Szamreta, Elizabeth A; Thompson, Pamela J; Tseng, Chiu-Chen; Vierkant, Robert A; Webb, Penelope M; Wentzensen, Nicolas; Wicklund, Kristine G; Winham, Stacey J; Wu, Anna H; Modugno, Francesmary; Schildkraut, Joellen M; Terry, Kathryn L; Kelemen, Linda E; Moysich, Kirsten B

2016-07-01

Despite a large body of literature evaluating the association between recreational physical activity and epithelial ovarian cancer (EOC) risk, the extant evidence is inconclusive, and little is known about the independent association between recreational physical inactivity and EOC risk. We conducted a pooled analysis of nine studies from the Ovarian Cancer Association Consortium to investigate the association between chronic recreational physical inactivity and EOC risk. In accordance with the 2008 Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. Multivariable logistic regression was utilized to estimate the ORs and 95% confidence intervals (CI) for the association between inactivity and EOC risk overall and by subgroups based upon histotype, menopausal status, race, and body mass index. The current analysis included data from 8,309 EOC patients and 12,612 controls. We observed a significant positive association between inactivity and EOC risk (OR = 1.34; 95% CI, 1.14-1.57), and similar associations were observed for each histotype. In this large pooled analysis examining the association between recreational physical inactivity and EOC risk, we observed consistent evidence of an association between chronic inactivity and all EOC histotypes. These data add to the growing body of evidence suggesting that inactivity is an independent risk factor for cancer. If the apparent association between inactivity and EOC risk is substantiated, additional work via targeted interventions should be pursued to characterize the dose of activity required to mitigate the risk of this highly fatal disease. Cancer Epidemiol Biomarkers Prev; 25(7); 1114-24. ©2016 AACR. ©2016 American Association for Cancer Research.

CDK6 protects epithelial ovarian cancer from platinum-induced death via FOXO3 regulation.

PubMed

Dall'Acqua, Alessandra; Sonego, Maura; Pellizzari, Ilenia; Pellarin, Ilenia; Canzonieri, Vincenzo; D'Andrea, Sara; Benevol, Sara; Sorio, Roberto; Giorda, Giorgio; Califano, Daniela; Bagnoli, Marina; Militello, Loredana; Mezzanzanica, Delia; Chiappetta, Gennaro; Armenia, Joshua; Belletti, Barbara; Schiappacassi, Monica; Baldassarre, Gustavo

2017-10-01

Epithelial ovarian cancer (EOC) is an infrequent but highly lethal disease, almost invariably treated with platinum-based therapies. Improving the response to platinum represents a great challenge, since it could significantly impact on patient survival. Here, we report that silencing or pharmacological inhibition of CDK6 increases EOC cell sensitivity to platinum. We observed that, upon platinum treatment, CDK6 phosphorylated and stabilized the transcription factor FOXO3, eventually inducing ATR transcription. Blockage of this pathway resulted in EOC cell death, due to altered DNA damage response accompanied by increased apoptosis. These observations were recapitulated in EOC cell lines in vitro , in xenografts in vivo , and in primary tumor cells derived from platinum-treated patients. Consistently, high CDK6 and FOXO3 expression levels in primary EOC predict poor patient survival. Our data suggest that CDK6 represents an actionable target that can be exploited to improve platinum efficacy in EOC patients. As CDK4/6 inhibitors are successfully used in cancer patients, our findings can be immediately transferred to the clinic to improve the outcome of EOC patients. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

The use of laser microdissection in the identification of suitable reference genes for normalization of quantitative real-time PCR in human FFPE epithelial ovarian tissue samples.

PubMed

Cai, Jing; Li, Tao; Huang, Bangxing; Cheng, Henghui; Ding, Hui; Dong, Weihong; Xiao, Man; Liu, Ling; Wang, Zehua

2014-01-01

Quantitative real-time PCR (qPCR) is a powerful and reproducible method of gene expression analysis in which expression levels are quantified by normalization against reference genes. Therefore, to investigate the potential biomarkers and therapeutic targets for epithelial ovarian cancer by qPCR, it is critical to identify stable reference genes. In this study, twelve housekeeping genes (ACTB, GAPDH, 18S rRNA, GUSB, PPIA, PBGD, PUM1, TBP, HRPT1, RPLP0, RPL13A, and B2M) were analyzed in 50 ovarian samples from normal, benign, borderline, and malignant tissues. For reliable results, laser microdissection (LMD), an effective technique used to prepare homogeneous starting material, was utilized to precisely excise target tissues or cells. One-way analysis of variance (ANOVA) and nonparametric (Kruskal-Wallis) tests were used to compare the expression differences. NormFinder and geNorm software were employed to further validate the suitability and stability of the candidate genes. Results showed that epithelial cells occupied a small percentage of the normal ovary indeed. The expression of ACTB, PPIA, RPL13A, RPLP0, and TBP were stable independent of the disease progression. In addition, NormFinder and geNorm identified the most stable combination (ACTB, PPIA, RPLP0, and TBP) and the relatively unstable reference gene GAPDH from the twelve commonly used housekeeping genes. Our results highlight the use of homogeneous ovarian tissues and multiple-reference normalization strategy, e.g. the combination of ACTB, PPIA, RPLP0, and TBP, for qPCR in epithelial ovarian tissues, whereas GAPDH, the most commonly used reference gene, is not recommended, especially as a single reference gene.

Ovarian endometriosis-associated stromal cells reveal persistently high affinity for iron.

PubMed

Mori, Masahiko; Ito, Fumiya; Shi, Lei; Wang, Yue; Ishida, Chiharu; Hattori, Yuka; Niwa, Masato; Hirayama, Tasuku; Nagasawa, Hideko; Iwase, Akira; Kikkawa, Fumitaka; Toyokuni, Shinya

2015-12-01

Ovarian endometriosis is a recognized risk for infertility and epithelial ovarian cancer, presumably due to iron overload resulting from repeated hemorrhage. To find a clue for early detection and prevention of ovarian endometriosis-associated cancer, it is mandatory to evaluate catalytic (labile) ferrous iron (catalytic Fe(II)) and to study iron manipulation in ovarian endometriotic lesions. By the use of tissues from women of ovarian endometriosis as well as endometrial tissue from women with and without endometriosis, we for the first time performed histological analysis and cellular detection of catalytic Fe(II) with a specific fluorescent probe (HMRhoNox-M), and further evaluated iron transport proteins in the human specimens and in co-culture experiments using immortalized human eutopic/ectopic endometrial stromal cells (ESCs) in the presence or absence of epithelial cells (EpCs). The amounts of catalytic Fe(II) were higher in ectopic endometrial stromal cells (ecESCs) than in normal eutopic endometrial stromal cells (n-euESCs) both in the tissues and in the corresponding immortalized ESCs. ecESCs exhibited higher transferrin receptor 1 expression both in vivo and in vitro and lower ferroportin expression in vivo than n-euESCs, leading to sustained iron uptake. In co-culture experiments of ESCs with iron-loaded EpCs, ecESCs received catalytic ferrous iron from EpCs, but n-euESCs did not. These data suggest that ecESC play a protective role for cancer-target epithelial cells by collecting excess iron, and that these characteristics are retained in the immortalized ecESCs. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

The Association of Peripheral Blood Regulatory T-Cell Concentrations With Epithelial Ovarian Cancer: A Brief Report.

PubMed

Cannioto, Rikki A; Sucheston-Campbell, Lara E; Hampras, Shalaka; Goode, Ellen L; Knutson, Keith; Ness, Roberta; Modugno, Francesmary; Wallace, Paul; Szender, J Brian; Mayor, Paul; Hong, Chi-Chen; Joseph, Janine M; Friel, Grace; Davis, Warren; Nesline, Mary; Eng, Kevin H; Edwards, Robert P; Kruszka, Bridget; Schmitt, Kristina; Odunsi, Kunle; Moysich, Kirsten B

2017-01-01

There is a mounting body of evidence demonstrating higher percentages of regulatory T (Treg) cells in the peripheral blood of patients with cancer in comparison to healthy controls, but there is a paucity of epidemiological literature characterizing circulating Treg cells among patients with epithelial ovarian cancer (EOC). To investigate the role of peripheral Treg cells in ovarian neoplasms, we conducted a case-control study to characterize circulating concentrations of Treg cells among patients with EOC, women with benign ovarian conditions, and healthy controls without a history of cancer. Participants were identified for inclusion due to their participation in the Data Bank and BioRepository program at Roswell Park Cancer Institute in Buffalo, NY. Patients included 71 women with a primary diagnosis of EOC and 195 women with a diagnosis of benign ovarian conditions. Controls included 101 age- and race-matched women without a history of cancer. Nonfasting, pretreatment peripheral blood levels of CD3+CD4+CD25+FOXP3+ Treg cells were measured using flow cytometric analyses and expressed as a percentage of total CD3+ cells and as a percentage of total CD3+CD4+ cells. Compared to healthy controls and women with benign ovarian conditions, patients with EOC had significantly higher frequency of Treg cells (P < 0.04). In multivariable logistic regression analyses using Treg frequency expressed as a percentage of CD+3 cells, we observed a significant positive association between Treg cell percentage and EOC risk, with each 1% increase associated with a 37% increased risk of EOC (odds ratio, 1.37; 95% confidence interval, 1.04-1.80). We observed a similar trend when Treg frequency was expressed as a percentage of CD3+CD+4 cells (odds ratio, 1.22; 95% confidence interval, 0.99-1.49). The current study provides support that peripheral Treg cell frequency is elevated in patients with EOC in comparison to women with benign ovarian conditions and healthy controls.

The association of peripheral blood regulatory T-cell concentrations with epithelial ovarian cancer: A brief report

PubMed Central

Hampras, Shalaka; Goode, Ellen L.; Knutson, Keith; Ness, Roberta; Modugno, Francesmary; Wallace, Paul; Szender, J. Brian; Mayor, Paul; Hong, Chi-Chen; Joseph, Janine M.; Friel, Grace; Davis, Warren; Nesline, Mary; Eng, Kevin H.; Edwards, Robert P.; Kruszka, Bridget; Schmitt, Kristina; Odunsi, Kunle; Moysich, Kirsten B.

2016-01-01

Objective There is a mounting body of evidence demonstrating higher percentages of regulatory T (Treg) cells in the peripheral blood of cancer patients in comparison to healthy controls, but there is a paucity of epidemiological literature characterizing circulating Treg cells among epithelial ovarian cancer (EOC) patients. To investigate the role of peripheral Treg cells in ovarian neoplasms, we conducted a case-control study to characterize circulating concentrations of Treg cells among EOC patients, women with benign ovarian conditions, and healthy controls without a history of cancer. Materials and Methods Participants were identified for inclusion due to their participation in the Data Bank and BioRepository program at Roswell Park Cancer Institute in Buffalo, NY. Patients included 71 women with a primary diagnosis of EOC and 195 women with a diagnosis of benign ovarian conditions. Controls included 101 age- and race-matched women without a history of cancer. Non-fasting, pre-treatment peripheral blood levels of CD3+CD4+CD25+FOXP3+ Treg cells were measured using flow cytometric analyses and expressed as a percentage of total CD3+ cells and as a percentage of total CD3+CD4+ cells. Results Compared to healthy controls and women with benign ovarian conditions, EOC patients had significantly higher frequency of Treg cells (p<0.04). In multivariable logistic regression analyses utilizing Treg frequency expressed as a percentage of CD+3 cells, we observed a significant positive association between Treg cell percentage and EOC risk, with each one percent increase associated with a 37% increased risk of EOC (OR=1.37, 95% CI: 1.04-1.80). We observed a similar trend when Treg frequency was expressed as a percentage of CD3+CD+4 cells (OR=1.22, 95% CI: 0.99-1.49). Conclusions The current study provides support that peripheral Treg cell frequency is elevated in EOC patients in comparison to women with benign ovarian conditions and healthy controls. PMID:27759594

Myeloperoxidase serves as a redox switch that regulates apoptosis in epithelial ovarian cancer.

PubMed

Saed, Ghassan M; Ali-Fehmi, Rouba; Jiang, Zhong L; Fletcher, Nicole M; Diamond, Michael P; Abu-Soud, Husam M; Munkarah, Adnan R

2010-02-01

Resistance to apoptosis is a key feature of cancer cells and is believed to be regulated by nitrosonium ion (NO(+))-induced S-nitrosylation of key enzymes. Nitric oxide (NO), produced by inducible nitric oxide synthase (iNOS), is utilized by MPO to generated NO(+). We sought to investigate the expression of myeloperoxidase (MPO) and iNOS in epithelial ovarian cancer (EOC) and determine their effect on S-nitrosylation of caspase-3 and its activity as well as apoptosis. MPO and iNOS expression were determined using immunofluorescence in SKOV-3 and MDAH-2774 and EOC tissue sections. S-nitrosylation of caspase-3 and its activity, levels of MPO and iNOS, as well as apoptosis, were evaluated in the EOC cells before and after silencing MPO or iNOS genes with specific siRNA probes utilizing real-time RT-PCR, ELISA, and TUNEL assays. MPO and iNOS are expressed in EOC cell lines and in over 60% of invasive EOC cases with no expression in normal ovarian epithelium. Indeed, silencing of MPO or iNOS gene expression resulted in decreased S-nitrosylation of caspase-3, increased caspase-3 activity, and increased apoptosis but with a more significant effect when silencing MPO. MPO and iNOS are colocalized to the same cells in EOC but not in the normal ovarian epithelium. Silencing of either MPO or iNOS significantly induced apoptosis, highlighting their role as a redox switch that regulates apoptosis in EOC. Understanding the mechanisms by which MPO functions as a redox switch in regulating apoptosis in EOC may lead to future diagnostic tools and therapeutic interventions. Copyright 2009 Elsevier Inc. All rights reserved.

7-(O)-Carboxymethyl daidzein conjugated to N-t-Boc-hexylenediamine: A Novel Compound Capable of Inducing Cell Death in Epithelial Ovarian Cancer Stem Cells

PubMed Central

Green, Jamie M.; Alvero, Ayesha B.; Kohen, Fortune; Mor, Gil

2009-01-01

One of the major difficulties in the treatment of epithelial ovarian cancer (EOC) is the high rate of recurrent disease. This is thought to be due to the survival of a population of chemo-resistant cells within the tumor, the ovarian cancer stem cells (OCSCs), that are able to regenerate the tumor following chemotherapy. Therefore, the identification of a compund that can target the OCSCs is one of the main steps in improving overall survival of ovarian cancer patients. The objective of this study was to determine the effect of N-t-boc-Daidzein, a novel daidzain derivative, on OCSCs. The efficacy of this compound was evaluated in OCSC and mature ovarian cancer cell (mOCC) lines isolated from malignant ovarian cancer asicites. Cells were treated with increasing concentrations of N-t-boc-Daidzein (0.003–10 μM) and cell growth was monitored by “real time in vitro micro-imaging” using the IncuCyte system. Cell viability was measured using the CellTiter 96 Assay. Apoptosis was determined by Caspase-Glo 3/7, 8, and 9 assays. The components of the apoptotic cascade were characterized by Western blot analysis. N-t-boc-Daidzein was able to significantly inhibit cell growth and decrease cell viability of OCSC as well as mOCC cells in a dose and time dependent maner. This effect was due to the induction of apoptosis, which is characterized by caspase activation, XIAP and AKT degradation, and mitochondrial depolarization. This study describes a novel compound that can target the OCSCs. These findings may provide vital aide in improving overall survival in patients with EOC. PMID:19738422

7-(O)-Carboxymethyl daidzein conjugated to N-t-Boc-hexylenediamine: a novel compound capable of inducing cell death in epithelial ovarian cancer stem cells.

PubMed

Green, Jamie M; Alvero, Ayesha B; Kohen, Fortune; Mor, Gil

2009-09-01

One of the major difficulties in the treatment of epithelial ovarian cancer (EOC) is the high rate of recurrent disease. This is thought to be due to the survival of a population of chemo-resistant cells within the tumor, the ovarian cancer stem cells (OCSCs), that are able to regenerate the tumor following chemotherapy. Therefore, the identification of a compund that can target the OCSCs is one of the main steps in improving overall survival of ovarian cancer patients. The objective of this study was to determine the effect of N-t-boc-Daidzein, a novel daidzain derivative, on OCSCs. The efficacy of this compound was evaluated in OCSC and mature ovarian cancer cell (mOCC) lines isolated from malignant ovarian cancer asicites. Cells were treated with increasing concentrations of N-t-boc-Daidzein (0.003-10 microM) and cell growth was monitored by "real time in vitro micro-imaging" using the IncuCyte system. Cell viability was measured using the CellTiter 96 Assay. Apoptosis was determined by Caspase-Glo 3/7, 8 and 9 assays. The components of the apoptotic cascade were characterized by western blot analysis. N-t-boc-Daidzein was able to significantly inhibit cell growth and decrease cell viability of OCSC as well as mOCC cells in a dose and time dependent maner. This effect was due to the induction of apoptosis, which is characterized by caspase activation, XIAP and AKT degradation, and mitochondrial depolarization. This study describes a novel compound that can target the OCSCs. These findings may provide vital aide in improving overall survival in patients with EOC.

Ovarian cancer statistics, 2018.

PubMed

Torre, Lindsey A; Trabert, Britton; DeSantis, Carol E; Miller, Kimberly D; Samimi, Goli; Runowicz, Carolyn D; Gaudet, Mia M; Jemal, Ahmedin; Siegel, Rebecca L

2018-05-29

In 2018, there will be approximately 22,240 new cases of ovarian cancer diagnosed and 14,070 ovarian cancer deaths in the United States. Herein, the American Cancer Society provides an overview of ovarian cancer occurrence based on incidence data from nationwide population-based cancer registries and mortality data from the National Center for Health Statistics. The status of early detection strategies is also reviewed. In the United States, the overall ovarian cancer incidence rate declined from 1985 (16.6 per 100,000) to 2014 (11.8 per 100,000) by 29% and the mortality rate declined between 1976 (10.0 per 100,000) and 2015 (6.7 per 100,000) by 33%. Ovarian cancer encompasses a heterogenous group of malignancies that vary in etiology, molecular biology, and numerous other characteristics. Ninety percent of ovarian cancers are epithelial, the most common being serous carcinoma, for which incidence is highest in non-Hispanic whites (NHWs) (5.2 per 100,000) and lowest in non-Hispanic blacks (NHBs) and Asians/Pacific Islanders (APIs) (3.4 per 100,000). Notably, however, APIs have the highest incidence of endometrioid and clear cell carcinomas, which occur at younger ages and help explain comparable epithelial cancer incidence for APIs and NHWs younger than 55 years. Most serous carcinomas are diagnosed at stage III (51%) or IV (29%), for which the 5-year cause-specific survival for patients diagnosed during 2007 through 2013 was 42% and 26%, respectively. For all stages of epithelial cancer combined, 5-year survival is highest in APIs (57%) and lowest in NHBs (35%), who have the lowest survival for almost every stage of diagnosis across cancer subtypes. Moreover, survival has plateaued in NHBs for decades despite increasing in NHWs, from 40% for cases diagnosed during 1992 through 1994 to 47% during 2007 through 2013. Progress in reducing ovarian cancer incidence and mortality can be accelerated by reducing racial disparities and furthering knowledge of etiology and

Assessment of published models and prognostic variables in epithelial ovarian cancer at Mayo Clinic

PubMed Central

Hendrickson, Andrea Wahner; Hawthorne, Kieran M.; Goode, Ellen L.; Kalli, Kimberly R.; Goergen, Krista M.; Bakkum-Gamez, Jamie N.; Cliby, William A.; Keeney, Gary L.; Visscher, Dan W.; Tarabishy, Yaman; Oberg, Ann L.; Hartmann, Lynn C.; Maurer, Matthew J.

2015-01-01

Objectives Epithelial ovarian cancer (EOC) is an aggressive disease in which first line therapy consists of a surgical staging/debulking procedure and platinum based chemotherapy. There is significant interest in clinically applicable, easy to use prognostic tools to estimate risk of recurrence and overall survival. In this study we used a large prospectively collected cohort of women with EOC to validate currently published models and assess prognostic variables. Methods Women with invasive ovarian, peritoneal, or fallopian tube cancer diagnosed between 2000-2011 and prospectively enrolled into the Mayo Clinic Ovarian Cancer registry were identified. Demographics and known prognostic markers as well as epidemiologic exposure variables were abstracted from the medical record and collected via questionnaire. Six previously published models of overall and recurrence-free survival were assessed for external validity. In addition, predictors of outcome were assessed in our dataset. Results Previously published models validated with a range of c-statistics (0.587-0.827), though application of models containing variables not part of routine practice were somewhat limited by missing data; utilization of all applicable models and comparison of results is suggested. Examination of prognostic variables identified only the presence of ascites and ASA score to be independent predictors of prognosis in our dataset, albeit with marginal gain in prognostic information, after accounting for stage and debulking. Conclusions Existing prognostic models for newly diagnosed EOC showed acceptable calibration in our cohort for clinical application. However, modeling of prospective variables in our dataset reiterates that stage and debulking remain the most important predictors of prognosis in this setting. PMID:25620544

Pathway modulations and epigenetic alterations in ovarian tumorbiogenesis

PubMed Central

Saldanha, Sabita N.; Tollefsbol, Trygve O.

2013-01-01

Cellular pathways are numerous and are highly integrated in function in the control of cellular systems. They collectively regulate cell division, proliferation, survival and apoptosis of cells and mutagenesis of key genes that control these pathways can initiate neoplastic transformations. Understanding these pathways is crucial to future therapeutic and preventive strategies of the disease. Ovarian cancers are of three major types; epithelial, germ-cell and stromal. However, ovarian cancers of epithelial origin, arising from the mesothelium, are the predominant form. Of the subtypes of ovarian cancer, the high-grade serous tumors are fatal, with low survival rate due to late detection and poor response to treatments. Close examination of preserved ovarian tissues and in vitro studies have provided insights into the mechanistic changes occurring in cells mediated by a few key genes. This review will focus on pathways and key genes of the pathways that are mutated or have aberrant functions in the pathology of ovarian cancer. Non-genetic mechanisms that are gaining prominence in the pathology of ovarian cancer, miRNAs and epigenetics, will also be discussed in the review. PMID:24105793

Stably Fluorescent Cell Line of Human Ovarian Epithelial Cancer Cells SK-OV-3ip-red.

PubMed

Konovalova, E V; Shulga, A A; Chumakov, S P; Khodarovich, Yu M; Woo, Eui-Jeon; Deev, S M

2017-11-01

Stable red fluorescing line of human ovarian epithelial cancer cells SK-OV-3ip-red was generated expressing gene coding for protein TurboFP635 (Katushka) fluorescing in the far-red spectrum region with excitation and emission peaks at 588 and 635 nm, respectively. Fluorescence of SK-OV-3ip-red line remained high during long-term cell culturing and after cryogenic freezing. The obtained cell line SK-OV-3ip-red can serve a basis for a model of a scattered tumor with numerous/extended metastases and used both for testing anticancer drugs inhibiting metastasis growth and for non-invasive monitoring of the growth dynamics with high precision.

Extracellular matrix metalloproteinase inducer (EMMPRIN) expression correlates positively with active angiogenesis and negatively with basic fibroblast growth factor expression in epithelial ovarian cancer.

PubMed

Szubert, Sebastian; Szpurek, Dariusz; Moszynski, Rafal; Nowicki, Michal; Frankowski, Andrzej; Sajdak, Stefan; Michalak, Slawomir

2014-03-01

The primary aim of this paper was to evaluate the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) and its relationship with proangiogenic factors and microvessel density (MVD) in ovarian cancer. The study group included 58 epithelial ovarian cancers (EOCs), 35 benign ovarian tumors, and 21 normal ovaries. The expression of EMMPRIN, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) was assessed by ELISA of tissue homogenates. Antibodies against CD105, CD31, and CD34 were used to immunohistochemically assess MVD. We have found significantly higher EMMPRIN expression in EOC than in benign ovarian tumors and normal ovaries. Similarly, the VEGF expression was higher in EOC than in benign ovarian tumors and normal ovaries. By contrast, bFGF expression was lower in EOC than in benign ovarian tumors and ovary samples. EMMPRIN expression in EOC was directly correlated with VEGF expression and CD105-MVD, but inversely correlated with bFGF expression. Grade 2/3 ovarian cancers had increased expression of EMMPRIN and VEGF, increased CD105-MVD, and lowered expression of bFGF compared to grade 1 ovarian cancers. Moreover, EMMPRIN expression was higher in advanced (FIGO III and IV) ovarian cancer. The upregulation of EMMPRIN and VEGF expression is correlated with increased CD105-MVD and silenced bFGF, which suggests early and/or reactivated angiogenesis in ovarian cancer. Aggressive EOC is characterized by the following: high expression of EMMPRIN and VEGF, high CD105-MVD, and low expression of bFGF.

Circulating 25-hydroxyvitamin D and risk of epithelial ovarian cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers.

PubMed

Zheng, Wei; Danforth, Kim N; Tworoger, Shelley S; Goodman, Marc T; Arslan, Alan A; Patel, Alpa V; McCullough, Marjorie L; Weinstein, Stephanie J; Kolonel, Laurence N; Purdue, Mark P; Shu, Xiao-Ou; Snyder, Kirk; Steplowski, Emily; Visvanathan, Kala; Yu, Kai; Zeleniuch-Jacquotte, Anne; Gao, Yu-Tang; Hankinson, Susan E; Harvey, Chinonye; Hayes, Richard B; Henderson, Brian E; Horst, Ronald L; Helzlsouer, Kathy J

2010-07-01

A role for vitamin D in ovarian cancer etiology is supported by ecologic studies of sunlight exposure, experimental mechanism studies, and some studies of dietary vitamin D intake and genetic polymorphisms in the vitamin D receptor. However, few studies have examined the association of circulating 25-hydroxyvitamin D (25(OH)D), an integrated measure of vitamin D status, with ovarian cancer risk. A nested case-control study was conducted among 7 prospective studies to evaluate the circulating 25(OH)D concentration in relation to epithelial ovarian cancer risk. Logistic regression models were used to estimate odds ratios and 95% confidence intervals among 516 cases and 770 matched controls. Compared with 25(OH)D concentrations of 50-<75 nmol/L, no statistically significant associations were observed for <37.5 (odds ratio (OR) = 1.21, 95% confidence interval (CI): 0.87, 1.70), 37.5-<50 (OR = 1.03, 95% CI: 0.75, 1.41), or > or =75 (OR = 1.11, 95% CI: 0.79, 1.55) nmol/L. Analyses stratified by tumor subtype, age, body mass index, and other variables were generally null but suggested an inverse association between 25(OH)D and ovarian cancer risk among women with a body mass index of > or =25 kg/m(2) (P(interaction) < 0.01). In conclusion, this large pooled analysis did not support an overall association between circulating 25(OH)D and ovarian cancer risk, except possibly among overweight women.

The Potential Role of the Proteases Cathepsin D and Cathepsin L in the Progression and Metastasis of Epithelial Ovarian Cancer

PubMed Central

Pranjol, Md Zahidul Islam; Gutowski, Nicholas; Hannemann, Michael; Whatmore, Jacqueline

2015-01-01

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies and has a poor prognosis due to relatively unspecific early symptoms, and thus often advanced stage, metastasized cancer at presentation. Metastasis of EOC occurs primarily through the transcoelomic route whereby exfoliated tumor cells disseminate within the abdominal cavity, particularly to the omentum. Primary and metastatic tumor growth requires a pool of proangiogenic factors in the microenvironment which propagate new vasculature in the growing cancer. Recent evidence suggests that proangiogenic factors other than the widely known, potent angiogenic factor vascular endothelial growth factor may mediate growth and metastasis of ovarian cancer. In this review we examine the role of some of these alternative factors, specifically cathepsin D and cathepsin L. PMID:26610586

The Potential Role of the Proteases Cathepsin D and Cathepsin L in the Progression and Metastasis of Epithelial Ovarian Cancer.

PubMed

Pranjol, Md Zahidul Islam; Gutowski, Nicholas; Hannemann, Michael; Whatmore, Jacqueline

2015-11-20

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies and has a poor prognosis due to relatively unspecific early symptoms, and thus often advanced stage, metastasized cancer at presentation. Metastasis of EOC occurs primarily through the transcoelomic route whereby exfoliated tumor cells disseminate within the abdominal cavity, particularly to the omentum. Primary and metastatic tumor growth requires a pool of proangiogenic factors in the microenvironment which propagate new vasculature in the growing cancer. Recent evidence suggests that proangiogenic factors other than the widely known, potent angiogenic factor vascular endothelial growth factor may mediate growth and metastasis of ovarian cancer. In this review we examine the role of some of these alternative factors, specifically cathepsin D and cathepsin L.

Vaccine Therapy With Sargramostim (GM-CSF) in Treating Patients With Her-2 Positive Stage III-IV Breast Cancer or Ovarian Cancer

ClinicalTrials.gov

2018-05-01

HER2-positive Breast Cancer; Stage III Ovarian Epithelial Cancer; Stage III Ovarian Germ Cell Tumor; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor

Treatment Option Overview (Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer)

MedlinePlus

... of Ovarian Germ Cell Tumors Ovarian Low Malignant Potential Tumors Symptoms, Tests, Prognosis, & Stages Treatment of Ovarian Low Malignant Potential Tumors Prevention of Ovarian, Fallopian Tube, & Primary Peritoneal ...

New paradigms for BRCA1/BRCA2 testing in women with ovarian cancer: results of the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study

PubMed Central

Plaskocinska, Inga; Shipman, Hannah; Drummond, James; Thompson, Edward; Buchanan, Vanessa; Newcombe, Barbara; Hodgkin, Charlotte; Barter, Elisa; Ridley, Paul; Ng, Rita; Miller, Suzanne; Dann, Adela; Licence, Victoria; Webb, Hayley; Tan, Li Tee; Daly, Margaret; Ayers, Sarah; Rufford, Barnaby; Earl, Helena; Parkinson, Christine; Duncan, Timothy; Jimenez-Linan, Mercedes; Sagoo, Gurdeep S; Abbs, Stephen; Hulbert-Williams, Nicholas; Pharoah, Paul; Crawford, Robin; Brenton, James D; Tischkowitz, Marc

2016-01-01

Background Over recent years genetic testing for germline mutations in BRCA1/BRCA2 has become more readily available because of technological advances and reducing costs. Objective To explore the feasibility and acceptability of offering genetic testing to all women recently diagnosed with epithelial ovarian cancer (EOC). Methods Between 1 July 2013 and 30 June 2015 women newly diagnosed with EOC were recruited through six sites in East Anglia, UK into the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study. Eligibility was irrespective of patient age and family history of cancer. The psychosocial arm of the study used self-report, psychometrically validated questionnaires (Depression Anxiety and Stress Scale (DASS-21); Impact of Event Scale (IES)) and cost analysis was performed. Results 232 women were recruited and 18 mutations were detected (12 in BRCA1, 6 in BRCA2), giving a mutation yield of 8%, which increased to 12% in unselected women aged <70 years (17/146) but was only 1% in unselected women aged ≥70 years (1/86). IES and DASS-21 scores in response to genetic testing were significantly lower than equivalent scores in response to cancer diagnosis (p<0.001). Correlation tests indicated that although older age is a protective factor against any traumatic impacts of genetic testing, no significant correlation exists between age and distress outcomes. Conclusions The mutation yield in unselected women diagnosed with EOC from a heterogeneous population with no founder mutations was 8% in all ages and 12% in women under 70. Unselected genetic testing in women with EOC was acceptable to patients and is potentially less resource-intensive than current standard practice. PMID:27208206

Assessing the genetic architecture of epithelial ovarian cancer histological subtypes.

PubMed

Cuellar-Partida, Gabriel; Lu, Yi; Dixon, Suzanne C; Fasching, Peter A; Hein, Alexander; Burghaus, Stefanie; Beckmann, Matthias W; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Vanderstichele, Adriaan; Doherty, Jennifer Anne; Rossing, Mary Anne; Chang-Claude, Jenny; Rudolph, Anja; Wang-Gohrke, Shan; Goodman, Marc T; Bogdanova, Natalia; Dörk, Thilo; Dürst, Matthias; Hillemanns, Peter; Runnebaum, Ingo B; Antonenkova, Natalia; Butzow, Ralf; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M; Edwards, Robert P; Kelley, Joseph L; Modugno, Francesmary; Moysich, Kirsten B; Ness, Roberta B; Cannioto, Rikki; Høgdall, Estrid; Høgdall, Claus; Jensen, Allan; Giles, Graham G; Bruinsma, Fiona; Kjaer, Susanne K; Hildebrandt, Michelle A T; Liang, Dong; Lu, Karen H; Wu, Xifeng; Bisogna, Maria; Dao, Fanny; Levine, Douglas A; Cramer, Daniel W; Terry, Kathryn L; Tworoger, Shelley S; Stampfer, Meir; Missmer, Stacey; Bjorge, Line; Salvesen, Helga B; Kopperud, Reidun K; Bischof, Katharina; Aben, Katja K H; Kiemeney, Lambertus A; Massuger, Leon F A G; Brooks-Wilson, Angela; Olson, Sara H; McGuire, Valerie; Rothstein, Joseph H; Sieh, Weiva; Whittemore, Alice S; Cook, Linda S; Le, Nhu D; Blake Gilks, C; Gronwald, Jacek; Jakubowska, Anna; Lubiński, Jan; Kluz, Tomasz; Song, Honglin; Tyrer, Jonathan P; Wentzensen, Nicolas; Brinton, Louise; Trabert, Britton; Lissowska, Jolanta; McLaughlin, John R; Narod, Steven A; Phelan, Catherine; Anton-Culver, Hoda; Ziogas, Argyrios; Eccles, Diana; Campbell, Ian; Gayther, Simon A; Gentry-Maharaj, Aleksandra; Menon, Usha; Ramus, Susan J; Wu, Anna H; Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Timorek, Agnieszka; Szafron, Lukasz; Cunningham, Julie M; Fridley, Brooke L; Winham, Stacey J; Bandera, Elisa V; Poole, Elizabeth M; Morgan, Terry K; Goode, Ellen L; Schildkraut, Joellen M; Pearce, Celeste L; Berchuck, Andrew; Pharoah, Paul D P; Webb, Penelope M; Chenevix-Trench, Georgia; Risch, Harvey A; MacGregor, Stuart

2016-07-01

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

Adult lifetime alcohol consumption and invasive epithelial ovarian cancer risk in a population-based case-control study.

PubMed

Cook, Linda S; Leung, Andy C Y; Swenerton, Kenneth; Gallagher, Richard P; Magliocco, Anthony; Steed, Helen; Koebel, Martin; Nation, Jill; Eshragh, Sima; Brooks-Wilson, Angela; Le, Nhu D

2016-02-01

Meta-analyses report a null association between recent alcohol consumption and ovarian cancer risk. However, because few studies investigated different types of alcohol over adult ages, we investigated adult lifetime and type (beer, wine, spirits) of consumption and risk. Consumption after age 20years was ascertained in 1144 invasive epithelial ovarian cancer cases and 2513 controls in a population-based case-control study (Alberta and British Columbia, Canada, 2001-2012). Non-drinkers consumed any types of alcohol <12 times per year on average. Logistic regression was use to estimate adjusted odds ratios [aOR] and 95% confidence intervals [CIs]. Wine consumption was associated with a risk reduction (aOR=0.67, 95% CI: 0.50-0.88) relative to non-drinkers, but not beer (aOR=1.06, 95% CI: 0.71-1.58) or spirits (aOR=0.98, 95% CI: 0.69-1.39). The reduced risk was stronger for exclusive red wine drinkers (aOR=0.44, 95% CI: 0.19-0.92) than white wine drinkers (aOR=0.79, 95% CI: 0.46-1.34), although most women drank both types of wine. Risk decreased with increasing cumulative consumption of any wine (P-trend<0.05) and was evident for the serous histotype. Wine consumption initiated prior to age 50 was associated with a risk reduction (e.g., at 40-49years, aOR=0.58, 95% CI: 0.42-0.78), but not drinking initiated after 50years of age. For any type, level, or age at initiation of alcohol consumption, we found no increased risks. For the moderate consumption in this study, higher levels of wine consumption were generally associated with risk reductions; reductions may be stronger for red wine. Our results suggest that alcohol consumption that is guideline concordant will not increase epithelial ovarian cancer risk. Copyright © 2015 Elsevier Inc. All rights reserved.

Activation of antioxidant pathways in ras-mediated oncogenic transformation of human surface ovarian epithelial cells revealed by functional proteomics and mass spectrometry.

PubMed

Young, Travis W; Mei, Fang C; Yang, Gong; Thompson-Lanza, Jennifer A; Liu, Jinsong; Cheng, Xiaodong

2004-07-01

Cellular transformation is a complex process involving genetic alterations associated with multiple signaling pathways. Development of a transformation model using defined genetic elements has provided an opportunity to elucidate the role of oncogenes and tumor suppressor genes in the initiation and development of ovarian cancer. To study the cellular and molecular mechanisms of Ras-mediated oncogenic transformation of ovarian epithelial cells, we used a proteomic approach involving two-dimensional electrophoresis and mass spectrometry to profile two ovarian epithelial cell lines, one immortalized with SV40 T/t antigens and the human catalytic subunit of telomerase and the other transformed with an additional oncogenic ras(V12) allele. Of approximately 2200 observed protein spots, we have identified >30 protein targets that showed significant changes between the immortalized and transformed cell lines using peptide mass fingerprinting. Among these identified targets, one most notable group of proteins altered significantly consists of enzymes involved in cellular redox balance. Detailed analysis of these protein targets suggests that activation of Ras-signaling pathways increases the threshold of reactive oxidative species (ROS) tolerance by up-regulating the overall antioxidant capacity of cells, especially in mitochondria. This enhanced antioxidant capacity protects the transformed cells from high levels of ROS associated with the uncontrolled growth potential of tumor cells. It is conceivable that an enhanced antioxidation capability may constitute a common mechanism for tumor cells to evade apoptosis induced by oxidative stresses at high ROS levels.

Systematic Identification of Druggable Epithelial-Stromal Crosstalk Signaling Networks in Ovarian Cancer.

PubMed

Yeung, Tsz-Lun; Sheng, Jianting; Leung, Cecilia S; Li, Fuhai; Kim, Jaeyeon; Ho, Samuel Y; Matzuk, Martin M; Lu, Karen H; Wong, Stephen T C; Mok, Samuel C

2018-05-31

Bulk tumor tissue samples are used for generating gene expression profiles in most research studies, making it difficult to decipher the stroma-cancer crosstalk networks. In the present study, we describe the use of microdissected transcriptome profiles for the identification of cancer-stroma crosstalk networks with prognostic value, which presents a unique opportunity for developing new treatment strategies for ovarian cancer. Transcriptome profiles from microdissected ovarian cancer-associated fibroblasts (CAFs) and ovarian cancer cells from patients with high-grade serous ovarian cancer (n = 70) were used as input data for the computational systems biology program CCCExplorer to uncover crosstalk networks between various cell types within the tumor microenvironment. The crosstalk analysis results were subsequently used for discovery of new indications for old drugs in ovarian cancer by computational ranking of candidate agents. Survival analysis was performed on ovarian tumor-bearing Dicer/Pten double-knockout mice treated with calcitriol, a US Food and Drug Administration-approved agent that suppresses the Smad signaling cascade, or vehicle control (9-11 mice per group). All statistical tests were two-sided. Activation of TGF-β-dependent and TGF-β-independent Smad signaling was identified in a particular subtype of CAFs and was associated with poor patient survival (patients with higher levels of Smad-regulated gene expression by CAFs: median overall survival = 15 months, 95% confidence interval [CI] = 12.7 to 17.3 months; vs patients with lower levels of Smad-regulated gene expression: median overall survival = 26 months, 95% CI = 15.9 to 36.1 months, P = .02). In addition, the activated Smad signaling identified in CAFs was found to be targeted by repositioning calcitriol. Calcitriol suppressed Smad signaling in CAFs, inhibited tumor progression in mice, and prolonged the median survival duration of ovarian cancer-bearing mice from 36 to 48 weeks (P = .04

Inhibition of Aurora-A kinase induces cell cycle arrest in epithelial ovarian cancer stem cells by affecting NFκB pathway

PubMed Central

Alvero, Ayesha B; Visintin, Irene

2011-01-01

Recurrent ovarian cancer is resistant to conventional chemotherapy. A sub-population of ovarian cancer cells, the epithelial ovarian cancer stem cells (EOC stem cells) have stemness properties, constitutive NFκB activity, and represent the chemoresistant population. Currently, there is no effective treatment that targets these cells. Aurora-A kinase (Aurora-A) is associated with tumor initiation and progression and is overexpressed in numerous malignancies. The aim of this study is to determine the effect of Aurora-A inhibition in EOC stem cells. EOC stem cells were treated with the Aurora-A inhibitor, MK-5108. Cell growth was monitored by Incucyte real-time imaging system, cell viability was measured using the Celltiter 96 assay and cytokine levels were quantified using xMAP technology. The intracellular changes associated with MK-5108 treatment are: (1) polyploidy and cell cycle arrest; (2) inhibition of NFκB activity; (3) decreased cytokine production; and (4) nuclear accumulation of IκBα. Thus, inhibition of Aurora-A decreases cell proliferation in the EOC stem cells by inducing cell cycle arrest and affecting the NFκB pathway. As EOC stem cells represent a source of recurrence and chemoresistance, these results suggest that Aurora-A inhibition may effectively target the cancer stem cell population in ovarian cancer. PMID:21623171

NSAID-activated gene 1 mediates pro-inflammatory signaling activation and paclitaxel chemoresistance in type I human epithelial ovarian cancer stem-like cells.

PubMed

Kim, Ki-Hyung; Park, Seong-Hwan; Do, Kee Hun; Kim, Juil; Choi, Kyung Un; Moon, Yuseok

2016-11-01

Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy in developed countries. Chronic endogenous sterile pro-inflammatory responses are strongly linked to EOC progression and chemoresistance to anti-cancer therapeutics. In the present study, the activity of epithelial NF-κB, a key pro-inflammatory transcription factor, was enhanced with the progress of EOC. This result was mechanistically linked with an increased expression of NSAID-Activated Gene 1 (NAG-1) in MyD88-positive type I EOC stem-like cells, compared with that in MyD88-negative type II EOC cells. Elevated NAG-1 as a potent biomarker of poor prognosis in the ovarian cancer was positively associated with the levels of NF-κB activation, chemokines and stemness markers in type I EOC cells. In terms of signal transduction, NAG-1-activated SMAD-linked and non-canonical TGFβ-activated kinase 1 (TAK-1)-activated pathways contributed to NF-κB activation and the subsequent induction of some chemokines and cancer stemness markers. In addition to effects on NF-κB-dependent gene regulation, NAG-1 was involved in expression of EGF receptor and subsequent activation of EGF receptor-linked signaling. The present study also provided evidences for links between NAG-1-linked signaling and chemoresistance in ovarian cancer cells. NAG-1 and pro-inflammatory NF-κB were positively associated with resistance to paclitaxel in MyD88-positive type I EOC cells. Mechanistically, this chemoresistance occurred due to enhanced activation of the SMAD-4- and non-SMAD-TAK-1-linked pathways. All of the present data suggested NAG-1 protein as a crucial mediator of EOC progression and resistance to the standard first-line chemotherapy against EOC, particularly in MyD88-positive ovarian cancer stem-like cells.

Investigating the clinical potential for 14-3-3 zeta protein to serve as a biomarker for epithelial ovarian cancer

PubMed Central

2013-01-01

Objective Recently, 14-3-3 zeta protein was identified as a potential serum biomarker of epithelial ovarian cancer (EOC). The goal of this study was to investigate the clinical potential of 14-3-3 zeta protein for monitoring EOC progression compared with CA-125 and HE4. Design Prospective follow-up study. Setting University of Pecs Medical Center Department of Obstetrics and Gynecology/Oncology (Pecs, Hungary). Population Thirteen EOC patients with advanced stage (FIGO IIb-IIIc) epithelial ovarian cancer that underwent radical surgery and received six consecutive cycles of first line chemotherapy (paclitaxel, carboplatin) in 21-day intervals. Methods Pre- and post-chemotherapy computed tomography (CT) scans were performed. Serum levels of CA-125, HE4, and 14-3-3 zeta protein were detected by enzyme-linked immunosorbent assay (ELISA) and quantitative electrochemiluminescence assay (ECLIA). Main outcome measures Serum levels of CA-125, HE4, and 14-3-3 zeta protein, as well as lesion size according to pre- and post-chemotherapy CT scans. Results Serum levels of CA-125 and HE4 were found to significantly decrease following chemotherapy, and this was consistent with the decrease in lesion size detected post-chemotherapy. In contrast, 14-3-3 zeta protein levels did not significantly differ in healthy postmenopausal patients versus EOC patients. Conclusions Determination of CA-125 and HE4 serum levels for the determination of the risk of ovarian malignancy algorithm (ROMA) represents a useful tool for the prediction of chemotherapy efficacy for EOC patients. However, levels of 14-3-3 zeta protein were not found to vary significantly as a consequence of treatment. Therefore we question if 14-3-3 zeta protein is a reliable biomarker, which correlates with the clinical behavior of EOC. PMID:24238270

Ten-year survival after epithelial ovarian cancer is not associated with BRCA mutation status.

PubMed

Kotsopoulos, Joanne; Rosen, Barry; Fan, Isabel; Moody, Joel; McLaughlin, John R; Risch, Harvey; May, Taymaa; Sun, Ping; Narod, Steven A

2016-01-01

After a diagnosis of ovarian cancer, positive BRCA mutation status confers a transient mortality benefit that diminishes with time. The majority of women who survive for 10-12 years are effectively cured of their disease. Thus, it is important to estimate the probability of long-term survival by BRCA mutation status and treatment-related factors. We included unselected epithelial ovarian cancers diagnosed in Ontario, Canada from 1995 to 1999 and from 2002 to 2004. Clinical information was obtained from medical records. Survival status was determined by linkage to the Ontario Cancer Registry. We estimated the annual mortality for these patients. We compared women who did and did not survive 10 years for a range of factors including BRCA mutation status and extent of residual disease post-surgery. Of the 1421 patients, 109 (7.7%) had BRCA1 mutations and 68 (4.8%) had BRCA2 mutations. A status of no residual disease was achieved by 39% of non-carriers and 19% of mutation carriers (P<0.0001). By 10-years of follow-up, 43% of non-carriers, 57% of BRCA1 mutation carriers and 69% of BRCA2 mutation carriers had died from ovarian cancer. Among women with stage III/IV serous cancers and no residual disease, the 10-year actuarial survival was 42% for non-carriers and 29% for mutation carriers (P=0.40). The initial survival advantage among women with BRCA mutations may reflect a higher initial sensitivity of BRCA carriers to chemotherapy, but this response does not predict long-term survival. The strongest predictor of long-term survival is status of no residual disease at resection. Copyright © 2015. Published by Elsevier Inc.

Menstrual pain and risk of epithelial ovarian cancer: Results from the Ovarian Cancer Association Consortium.

PubMed

Babic, Ana; Harris, Holly R; Vitonis, Allison F; Titus, Linda J; Jordan, Susan J; Webb, Penelope M; Risch, Harvey A; Rossing, Mary Anne; Doherty, Jennifer A; Wicklund, Kristine; Goodman, Marc T; Modugno, Francesmary; Moysich, Kirsten B; Ness, Roberta B; Kjaer, Susanne K; Schildkraut, Joellen; Berchuck, Andrew; Pearce, Celeste L; Wu, Anna H; Cramer, Daniel W; Terry, Kathryn L

2018-02-01

Menstrual pain, a common gynecological condition, has been associated with increased risk of ovarian cancer in some, but not all studies. Furthermore, potential variations in the association between menstrual pain and ovarian cancer by histologic subtype have not been adequately evaluated due to lack of power. We assessed menstrual pain using either direct questions about having experienced menstrual pain, or indirect questions about menstrual pain as indication for use of hormones or medications. We used multivariate logistic regression to calculate the odds ratio (OR) for the association between severe menstrual pain and ovarian cancer, adjusting for potential confounders and multinomial logistic regression to calculate ORs for specific histologic subtypes. We observed no association between ovarian cancer and menstrual pain assessed by indirect questions. Among studies using direct question, severe pain was associated with a small but significant increase in overall risk of ovarian cancer (OR = 1.07, 95% CI: 1.01-1.13), after adjusting for endometriosis and other potential confounders. The association appeared to be more relevant for clear cell (OR = 1.48, 95% CI: 1.10-1.99) and serous borderline (OR = 1.31, 95% CI: 1.05-1.63) subtypes. In this large international pooled analysis of case-control studies, we observed a small increase in risk of ovarian cancer for women reporting severe menstrual pain. While we observed an increased ovarian cancer risk with severe menstrual pain, the possibility of recall bias and undiagnosed endometriosis cannot be excluded. Future validation in prospective studies with detailed information on endometriosis is needed. © 2017 UICC.

Statin use and mortality among ovarian cancer patients: A population-based cohort study.

PubMed

Verdoodt, Freija; Kjaer Hansen, Merete; Kjaer, Susanne K; Pottegård, Anton; Friis, Søren; Dehlendorff, Christian

2017-07-15

Statin use has been suggested to improve prognosis in cancer patients, however, for ovarian cancer, the evidence is sparse. From the Danish Cancer Registry, we identified patients aged 30-84 years with a histologically verified first diagnosis of epithelial ovarian cancer between 2000 and 2013. Data on filled prescriptions, death, and potential confounding factors were obtained from nationwide registers. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnostic statin use and all-cause or ovarian cancer-specific mortality. Among 4,419 patients with epithelial ovarian cancer, post-diagnostic statin use was not statistically significantly associated with all-cause (HR: 0.90, 95% CI: 0.78-1.04) or ovarian cancer-specific mortality (HR: 0.90, 95% CI: 0.76-1.08). There was little evidence of a dose-response relationship and the neutral associations persisted in sensitivity analyses. In women with endometrioid or clear cell tumour histology, cancer-specific mortality was reduced by 30-40% among statin users compared to non-users, however the analyses were limited by small numbers. Significantly reduced mortality with statin use was observed in subcohorts of new users of statins and of patients not using low-dose aspirin. In conclusion, we found no strong evidence of an association between post-diagnostic statin use and reduced mortality in ovarian cancer patients. However, our finding of potential differential susceptibility to statins among patients with different histologic types of ovarian cancer warrants further evaluation. © 2017 UICC.

Metformin Hydrochloride, Carboplatin, and Paclitaxel in Treating Patients With Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

ClinicalTrials.gov

2017-01-24

Ovarian Papillary Serous Carcinoma; Ovarian Serous Cystadenocarcinoma; Recurrent Fallopian Tube Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Primary Peritoneal Cavity Cancer

Second-Line Intraperitoneal Chemotherapy for Recurrent Epithelial Ovarian, Tubal and Peritoneal Cancer: A Propensity Score-Matching Study.

PubMed

Lu, Chien-Hsing; Chang, Yen-Hou; Lee, Wai-Hou; Chang, Yi; Peng, Chia-Wen; Chuang, Chi-Mu

2016-01-01

The superiority of frontline intraperitoneal (IP) over intravenous (IV) chemotherapy is well established in the treatment of epithelial ovarian cancer. However, the role of IP chemotherapy in the second-line setting has rarely been investigated. Consecutive patients diagnosed with recurrent epithelial, tubal and peritoneal cancers between January 2000 and December 2012 were recruited using a propensity score-matching technique to adjust relevant risk factors. In total, 310 patients were included in the final analysis (94 for platinum-refractory/resistant disease and 216 for platinum-sensitive disease). IP chemotherapy demonstrated significantly longer median progression-free survival than IV chemotherapy (4.9 vs. 2.4 months, p < 0.001, for platinum-refractory/resistant disease, and 9.8 vs. 6.9 months, p < 0.001, for platinum-sensitive disease). Second-line IP chemotherapy confers longer progression-free survival than IV chemotherapy. Large-scale clinical trials should be conducted to validate the true efficacy. © 2016 S. Karger AG, Basel.

Determine the Role of Canonical Wnt Signaling in Ovarian Tumorigenesis

DTIC Science & Technology

2011-10-01

oncogenic Ras. Nature, 2000. 406(6792): p. 207-10. 11 16. Kuilman, T., et al., The essence of senescence. Genes Dev, 2010. 24(22): p. 2463- 79. 17...Benjamin G. Bitler, Jasmine P. Nicodemus, Hua Li, et al. Senescence Wnt5a Suppresses Epithelial Ovarian Cancer by Promoting Cellular...Suppresses Epithelial Ovarian Cancer by Promoting Cellular Senescence Benjamin G. Bitler1, Jasmine P. Nicodemus1, Hua Li1, Qi Cai2, Hong Wu3, Xiang

Gene Set−Based Integrative Analysis Revealing Two Distinct Functional Regulation Patterns in Four Common Subtypes of Epithelial Ovarian Cancer

PubMed Central

Chang, Chia-Ming; Chuang, Chi-Mu; Wang, Mong-Lien; Yang, Yi-Ping; Chuang, Jen-Hua; Yang, Ming-Jie; Yen, Ming-Shyen; Chiou, Shih-Hwa; Chang, Cheng-Chang

2016-01-01

Clear cell (CCC), endometrioid (EC), mucinous (MC) and high-grade serous carcinoma (SC) are the four most common subtypes of epithelial ovarian carcinoma (EOC). The widely accepted dualistic model of ovarian carcinogenesis divided EOCs into type I and II categories based on the molecular features. However, this hypothesis has not been experimentally demonstrated. We carried out a gene set-based analysis by integrating the microarray gene expression profiles downloaded from the publicly available databases. These quantified biological functions of EOCs were defined by 1454 Gene Ontology (GO) term and 674 Reactome pathway gene sets. The pathogenesis of the four EOC subtypes was investigated by hierarchical clustering and exploratory factor analysis. The patterns of functional regulation among the four subtypes containing 1316 cases could be accurately classified by machine learning. The results revealed that the ERBB and PI3K-related pathways played important roles in the carcinogenesis of CCC, EC and MC; while deregulation of cell cycle was more predominant in SC. The study revealed that two different functional regulation patterns exist among the four EOC subtypes, which were compatible with the type I and II classifications proposed by the dualistic model of ovarian carcinogenesis. PMID:27527159

New paradigms for BRCA1/BRCA2 testing in women with ovarian cancer: results of the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study.

PubMed

Plaskocinska, Inga; Shipman, Hannah; Drummond, James; Thompson, Edward; Buchanan, Vanessa; Newcombe, Barbara; Hodgkin, Charlotte; Barter, Elisa; Ridley, Paul; Ng, Rita; Miller, Suzanne; Dann, Adela; Licence, Victoria; Webb, Hayley; Tan, Li Tee; Daly, Margaret; Ayers, Sarah; Rufford, Barnaby; Earl, Helena; Parkinson, Christine; Duncan, Timothy; Jimenez-Linan, Mercedes; Sagoo, Gurdeep S; Abbs, Stephen; Hulbert-Williams, Nicholas; Pharoah, Paul; Crawford, Robin; Brenton, James D; Tischkowitz, Marc

2016-10-01

Over recent years genetic testing for germline mutations in BRCA1/BRCA2 has become more readily available because of technological advances and reducing costs. To explore the feasibility and acceptability of offering genetic testing to all women recently diagnosed with epithelial ovarian cancer (EOC). Between 1 July 2013 and 30 June 2015 women newly diagnosed with EOC were recruited through six sites in East Anglia, UK into the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study. Eligibility was irrespective of patient age and family history of cancer. The psychosocial arm of the study used self-report, psychometrically validated questionnaires (Depression Anxiety and Stress Scale (DASS-21); Impact of Event Scale (IES)) and cost analysis was performed. 232 women were recruited and 18 mutations were detected (12 in BRCA1, 6 in BRCA2), giving a mutation yield of 8%, which increased to 12% in unselected women aged <70 years (17/146) but was only 1% in unselected women aged ≥70 years (1/86). IES and DASS-21 scores in response to genetic testing were significantly lower than equivalent scores in response to cancer diagnosis (p<0.001). Correlation tests indicated that although older age is a protective factor against any traumatic impacts of genetic testing, no significant correlation exists between age and distress outcomes. The mutation yield in unselected women diagnosed with EOC from a heterogeneous population with no founder mutations was 8% in all ages and 12% in women under 70. Unselected genetic testing in women with EOC was acceptable to patients and is potentially less resource-intensive than current standard practice. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Genetic risk assessment for women with epithelial ovarian cancer: referral patterns and outcomes in a university gynecologic oncology clinic.

PubMed

Petzel, Sue V; Vogel, Rachel Isaksson; Bensend, Tracy; Leininger, Anna; Argenta, Peter A; Geller, Melissa A

2013-10-01

Little is known about genetic service utilization and ovarian cancer. We identified the frequency and outcome of genetic counseling referral, predictors of referral, and referral uptake for ovarian cancer patients. Using pathology reports, we identified all epithelial ovarian cancer patients seen in a university gynecologic oncology clinic (1/04-8/06). Electronic medical records (EMR) were used to document genetic service referral, time from diagnosis-to-referral, point-in-treatment at referral, personal/family cancer history, demographics, and genetic test results. Groups were compared using chi-squared and Fisher's exact test for categorical variables and t-tests for continuous variables. The study population consisted of 376 women with ovarian cancer, 72 (19 %) of who were referred for genetic counseling/testing, primarily during surveillance. Of those referred, 42 (58 %) had personal or family genetic counseling and 34 (47 %) were ultimately tested or identified due to known family mutation. Family history and prior cancer were associated with referral. Family history, living in a larger community, higher-stage disease, and serous histology were associated with undergoing genetic counseling. Risk assessment identified 20 BRCA1/2 (5.3 %) and 1 HNPCC (0.3 %) mutation carriers. Based on recent estimates that 11.7-16.6 % of women with ovarian cancer are BRCA carriers and 2 % are HNPCC carriers, results suggest under-identification of carriers and under-utilization of genetic services by providers and patients. Interventions to increase medical providers' referrals, even in a specialized oncology clinic, are necessary and may include innovations in educating these providers using web-based methods. Ease of referral by the introduction of an electronic cancer genetic referral form represents another new direction that may increase genetic risk assessment for high-risk women with ovarian cancer.

Current and future role of circulating tumor cells in patients with epithelial ovarian cancer.

PubMed

Van Berckelaer, C; Brouwers, A J; Peeters, D J E; Tjalma, W; Trinh, X B; van Dam, P A

2016-12-01

Circulating tumor cells (CTCs) are viable tumor cells that are released into the circulatory system. CTCs have shown a prognostic value in numerous solid tumors. CTC research in epithelial ovarian carcinoma (EOC) has attracted only little attention. Since the primary route of metastasis in EOC is considered to be direct peritoneal spread in the abdominal cavity and distant metastases only occur in one third of the patients, it was thought that there is not enough shedding of tumor cells in the circulation. Nevertheless recent studies revealed an important role of hematogenous spread in EOC and showed that CTC status is associated with advanced tumor stage, CA-125 levels and residual disease after surgery. Furthermore the presence of CTCs correlates with shorter overall and disease free survival. However this prognostic value of CTCs in EOC seems to depend on the used isolation and detection methods. In EOC function- or density based enrichment methods seem to offer more promising results then epithelial cell adhesion molecule (EpCAM)-based approaches. This can be explained by a low number of EpCAM positive CTCs in EOC and the downregulation of EpCAM during epithelial-to-mesenchymal transition (EMT). The presence of CTCs might also have predictive value as CTC status was associated with treatment response in two studies and CTCs showed to be a better monitoring tool then CA-125 in a small population. The (genotypic) characterization of CTCs might become even more important in the future paving the way for CTCs to a true predictive "liquid tumor biopsy". Copyright © 2016 Elsevier Ltd. All rights reserved.

Overexpression of SnoN/SkiL, amplified at the 3q26.2 locus, in ovarian cancers: A role in ovarian pathogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nanjundan, Meera; Cheng, Kwai Wa; Zhang, Fan

2008-07-18

High-resolution array comparative genomic hybridization of 235 serous epithelial ovarian cancers demonstrated a regional increase at 3q26.2 encompassing SnoN/SkiL, a coregulator of SMAD/TGF{beta} signaling. SnoN RNA transcripts were elevated in {approx}80% of advanced stage serous epithelial ovarian cancers. In both immortalized normal (TIOSE) and ovarian carcinoma cell lines (OVCA), SnoN RNA levels were increased by TGF{beta} stimulation and altered by LY294002 and JNK II inhibitor treatment suggesting that the PI3K and JNK signaling pathways may regulate TGF{beta}-induced increases in SnoN RNA. In TIOSE, SnoN protein levels were reduced 15min post TGF{beta}-stimulation, likely by proteosome-mediated degradation. In contrast, in OVCA, SnoNmore » levels were elevated 3h post-stimulation potentially as a result of inhibition of the proteosome. To elucidate the role of SnoN in ovarian tumorigenesis, we explored the effects of both increasing and decreasing SnoN levels. In both TIOSE and OVCA, SnoN siRNA decreased cell growth between 20 and 50% concurrent with increased p21 levels. In TIOSE, transient expression of SnoN repressed TGF{beta} induction of PAI-1 promoters with little effect on the p21 promoter or resultant cell growth. In contrast to the effects of transient expression, stable expression of SnoN in TIOSE led to growth arrest through induction of senescence. Collectively, these results implicate SnoN levels in multiple roles during ovarian carcinogenesis: promoting cellular proliferation in ovarian cancer cells and as a positive mediator of cell cycle arrest and senescence in non-transformed ovarian epithelial cells.« less

Molecular Signature for Lymphatic Invasion Associated with Survival of Epithelial Ovarian Cancer.

PubMed

Paik, E Sun; Choi, Hyun Jin; Kim, Tae-Joong; Lee, Jeong-Won; Kim, Byoung-Gie; Bae, Duk-Soo; Choi, Chel Hun

2018-04-01

We aimed to develop molecular classifier that can predict lymphatic invasion and their clinical significance in epithelial ovarian cancer (EOC) patients. We analyzed gene expression (mRNA, methylated DNA) in data from The Cancer Genome Atlas. To identify molecular signatures for lymphatic invasion, we found differentially expressed genes. The performance of classifier was validated by receiver operating characteristics analysis, logistic regression, linear discriminant analysis (LDA), and support vector machine (SVM). We assessed prognostic role of classifier using random survival forest (RSF) model and pathway deregulation score (PDS). For external validation,we analyzed microarray data from 26 EOC samples of Samsung Medical Center and curatedOvarianData database. We identified 21 mRNAs, and seven methylated DNAs from primary EOC tissues that predicted lymphatic invasion and created prognostic models. The classifier predicted lymphatic invasion well, which was validated by logistic regression, LDA, and SVM algorithm (C-index of 0.90, 0.71, and 0.74 for mRNA and C-index of 0.64, 0.68, and 0.69 for DNA methylation). Using RSF model, incorporating molecular data with clinical variables improved prediction of progression-free survival compared with using only clinical variables (p < 0.001 and p=0.008). Similarly, PDS enabled us to classify patients into high-risk and low-risk group, which resulted in survival difference in mRNA profiles (log-rank p-value=0.011). In external validation, gene signature was well correlated with prediction of lymphatic invasion and patients' survival. Molecular signature model predicting lymphatic invasion was well performed and also associated with survival of EOC patients.

Expression of M2-polarized macrophages is associated with poor prognosis for advanced epithelial ovarian cancer.

PubMed

Lan, Chunyan; Huang, Xin; Lin, Suxia; Huang, Huiqiang; Cai, Qichun; Wan, Ting; Lu, Jiabin; Liu, Jihong

2013-06-01

Macrophages are polarized into two functionally distinct forms, M1 and M2, in response to different microenvironment. Tumor-associated macrophages (TAMs) generally have M2 phenotype and promote tumor progression. Few studies to date have described the infiltration of M2-polarized macrophages in ovarian cancer. We used two macrophages markers, CD68 and CD163, to analyze the expression of TAMs and to clarify the relationship between the M2 form and survival in advanced ovarian cancer. Clinical data of 110 patients with stages III-IV epithelial ovarian cancer at Sun Yat-sen University Cancer Center between 1999 and 2007 were retrospectively reviewed. Immunohistochemical staining of CD68 and CD163 was performed. Correlations between macrophage density and patient survival were analyzed. Our data showed that no significant difference was observed in survival between patients in the high- and the low-CD68 expression groups. In contrast, the progression-free survival (PFS) rates (p = 0.003) and overall survival (OS) rates (p = 0.004) were significantly higher in the low-CD163 expression group than in the high-CD163 expression group, respectively. Similarly, we also observed significantly improved 3-year PFS (49.8% vs. 11.0%, p < 0.001) and OS (77.4% vs. 45.0%, p < 0.001) rates in patients in the low-CD163/CD68 ratio group when compared with the high-CD163/CD68 ratio group. Multivariate analysis identified the density of CD163-positive cells as well as the ratio of CD163/CD68 as negative predictors for PFS and OS, respectively. Our results show that the infiltration of CD163-positive M2 macrophages as well as activation of macrophages towards the M2 phenotype may contribute to poor survival in advanced ovarian cancer.

The relationship between cisplatin resistance and histone deacetylase isoform overexpression in epithelial ovarian cancer cell lines

PubMed Central

Kim, Min-Gyun; Pak, Jhang Ho; Choi, Won Ho; Park, Jeong-Yeol; Nam, Joo-Hyun

2012-01-01

Objective To investigate the relationship between cisplatin resistance and histone deacetylase (HDAC) isoform overexpression in ovarian cancer cell lines. Methods Expression of four HDAC isoforms (HDAC 1, 2, 3, and 4) in two ovarian cancer cell lines, SKOV3 and OVCAR3, exposed to various concentrations of cisplatin was examined by western blot analyses. Cells were transfected with plasmid DNA of each HDAC. The overexpression of protein and mRNA of each HDAC was confirmed by western blot and reverse transcriptase-polymerase chain reaction analyses, respectively. The cell viability of the SKOV3 and OVCAR3 cells transfected with HDAC plasmid DNA was measured using the cell counting kit-8 assay after treatment with cisplatin. Results The 50% inhibitory concentration of the SKOV3 and OVCAR3 cells can be determined 15-24 hours after treatment with 15 µg/mL cisplatin. The expression level of acetylated histone 3 protein in SKOV3 cells increased after exposure to cisplatin. Compared with control cells at 24 hours after cisplatin exposure, the viability of SKOV3 cells overexpressing HDAC 1 and 3 increased by 15% and 13% (p<0.05), respectively. On the other hand, OVCAR3 cells that overexpressed HDAC 2 and 4 exhibited increased cell viability by 23% and 20% (p<0.05), respectively, compared with control cells 24 hours after exposure to cisplatin. Conclusion In SKOV3 and OVCAR3 epithelial ovarian cancer cell lines, the correlation between HDAC overexpression and cisplatin resistance was confirmed. However, the specific HDAC isoform associated with resistance to cisplatin varied depending on the ovarian cancer cell line. These results may suggest that each HDAC isoform conveys cisplatin resistance via different mechanisms. PMID:22808361

Models of ovarian cancer metastasis: Murine models

PubMed Central

Šale, Sanja; Orsulic, Sandra

2008-01-01

Mice have mainly been used in ovarian cancer research as immunodeficient hosts for cell lines derived from the primary tumors and ascites of ovarian cancer patients. These xenograft models have provided a valuable system for pre-clinical trials, however, the genetic complexity of human tumors has precluded the understanding of key events that drive metastatic dissemination. Recently developed immunocompetent, genetically defined mouse models of epithelial ovarian cancer represent significant improvements in the modeling of metastatic disease. PMID:19337569

Treatment Options by Stage (Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer)

MedlinePlus

... of Ovarian Germ Cell Tumors Ovarian Low Malignant Potential Tumors Symptoms, Tests, Prognosis, & Stages Treatment of Ovarian Low Malignant Potential Tumors Prevention of Ovarian, Fallopian Tube, & Primary Peritoneal ...

The Inhibitory Effect of Doxycycline on Cisplatin-Sensitive and -Resistant Epithelial Ovarian Cancer

PubMed Central

Ma, Bei; Xu, Ming-juan

2014-01-01

Background Detecting a new effective and hypotoxic anticancer drug is an emerging new strategy for cancer chemotherapy. Doxycycline (DC) is a kind of antibiotics but also inhibits tumorigenesis. Methods MTT and cell invasion assay, flow cytometry, western-blot analysis and nude mice were used to investigate the effects and underlying mechanisms of doxycycline on epithelial ovarian cancer cells. Results Doxycycline inhibited the proliferation and invasion of SKOV3 and SKOV3/DDP; induced moderate apoptosis of SKOV3/DDP. CXCR4 expression at both mRNA and protein levels was downregulated in both cell lines when treated with doxycycline. Akt and ERK1/2 were involved in doxycycline effect on cell proliferation of SKOV3 but not of SKOV3/DDP. Akt and EKR1/2 phosphorylation were activated by SDF-1α, which was then inhibited by doxycycline in SKOV3. Pro-caspase-3 expression was significantly higher in SKOV3 than that in SKOV3/DDP which was upregulated when treated with doxycycline. In vivo, doxycycline inhibited peritoneal tumor xenograft and decreased malignant ascites. Conclusion Doxycycline not only has an inhibitory effect on ovarian cancer, but also can increase sensitivity to cisplatin. SDF-1α/CXCR4-regulated Akt and ERK 1/2 activations are probably involved in the antitumor effect of doxycycline on SKOV3 cells, while upregulation of pro-caspase-3 may be the main mechanism involved in SKOV3/DDP cells. PMID:24598933

CD73 Regulates Stemness and Epithelial-Mesenchymal Transition in Ovarian Cancer-Initiating Cells.

PubMed

Lupia, Michela; Angiolini, Francesca; Bertalot, Giovanni; Freddi, Stefano; Sachsenmeier, Kris F; Chisci, Elisa; Kutryb-Zajac, Barbara; Confalonieri, Stefano; Smolenski, Ryszard T; Giovannoni, Roberto; Colombo, Nicoletta; Bianchi, Fabrizio; Cavallaro, Ugo

2018-04-10

Cancer-initiating cells (CICs) have been implicated in tumor development and aggressiveness. In ovarian carcinoma (OC), CICs drive tumor formation, dissemination, and recurrence, as well as drug resistance, thus accounting for the high death-to-incidence ratio of this neoplasm. However, the molecular mechanisms that underlie such a pathogenic role of ovarian CICs (OCICs) remain elusive. Here, we have capitalized on primary cells either from OC or from its tissues of origin to obtain the transcriptomic profile associated with OCICs. Among the genes differentially expressed in OCICs, we focused on CD73, which encodes the membrane-associated 5'-ectonucleotidase. The genetic inactivation of CD73 in OC cells revealed that this molecule is causally involved in sphere formation and tumor initiation, thus emerging as a driver of OCIC function. Furthermore, functional inhibition of CD73 via either a chemical compound or a neutralizing antibody reduced sphere formation and tumorigenesis, highlighting the druggability of CD73 in the context of OCIC-directed therapies. The biological function of CD73 in OCICs required its enzymatic activity and involved adenosine signaling. Mechanistically, CD73 promotes the expression of stemness and epithelial-mesenchymal transition-associated genes, implying a regulation of OCIC function at the transcriptional level. CD73, therefore, is involved in OCIC biology and may represent a therapeutic target for innovative treatments aimed at OC eradication. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

BORIS/CTCFL mRNA isoform expression and epigenetic regulation in epithelial ovarian cancer

PubMed Central

Link, Petra A.; Zhang, Wa; Odunsi, Kunle; Karpf, Adam R.

2013-01-01

Cancer germline (CG) genes are normally expressed in germ cells and aberrantly expressed in a variety of cancers; their immunogenicity has led to the widespread development of cancer vaccines targeting these antigens. BORIS/CTCFL is an autosomal CG antigen and promising cancer vaccine target. BORIS is the only known paralog of CTCF, a gene intimately involved in genomic imprinting, chromatin insulation, and nuclear regulation. We have previously shown that BORIS is expressed in epithelial ovarian cancer (EOC) and that its expression coincides with promoter and global DNA hypomethylation. Recently, 23 different BORIS mRNA variants have been described, and have been functionally grouped into six BORIS isoform families (sf1–sf6). In the present study, we have characterized the expression of BORIS isoform families in normal ovary (NO) and EOC, the latter of which were selected to include two groups with widely varying global DNA methylation status. We find selective expression of BORIS isoform families in NO, which becomes altered in EOC, primarily by the activation of BORIS sf1 in EOC. When comparing EOC samples based on methylation status, we find that BORIS sf1 and sf2 isoform families are selectively activated in globally hypomethylated tumors. In contrast, CTCF is downregulated in EOC, and the ratio of BORIS sf1, sf2, and sf6 isoform families as a function of CTCF is elevated in hypomethylated tumors. Finally, the expression of all BORIS isoform families was induced to varying extents by epigenetic modulatory drugs in EOC cell lines, particularly when DNMT and HDAC inhibitors were used in combination. PMID:23390377

Variation in neoadjuvant chemotherapy utilization for epithelial ovarian cancer at high volume hospitals in the United States and associated survival.

PubMed

Barber, Emma L; Dusetzina, Stacie B; Stitzenberg, Karyn B; Rossi, Emma C; Gehrig, Paola A; Boggess, John F; Garrett, Joanne M

2017-06-01

To estimate variation in the use of neoadjuvant chemotherapy by high volume hospitals and to determine the association between hospital utilization of neoadjuvant chemotherapy and survival. We identified incident cases of stage IIIC or IV epithelial ovarian cancer in the National Cancer Database from 2006 to 2012. Inclusion criteria were treatment at a high volume hospital (>20 cases/year) and treatment with both chemotherapy and surgery. A logistic regression model was used to predict receipt of neoadjuvant chemotherapy based on case-mix predictors (age, comorbidities, stage etc). Hospitals were categorized by the observed-to-expected ratio for neoadjuvant chemotherapy use as low, average, or high utilization hospitals. Survival analysis was performed. We identified 11,574 patients treated at 55 high volume hospitals. Neoadjuvant chemotherapy was used for 21.6% (n=2494) of patients and use varied widely by hospital, from 5%-55%. High utilization hospitals (n=1910, 10 hospitals) had a median neoadjuvant chemotherapy rate of 39% (range 23-55%), while low utilization hospitals (n=2671, 14 hospitals) had a median rate of 10% (range 5-17%). For all ovarian cancer patients adjusting for clinical and socio-demographic factors, treatment at a hospital with average or high neoadjuvant chemotherapy utilization was associated with a decreased rate of death compared to treatment at a low utilization hospital (HR 0.90 95% CI 0.83-0.97 and HR 0.85 95% CI 0.75-0.95). Wide variation exists in the utilization of neoadjuvant chemotherapy to treat stage IIIC and IV epithelial ovarian cancer even among high volume hospitals. Patients treated at hospitals with low rates of neoadjuvant chemotherapy utilization experience decreased survival. Copyright © 2017 Elsevier Inc. All rights reserved.

Variation in Neoadjuvant Chemotherapy Utilization for Epithelial Ovarian Cancer at High Volume Hospitals in the United States and Associated Survival

PubMed Central

Barber, Emma L; Dusetzina, Stacie B; Stitzenberg, Karyn B; Rossi, Emma C; Gehrig, Paola A; Boggess, John F; Garrett, Joanne M

2017-01-01

Objective To estimate variation in the use of neoadjuvant chemotherapy by high volume hospitals and to determine the association between hospital utilization of neoadjuvant chemotherapy and survival. Methods We identified incident cases of stage IIIC or IV epithelial ovarian cancer in the National Cancer Database from 2006–2012. Inclusion criteria were treatment at a high volume hospital (>20 cases/yr) and treatment with both chemotherapy and surgery. A logistic regression model was used to predict receipt of neoadjuvant chemotherapy based on case-mix predictors (age, comorbidities, stage etc). Hospitals were categorized by the observed-to-expected ratio for neoadjuvant chemotherapy use as low, average, or high utilization hospitals. Survival analysis was performed. Results We identified 11,574 patients treated at 55 high volume hospitals. Neoadjuvant chemotherapy was used for 21.6% (n=2494) of patients and use varied widely by hospital, from 5%–55%. High utilization hospitals (n=1910, 10 hospitals) had a median neoadjuvant chemotherapy rate of 39% (range 23–55%), while low utilization hospitals (n=2671, 14 hospitals) had a median rate of 10% (range 5–17%). For all ovarian cancer patients adjusting for clinical and socio-demographic factors, treatment at a hospital with average or high neoadjuvant chemotherapy utilization was associated with a decreased rate of death compared to treatment at a low utilization hospital (HR 0.90 95%CI 0.83–0.97 and HR 0.85 95%CI 0.75–0.95). Conclusions Wide variation exists in the utilization of neoadjuvant chemotherapy to treat stage IIIC and IV epithelial ovarian cancer even among high volume hospitals. Patients treated at hospitals with low rates of neoadjuvant chemotherapy utilization experience decreased survival. PMID:28366545

CA-125 AUC as a predictor for epithelial ovarian cancer relapse.

PubMed

Mano, António; Falcão, Amílcar; Godinho, Isabel; Santos, Jorge; Leitão, Fátima; de Oliveira, Carlos; Caramona, Margarida

2008-01-01

The aim of the present work was to evaluate the usefulness of CA-125 normalized in time area under the curve (CA-125 AUC) to signalise epithelial ovarian cancer relapse. Data from a hundred and eleven patients were submitted to two different approaches based on CA-125 AUC increase values to predict patient relapse. In Criterion A total CA-125 AUC normalized in time value (AUC(i)) was compared with the immediately previous one (AUC(i-1)) using the formulae AUC(i) > or = F * AUC(i-1) (several F values were tested) to find the appropriate close related increment associated to patient relapse. In Criterion B total CA-125 AUC normalised in time was calculated and several cut-off values were correlated with patient relapse prediction capacity. In Criterion A the best accuracy was achieved with a factor (F) of 1.25 (increment of 25% from the previous status), while in Criterion B the best accuracies were achieved with cut-offs of 25, 50, 75 and 100 IU/mL. The mean lead time to relapse achieved with Criterion A was 181 days, while with Criterion B they were, respectively, 131, 111, 63 and 11 days. Based on our results we believe that conjugation and sequential application of both criteria in patient relapse detection should be highly advisable. CA-125 AUC rapid burst in asymptomatic patients should be firstly evaluated using Criterion A with a high accuracy (0.85) and with a substantial mean lead time to relapse (181 days). If a negative answer was obtained then Criterion B should performed to confirm the absence of relapse.

Amplification and overexpression of aurora kinase A (AURKA) in immortalized human ovarian epithelial (HOSE) cells.

PubMed

Chung, C M; Man, C; Jin, Y; Jin, C; Guan, X Y; Wang, Q; Wan, T S K; Cheung, A L M; Tsao, S W

2005-07-01

Immortalization is an early and essential step of human carcinogenesis. Amplification of chromosome 20q has been shown to be a common event in immortalized cells and cancers. We have previously reported that gain and amplification of chromosome 20q is a non-random and common event in immortalized human ovarian surface epithelial (HOSE) cells. The chromosome 20q harbors genes including TGIF2 (20q11.2-q12), AIB1 (20q12), PTPN1 (20q13.1), ZNF217 (20q13.2), and AURKA (20q13.2-q13.3), which were previously reported to be amplified and overexpressed in ovarian cancers. Some of these genes may be involved in immortalization of HOSE cells and represent crucial premalignant changes in ovarian surface epithelium. Investigation of the involvement of these genes was examined in four pairs of pre-crisis (preimmortalized) and post-crisis (immortalized) HOSE cells. Overexpression of AURKA (Aurora kinase A), also known as BTAK and STK15, by both real time-quantitative polymerase chain reaction (RT-QPCR) and Western blotting was detected in all the four immortalized HOSE cells examined while overexpression of AIB1 and ZNF217 was observed in two of four immortalized HOSE cells examined. Overexpression of TGIF2 and PTPN1 was not significant in our immortalized HOSE cell systems. The degree of overexpression of AURKA was shown to be closely associated with the amplification of chromosome 20q in immortalized HOSE cells. Fluorescence in situ hybridization (FISH) with labeled P1 artificial clone (PAC) confirmed the amplification of the chromosomal region (20q13.2-13.3) where AURKA resides. DNA amplification of AURKA was also confirmed using semi-quantitative PCR. Our study showed that amplification and overexpression of AURKA is a common and significant event during immortalization of HOSE cells and may represent an important premalignant change in ovarian carcinogenesis. Copyright (c) 2005 Wiley-Liss, Inc.

Differential co-expression analysis reveals a novel prognostic gene module in ovarian cancer.

PubMed

Gov, Esra; Arga, Kazim Yalcin

2017-07-10

Ovarian cancer is one of the most significant disease among gynecological disorders that women suffered from over the centuries. However, disease-specific and effective biomarkers were still not available, since studies have focused on individual genes associated with ovarian cancer, ignoring the interactions and associations among the gene products. Here, ovarian cancer differential co-expression networks were reconstructed via meta-analysis of gene expression data and co-expressed gene modules were identified in epithelial cells from ovarian tumor and healthy ovarian surface epithelial samples to propose ovarian cancer associated genes and their interactions. We propose a novel, highly interconnected, differentially co-expressed, and co-regulated gene module in ovarian cancer consisting of 84 prognostic genes. Furthermore, the specificity of the module to ovarian cancer was shown through analyses of datasets in nine other cancers. These observations underscore the importance of transcriptome based systems biomarkers research in deciphering the elusive pathophysiology of ovarian cancer, and here, we present reciprocal interplay between candidate ovarian cancer genes and their transcriptional regulatory dynamics. The corresponding gene module might provide new insights on ovarian cancer prognosis and treatment strategies that continue to place a significant burden on global health.

PMS2 expression in epithelial ovarian cancer is posttranslationally regulated by Akt and essential for platinum-induced apoptosis.

PubMed

Jia, Jinghui; Wang, Zehua; Cai, Jing; Zhang, Yuan

2016-03-01

Epithelial ovarian cancer (EOC) is the most lethal of the gynecologic malignancies, mainly due to the advanced stage at diagnosis and development of cisplatin resistance. The sensitivity of tumor cells to cisplatin is frequently affected by defect in DNA mismatch repair (MMR), which repairs mispaired DNA sequences and regulates DNA-damage-induced apoptosis. However, the role of postmeiotic segregation increased 2 (PMS2), a member of MMR protein family, in cisplatin resistance remains elusive. In the present study, we demonstrated the frequent deficiency of PMS2 and phosphorylation of Akt in EOC cell lines and tissues. Results of complex immunoprecipitation (co-IP) and protein stability assay indicated that activated Akt could directly bind to PMS2 and cause degradation of PMS2 in EOC cells. In addition, functional experiments revealed that PMS2 was required for cisplatin-induced apoptosis and cell cycle arrest in G2/M phase. These findings provide a novel insight into molecular mechanisms linking MMR with chemoresistance and suggest that stabilization of PMS2 expression may be useful in overcoming the cisplatin resistance in EOC.

Whole abdomen radiation for minimal residual epithelial ovarian carcinoma after surgical resection and maximal first-line chemotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cain, J.M.; Russell, A.H.; Greer, B.E.

1988-02-01

Ten patients with Stage III epithelial ovarian received whole abdomen radiation therapy after extensive courses of chemotherapy and second or third laparotomies. All patients had less than 2-mm diameter residual disease. The major side effect was bone marrow suppression which led to decreased dose or field size in four patients. Five patients have recurred and three of these have died. Further treatment after recurrence was compromised by bone marrow suppression. While 40-50% of selected patients may respond to this approach, numerous alternatives are being explored that would not handicap further treatment to the same degree and may have equal responsemore » rates.« less

LncRNA PCGEM1 Induces Ovarian Carcinoma Tumorigenesis and Progression Through RhoA Pathway.

PubMed

Chen, Shuo; Wang, Li-Li; Sun, Kai-Xuan; Liu, Yao; Guan, Xue; Zong, Zhi-Hong; Zhao, Yang

2018-06-27

Prostate cancer gene expression marker 1 (PCGEM1) is a long noncoding RNA (lncRNA) and is well known as a promoter in prostate cancer and osteoarthritis synoviocytes. However, the role PCGEM1 plays in epithelial ovarian cancer is unknown. PCGEM1 expression was examined in epithelial ovarian cancer and normal ovarian tissues using reverse transcription-PCR. Ovarian cancer cell phenotypes and genotypes were examined after PCGEM1 overexpression or downregulation in vitro; besides, the effects of PCGEM1 overexpression was also examined in vivo. PCGEM1 expression level was higher in epithelial ovarian cancer tissues than in normal ovarian tissues and was positively associated with differentiation (Well vs. Mod/Poor). Upregulation of PCGEM1 induced cancer cell proliferation, migration, and invasion, but decreased cell apoptosis through upregulating RhoA, YAP (Yes-associated protein), MMP2 (matrix metalloproteinase 2), Bcl-xL, and P70S6K expression; while PCGEM1 downregulation had the opposite effect. The nude mouse xenograft assay demonstrated that PCGEM1 overexpression promoted tumor growth. Furthermore, silencing RhoA expression reversed the effect of PCGEM1 and significantly inhibited RhoA, YAP, MMP2, Bcl-xL, and P70S6K protein expression. In conclusion, we suggest that PCGEM1 may be an inducer in epithelial ovarian cancer tumorigenesis and progression by upregulating RhoA and the subsequent expression of YAP, P70S6K, MMP2, and Bcl-xL. © 2018 The Author(s). Published by S. Karger AG, Basel.

Polymorphism in the GALNT1 Gene and Epithelial Ovarian Cancer in Non-Hispanic White Women: The Ovarian Cancer Association Consortium

PubMed Central

Phelan, Catherine M.; Tsai, Ya-Yu; Goode, Ellen L.; Vierkant, Robert A.; Fridley, Brooke L.; Beesley, Jonathan; Chen, Xiao Qing; Webb, Penelope M.; Chanock, Stephen; Cramer, Daniel W.; Moysich, Kirsten; Edwards, Robert P.; Chang-Claude, Jenny; Garcia-Closas, Montserrat; Yang, Hannah; Wang-Gohrke, Shan; Hein, Rebecca; Green, Adele C.; Lissowska, Jolanta; Carney, Michael E.; Lurie, Galina; Wilkens, Lynne R.; Ness, Roberta B.; Pearce, Celeste Leigh; Wu, Anna H.; Van Den Berg, David J.; Stram, Daniel O.; Terry, Kathryn L.; Whiteman, David C.; Whittemore, Alice S.; DiCioccio, Richard A.; McGuire, Valerie; Doherty, Jennifer A.; Rossing, Mary Anne; Anton-Culver, Hoda; Ziogas, Argyrios; Hogdall, Claus; Hogdall, Estrid; Kjaer, Susanne Krüger; Blaakaer, Jan; Quaye, Lydia; Ramus, Susan J.; Jacobs, Ian; Song, Honglin; Pharoah, Paul D.P.; Iversen, Edwin S.; Marks, Jeffrey R.; Pike, Malcolm C.; Gayther, Simon A.; Cunningham, Julie M.; Goodman, Marc T.; Schildkraut, Joellen M.; Chenevix-Trench, Georgia; Berchuck, Andrew; Sellers, Thomas A.

2010-01-01

Aberrant glycosylation is a well-described hallmark of cancer. In a previous ovarian cancer case control study that examined polymorphisms in 26 glycosylation-associated genes, we found strong statistical evidence (P = 0.00017) that women who inherited two copies of a single-nucleotide polymorphism in the UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase, GALNT1, had decreased ovarian cancer risk. The current study attempted to replicate this observation. The GALNT1 single-nucleotide polymorphism rs17647532 was genotyped in 6,965 cases and 8,377 controls from 14 studies forming the Ovarian Cancer Association Consortium. The fixed effects estimate per rs17647532 allele was null (odds ratio, 0.99; 95% confidence interval, 0.92–1.07). When a recessive model was fit, the results were unchanged. Test for hetero geneity of the odds ratios revealed consistency across the 14 replication sites but significant differences compared with the original study population (P = 0.03). This study underscores the need for replication of putative findings in genetic association studies. PMID:20142253

Phytoestrogen consumption from foods and supplements and epithelial ovarian cancer risk: a population-based case control study

PubMed Central

2011-01-01

Background While there is extensive literature evaluating the impact of phytoestrogen consumption on breast cancer risk, its role on ovarian cancer has received little attention. Methods We conducted a population-based case-control study to evaluate phytoestrogen intake from foods and supplements and epithelial ovarian cancer risk. Cases were identified in six counties in New Jersey through the New Jersey State Cancer Registry. Controls were identified by random digit dialing, CMS (Centers for Medicare and Medicaid Service) lists, and area sampling. A total of 205 cases and 390 controls were included in analyses. Unconditional logistic regression analyses were conducted to examine associations with total phytoestrogens, as well as isoflavones (daidzein, genistein, formononetin, and glycitein), lignans (matairesinol, lariciresinol, pinoresinol, secoisolariciresinol), and coumestrol. Results No statistically significant associations were found with any of the phytoestrogens under evaluation. However, there was a suggestion of an inverse association with total phytoestrogen consumption (from foods and supplements), with an odds ratio (OR) of 0.62 (95% CI: 0.38-1.00; p for trend: 0.04) for the highest vs. lowest tertile of consumption, after adjusting for reproductive covariates, age, race, education, BMI, and total energy. Further adjustment for smoking and physical activity attenuated risk estimates (OR: 0.66; 95% CI: 0.41-1.08). There was little evidence of an inverse association for isoflavones, lignans, or coumestrol. Conclusions This study provided some suggestion that phytoestrogen consumption may decrease ovarian cancer risk, although results did not reach statistical significance. PMID:21943063

Tumor-associated macrophages drive spheroid formation during early transcoelomic metastasis of ovarian cancer

PubMed Central

Yin, Mingzhu; Li, Xia; Tan, Shu; Zhou, Huanjiao Jenny; Ji, Weidong; Bellone, Stefania; Xu, Xiaocao; Zhang, Haifeng; Santin, Alessandro D.; Lou, Ge

2016-01-01

Tumor-associated macrophages (TAMs) can influence ovarian cancer growth, migration, and metastasis, but the detailed mechanisms underlying ovarian cancer metastasis remain unclear. Here, we have shown a strong correlation between TAM-associated spheroids and the clinical pathology of ovarian cancer. Further, we have determined that TAMs promote spheroid formation and tumor growth at early stages of transcoelomic metastasis in an established mouse model for epithelial ovarian cancer. M2 macrophage–like TAMs were localized in the center of spheroids and secreted EGF, which upregulated αMβ2 integrin on TAMs and ICAM-1 on tumor cells to promote association between tumor cells and TAM. Moreover, EGF secreted by TAMs activated EGFR on tumor cells, which in turn upregulated VEGF/VEGFR signaling in surrounding tumor cells to support tumor cell proliferation and migration. Pharmacological blockade of EGFR or antibody neutralization of ICAM-1 in TAMs blunted spheroid formation and ovarian cancer progression in mouse models. These findings suggest that EGF secreted from TAMs plays a critical role in promoting early transcoelomic metastasis of ovarian cancer. As transcoelomic metastasis is also associated with many other cancers, such as pancreatic and colon cancers, our findings uncover a mechanism for TAM-mediated spheroid formation and provide a potential target for the treatment of ovarian cancer and other transcoelomic metastatic cancers. PMID:27721235

Induction of a menopausal state alters the growth and histology of ovarian tumors in a mouse model of ovarian cancer.

PubMed

Laviolette, Laura A; Ethier, Jean-François; Senterman, Mary K; Devine, Patrick J; Vanderhyden, Barbara C

2011-05-01

Ovarian cancer is often diagnosed in women after menopause when the levels of the serum gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are increased because of the depletion of growing follicles within the ovary. The ability of FSH and LH to modulate the disease has not been well studied owing to a lack of physiologically relevant models of ovarian cancer. In this study, 4-vinylcyclohexene diepoxide (VCD) was used to deplete ovarian follicles and increase the levels of circulating FSH and LH in the tgCAG-LS-TAg mouse model of ovarian cancer. VCD-induced follicle depletion was performed either before or after induction of the oncogene SV40 large and small T-antigens in the ovarian surface epithelial cells of tgCAG-LS-TAg mice, which was mediated by the intrabursal delivery of an adenovirus expressing Cre recombinase (AdCre). tgCAG-LS-TAg mice injected with AdCre developed undifferentiated ovarian tumors with mixed epithelial and stromal components and some features of sex cord stromal tumors. Treatment with VCD before or after AdCre injection yielded tumors of similar histology, but with the unique appearance of Sertoli cell nests. In mice treated with VCD before the induction of tumorigenesis, the ovarian tumors tended to grow more slowly. The human ovarian cancer cell lines SKOV3 and OVCAR3 responded similarly to increased levels of gonadotropins in a second model of menopause, growing more slowly in ovariectomized mice compared with cycling controls. These results suggest that follicle depletion and increased gonadotropin levels can alter the histology and the rate of growth of ovarian tumors.

Clinical Practice of Adjuvant Chemotherapy in Patients with Early-Stage Epithelial Ovarian Cancer.

PubMed

Frielink, Lindy M J; Pijlman, Brenda M; Ezendam, Nicole P M; Pijnenborg, Johanna M A

2016-01-01

Adjuvant platinum-based chemotherapy improves survival in women with early-stage epithelial ovarian cancer (EOC). Yet, there is a wide variety in clinical practice. All patients diagnosed with FIGO I and IIa EOC (2006-2010) in the south of the Netherlands were analyzed. The percentage of patients that received adjuvant chemotherapy was determined as well as the comprehensiveness of staging and outcome. Forty percent (54/135) of the patients with early-stage EOC received adjuvant chemotherapy. Treatment with adjuvant chemotherapy was associated with FIGO stage, clear-cell histology and nonoptimal staging. Optimal staging was achieved in 50%, and nonoptimal staging was associated with advanced age, comorbidity and treatment in a non-referral hospital. Overall, there was no difference in outcome between patients with and without adjuvant chemotherapy. Yet, in grade 3 tumors, adjuvant chemotherapy seems beneficial. Selective treatment of patients with early-stage EOC might reduce adjuvant chemotherapy without compromising outcome. © 2016 S. Karger AG, Basel.

Progesterone Prevents High-Grade Serous Ovarian Cancer by Inducing Necroptosis of p53-Defective Fallopian Tube Epithelial Cells.

PubMed

Wu, Na-Yiyuan; Huang, Hsuan-Shun; Chao, Tung Hui; Chou, Hsien Ming; Fang, Chao; Qin, Chong-Zhen; Lin, Chueh-Yu; Chu, Tang-Yuan; Zhou, Hong Hao

2017-03-14

High-grade serous ovarian carcinoma (HGSOC) originates mainly from the fallopian tube (FT) epithelium and always carries early TP53 mutations. We previously reported that tumors initiate in the FT fimbria epithelium because of apoptotic failure and the expansion of cells with DNA double-strand breaks (DSB) caused by bathing of the FT epithelial cells in reactive oxygen species (ROSs) and hemoglobin-rich follicular fluid (FF) after ovulation. Because ovulation is frequent and HGSOC is rare, we hypothesized that luteal-phase progesterone (P4) could eliminate p53-defective FT cells. Here we show that P4, via P4 receptors (PRs), induces necroptosis in Trp53 -/- mouse oviduct epithelium and in immortalized human p53-defective fimbrial epithelium through the TNF-α/RIPK1/RIPK3/MLKL pathway. Necroptosis occurs specifically at diestrus, recovers at the proestrus phase of the estrus cycle, and can be augmented with P4 supplementation. These results reveal the mechanism of the well-known ability of progesterone to prevent ovarian cancer. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Two microRNA signatures for malignancy and immune infiltration predict overall survival in advanced epithelial ovarian cancer.

PubMed

Korsunsky, Ilya; Parameswaran, Janaki; Shapira, Iuliana; Lovecchio, John; Menzin, Andrew; Whyte, Jill; Dos Santos, Lisa; Liang, Sharon; Bhuiya, Tawfiqul; Keogh, Mary; Khalili, Houman; Pond, Cassandra; Liew, Anthony; Shih, Andrew; Gregersen, Peter K; Lee, Annette T

2017-10-01

MicroRNAs have been established as key regulators of tumor gene expression and as prime biomarker candidates for clinical phenotypes in epithelial ovarian cancer (EOC). We analyzed the coexpression and regulatory structure of microRNAs and their co-localized gene targets in primary tumor tissue of 20 patients with advanced EOC in order to construct a regulatory signature for clinical prognosis. We performed an integrative analysis to identify two prognostic microRNA/mRNA coexpression modules, each enriched for consistent biological functions. One module, enriched for malignancy-related functions, was found to be upregulated in malignant versus benign samples. The second module, enriched for immune-related functions, was strongly correlated with imputed intratumoral immune infiltrates of T cells, natural killer cells, cytotoxic lymphocytes, and macrophages. We validated the prognostic relevance of the immunological module microRNAs in the publicly available The Cancer Genome Atlas data set. These findings provide novel functional roles for microRNAs in the progression of advanced EOC and possible prognostic signatures for survival. © American Federation for Medical Research (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Clinicopathologic features of ovarian neoplasms with emphasis on borderline ovarian tumors: an institutional perspective.

PubMed

Hashmi, Atif Ali; Hussain, Zubaida Fida; Bhagwani, Aneel Roy; Edhi, Muhammad Muzzammil; Faridi, Naveen; Hussain, Syed Danish; Khan, Mehmood

2016-04-06

Ovarian cancer is the most lethal gynecologic malignancy and it represents third most common malignancy in Karachi (after breast and oral cancer). Due to lack of well established cancer registry in our country, changing trends of ovarian tumors has not been determined. Therefore we aimed to establish the current trends and classification of ovarian tumors in our setup according to latest WHO guidelines. We retrospectively analyzed 162 cases of ovarian tumors that underwent surgical resection from January 2009 till December 2014. Specimens were received in histopathology department, Liaquat National hospital and cases were examined by senior histopathologists and classified according to latest WHO guidelines. Various histopathologic parameters including capsular invasion, omental and lymph node meatstasis along with uterine and fallopian tube involvement were determined apart from tumor type and grade. Mean age at diagnosis was 35.8 years (± 15.5). surface epithelial tumors were most common, 109 cases (67.2%) followed by germ cell tumors, 44 cases (27.1%) and sex cord stromal tumors, 8 cases (4.9%). Serous tumors were most common surface epithelial tumors with 90% benign morphology. On the other hand, mucinous tumors showed a higher percentage of borderline and malignant features (16.7 and 14.6% respectively). Higher incidence of capsular invasion and omental metastasis was noted in endometroid and serous carcinoma compared to mucinous tumors. We noted a higher frequency of young age ovarian cancers in our set up. Serous and endometroid carcinomas were found to be associated with adverse prognostic factors like capsular invasion and omental metastasis. Moreover a significantly higher proportion of ovarian tumors constitute mucinous histology including borderline tumors. Whether this represents a changing trend towards biology of these tumors in this part of the world needs to be uncovered by further studies.

Role of Fallopian Tubes in the Development of Ovarian Cancer.

PubMed

Corzo, Camila; Iniesta, Maria D; Patrono, Maria Guadalupe; Lu, Karen H; Ramirez, Pedro T

2017-02-01

Ovarian cancer is the leading cause of death from gynecologic malignancy and the fifth cause of cancer death in women in the United States. The most common and lethal histologic subtype of epithelial ovarian cancer is high-grade serous carcinoma (HGSC), which generally presents at an advanced stage. HGSC may be associated with BRCA1 and BRCA2 mutations. Historically, HGSC was believed to originate from the ovarian epithelial cells. However, more recent evidence supports the idea that most ovarian cancers originate in the fallopian tube epithelium in both high-risk women and in the general population. Serous tubal intraepithelial carcinomas may ultimately evolve into ovarian or peritoneal cancer. As a result, prophylactic salpingectomy with conservation of the ovaries has become an increasingly more common practice for premenopausal women undergoing risk-reducing surgery. Because the fallopian tube is now recognized as the most common potential site of origin of ovarian carcinoma, there is ongoing research to explore molecular and genetic factors that may be critical in the development of this disease. Further research is needed to identify novel opportunities for early detection and screening of ovarian cancer with the ultimate goal of increasing overall survival. Copyright © 2016 AAGL. Published by Elsevier Inc. All rights reserved.

[Expression of Jagged1 mRNA in human epithelial ovarian carcinoma tissues and effect of RNA interference of Jagged1 on growth of xenograft in nude mice].

PubMed

Liu, G Y; Gao, Z H; Li, L; Song, T T; Sheng, X G

2016-06-25

To investigate the expression of Jagged1 in human epithelial ovarian carcinoma tissues and the effect of Jagged1 on growth of xenograft in nude mice. (1) Forty-eight cases of ovarian cancer and 30 cases of patients with benign epithelial ovarian tumor in the Henan Province Xinxiang Central Hospital during Feb. 2011 to Mar. 2014 were enrolled in this study. The mRNA expression of Jagged1, Notch1 and the downstream target genes Hes1, Hey1 were analyzed by using realtime PCR method. (2) The ovarian cancer xenograft models in nude mice were constructed by injecting SKOV3 cells in axillary subcutaneouswere. The nude mice were randomly divided into Jagged1 interference group, blank plasmid group and control group. Each group had 10 mice. They were transfected with pcDNA3.1(+)-siRNA-Jagged1, blank plasmid pDC3.1 and phosphate buffer, respectively. The tumor volumes and tumor masses were measured 14 days after transfection and the inhibition rate was calculated. The relative mRNA expression of Jagged1, Notch1, Hes1 and Hey1 in xenograft tissues after transfection in each group was detected by using realtime PCR technique and the relative protein expression of Jagged1, Notch1, Hes1 and Hey1 in xenograft tissues was detected by utilizing western blot method. (1) The relative mRNA expression of Jagged1, Notch1, Hes1 and Hey1 in ovarian cancer tissues were higher than benign ovarian tumor tissues, the differences were statistically significant (P<0.01). (2) The tumor volume was (491± 68) mm(3) and tumor mass was (2.6±0.4) g in Jagged1 interference group, which were significantly lower than that in the blank plasmid group [(842±88) mm(3) and (4.4±0.8) g, respectively] and that in the control group [(851±90) mm(3) and (4.5±0.9) g, respectively; P<0.05], the tumor inhibition rate was 42.2% in Jagged1 interference group, which was significantly higher than that in the blank plasmid group and that in the control group (2.2% and 0, respectively), the differences were

BRCA2 Arg372Hispolymorphism and epithelial ovarian cancer risk.

PubMed

Auranen, Annika; Spurdle, Amanda B; Chen, Xiaoqing; Lipscombe, Julian; Purdie, David M; Hopper, John L; Green, Adele; Healey, Catherine S; Redman, Karen; Dunning, Alison M; Pharoah, Paul D; Easton, Douglas F; Ponder, Bruce A J; Chenevix-Trench, Georgia; Novik, Karen L

2003-01-20

The BRCA2 372 HH genotype defined by the BRCA2 N372H nonconservative amino acid substitution polymorphism was recently reported to be associated with a small increased risk of breast cancer. We investigated whether this polymorphism was associated with ovarian cancer risk by conducting British and Australian case-control comparisons in parallel, including a total sample of 1,121 ovarian cancer cases and 2,643 controls. There was no difference in genotype frequency between control groups from the 2 studies (p = 0.9). The HH genotype was associated with an increased risk of ovarian cancer in both studies, and the risk estimate for the pooled studies was 1.36 (95% CI 1.04-1.77, p = 0.03). There was also a suggestion that this risk may be greater for ovarian cancers of the serous subtype for both studies, with an OR (95% CI) of 1.66 (1.17-2.54) for the 2 studies combined (p = 0.005). The BRCA2 372 HH genotype appears to be associated with an increased risk of ovarian cancer of a similar magnitude to that reported for breast cancer. Copyright 2002 Wiley-Liss, Inc.

JNK-1 Inhibition Leads to Antitumor Activity in Ovarian Cancer

PubMed Central

Vivas-Mejia, Pablo; Benito, Juliana Maria; Fernandez, Ariel; Han, Hee-Dong; Mangala, Lingegowda; Rodriguez-Aguayo, Cristian; Chavez-Reyes, Arturo; Lin, Yvonne G.; Nick, Alpa M.; Stone, Rebecca L.; Kim, Hye Sun; Claret, Francois-Xavier; Bornmann, William; Hennessy, Bryan TJ.; Sanguino, Angela; Peng, Zhengong; Sood, Anil K.; Lopez-Berestein, Gabriel

2011-01-01

Purpose To demonstrate the functional, clinical and biological significance of JNK-1 in ovarian carcinoma. Experimental Design Analysis of the impact of JNK on 116 epithelial ovarian cancers was conducted. The role of JNK in vitro and in experimental models of ovarian cancer was assessed. We studied the role of WBZ_4, a novel JNK inhibitor redesigned from imatinib based on targeting wrapping defects, in cell lines and in experimental models of ovarian cancer. Results We found a significant association of pJNK with progression free survival in the 116 epithelial ovarian cancers obtained at primary debulking therapy. WBZ_4 led to cell growth inhibition and increased apoptosis in a dose dependent fashion in four ovarian cancer cell lines. In vivo, while imatinib had no effect on tumor growth, WBZ_4 inhibited tumor growth in orthotopic murine models of ovarian cancer. The anti-tumor effect was further increased in combination with docetaxel. Silencing of JNK-1 with systemically administered siRNA led to significantly reduced tumor weights as compared to non-silencing siRNA controls, indicating that indeed the antitumor effects observed were due to JNK-1 inhibition. Conclusions These studies identify JNK-1 as an attractive therapeutic target in ovarian carcinoma and that the re-designed WBZ_4 compound should be considered for further clinical development. PMID:20028751

PTN Signaling: Components and Mechanistic Insights in Human Ovarian Cancer

PubMed Central

Sethi, Geetika; Kwon, Youngjoo; Burkhalter, Rebecca J; Pathak, Harsh B.; Madan, Rashna; McHugh, Sarah; Atay, Safinur; Murthy, Smruthi; Tawfik, Ossama W.; Godwin, Andrew K.

2015-01-01

Molecular vulnerabilities represent promising candidates for the development of targeted therapies that hold the promise to overcome the challenges encountered with non-targeted chemotherapy for the treatment of ovarian cancer. Through a synthetic lethality screen, we previously identified pleiotrophin (PTN) as a molecular vulnerability in ovarian cancer and showed that siRNA mediated PTN knockdown induced apoptotic cell death in epithelial ovarian cancer (EOC) cells. Although it is well known that PTN elicits its pro-tumorigenic effects through its receptor, protein tyrosine phosphatase receptor Z1 (PTPRZ1), little is known about the potential importance of this pathway in the pathogenesis of ovarian cancer. In this study we show that PTN is expressed, produced, and secreted in a panel of EOC cell lines. PTN levels in serous ovarian tumor tissues are on average 3.5-fold higher relative to normal tissue and PTN is detectable in serum samples of patients with EOC. PTPRZ1 is also expressed and produced by EOC cells and is found to be up-regulated in serous ovarian tumor tissue relative to normal ovarian surface epithelial tissue (p<0.05). Gene silencing of PTPRZ1 in EOC cell lines using siRNA mediated knockdown shows that PTPRZ1 is essential for viability and results in significant apoptosis with no effect on the cell cycle phase distribution. In order to determine how PTN mediates survival, we silenced the gene using siRNA mediated knockdown and performed expression profiling of 36 survival-related genes. Through computational mapping of the differentially expressed genes, members of the MAPK (mitogen-activated protein kinase) family were found to be likely effectors of PTN signaling in EOC cells. Our results provide the first experimental evidence that PTN and its signaling components may be of significance in the pathogenesis of epithelial ovarian cancer and provide a rationale for clinical evaluation of MAPK inhibitors in PTN and/or PTPRZ1 expressing ovarian

Molecular pathogenesis of ovarian clear cell carcinoma.

PubMed

Gounaris, Ioannis; Brenton, James D

2015-01-01

Ovarian clear cell carcinoma is a distinct subtype of epithelial ovarian cancer, characterized by an association with endometriosis, glycogen accumulation and resistance to chemotherapy. Key driver events, including ARID1A mutations and HNF1B overexpression, have been recently identified and their functional characterization is ongoing. Additionally, the role of glycogen in promoting the malignant phenotype is coming under scrutiny. Appreciation of the notion that ovarian clear cell carcinoma is essentially an ectopic uterine cancer will hopefully lead to improved animal models of the disease, in turn paving the way for effective treatments.

Diagnostic and referral intervals for Manitoba women with epithelial ovarian cancer - the Manitoba Ovarian Cancer Outcomes (MOCO) study group: a retrospective cross-sectional study

PubMed Central

Love, Allison J.; Lambert, Pascal; Turner, Donna; Lotocki, Robert; Dean, Erin; Popowich, Shaundra; Altman, Alon D.; Nachtigal, Mark W.

2017-01-01

Background: Epithelial ovarian cancer has the highest mortality of all gynecologic cancers. The poor survival rates are often attributed to the advanced stage at which most of these cancers are detected. We sought to examine the effects of patient demographics, comorbidities and presenting symptoms on diagnostic and referral intervals by location of first presentation (emergency department v. elsewhere) and to identify factors that affect these intervals. Methods: We performed a retrospective analysis of chart and medical record data for ovarian cancers, with the exceptions of sex cord and germ cell tumours, diagnosed between 2004 and 2010 in Manitoba, Canada. Data were collected on baseline characteristics, time to diagnosis and referral, number and type of physician visits and emergency department visits. Results: The final cohort consisted of 601 patients. Sixty-three percent of patients received their diagnosis within 60 days of initial presentation, and 75.2% had their cancer diagnosed within 2 physician encounters. The median diagnostic interval for all stages of patients presenting to the emergency department was 7 days, compared with 55 days for patients presenting elsewhere. Early stage patients not presenting to the emergency department had their diagnosis a median of 34.0 days later than patients with advanced disease (95% confidence interval [CI] 22.22 to 45.69, p < 0.0001). The presence of some symptoms was associated with shortened diagnostic intervals. Patients with serous, clear-cell or endometrioid histotypes were less likely to have first presentation beginning in the emergency department (odds ratio [OR] 0.40, 95% CI 0.24 to 0.64, p = 0.0001; OR 0.28, 95% CI 0.14 to 0.59, p = 0.007) than those with unclassified epithelial histotype. Interpretation: For this group of patients, the main factor associated with diagnostic and referral intervals is presentation to the emergency department. These patients likely required more urgent attention for their

Brain metastases in women with epithelial ovarian cancer: multimodal treatment including surgery or gamma-knife radiation is associated with prolonged survival.

PubMed

Niu, Xiaoyu; Rajanbabu, Anupama; Delisle, Megan; Peng, Feng; Vijaykumar, Dehannathuparambil K; Pavithran, Keechilattu; Feng, Yukuan; Lau, Susie; Gotlieb, Walter H; Press, Joshua Z

2013-09-01

To explore the impact of treatment modality on survival in patients with brain metastases from epithelial ovarian cancer. We conducted a retrospective review of cases of ovarian cancer with brain metastases treated at institutions in three countries (Canada, China, and India) and conducted a search for studies regarding brain metastases in ovarian cancer reporting survival related to treatment modality. Survival was analyzed according to treatment regimens involving (1) some form of surgical excision or gamma-knife radiation with or without other modalities, (2) other modalities without surgery or gamma-knife radiation, or (3) palliation only. Twelve patients (mean age 56 years) with detailed treatment/outcome data were included; five were from China, four from Canada, and three from India. Median time from diagnosis of ovarian cancer to brain metastasis was 19 months (range 10 to 37 months), and overall median survival time from diagnosis of ovarian cancer was 38 months (13 to 82 months). Median survival time from diagnosis of brain metastasis was 17 months (1 to 45 months). Among patients who had multimodal treatment including gamma-knife radiotherapy or surgical excision, the median survival time after the identification of brain metastasis was 25.6 months, compared with 6.0 months in patients whose treatment did not include this type of focused localized modality (P = 0.006). Analysis of 20 studies also indicated that use of gamma-knife radiotherapy and excisional surgery in multi-modal treatment resulted in improved median survival interval (25 months vs. 6.0 months, P < 0.001). In the subset of patients with brain metastases from ovarian cancer, prolonged survival may result from use of multidisciplinary therapy, particularly if metastases are amenable to localized treatments such as gamma-knife radiotherapy and surgical excision.

Assessment of moderate coffee consumption and risk of epithelial ovarian cancer: a Mendelian randomization study.

PubMed

Ong, Jue-Sheng; Hwang, Liang-Dar; Cuellar-Partida, Gabriel; Martin, Nicholas G; Chenevix-Trench, Georgia; Quinn, Michael C J; Cornelis, Marilyn C; Gharahkhani, Puya; Webb, Penelope M; MacGregor, Stuart

2018-04-01

Coffee consumption has been shown to be associated with various health outcomes in observational studies. However, evidence for its association with epithelial ovarian cancer (EOC) is inconsistent and it is unclear whether these associations are causal. We used single nucleotide polymorphisms associated with (i) coffee and (ii) caffeine consumption to perform Mendelian randomization (MR) on EOC risk. We conducted a two-sample MR using genetic data on 44 062 individuals of European ancestry from the Ovarian Cancer Association Consortium (OCAC), and combined instrumental variable estimates using a Wald-type ratio estimator. For all EOC cases, the causal odds ratio (COR) for genetically predicted consumption of one additional cup of coffee per day was 0.92 [95% confidence interval (CI): 0.79, 1.06]. The COR was 0.90 (95% CI: 0.73, 1.10) for high-grade serous EOC. The COR for genetically predicted consumption of an additional 80 mg caffeine was 1.01 (95% CI: 0.92, 1.11) for all EOC cases and 0.90 (95% CI: 0.73, 1.10) for high-grade serous cases. We found no evidence indicative of a strong association between EOC risk and genetically predicted coffee or caffeine levels. However, our estimates were not statistically inconsistent with earlier observational studies and we were unable to rule out small protective associations.

A Method to Evaluate Genome-Wide Methylation in Archival Formalin-Fixed, Paraffin-Embedded Ovarian Epithelial Cells

PubMed Central

Li, Qiling; Li, Min; Ma, Li; Li, Wenzhi; Wu, Xuehong; Richards, Jendai; Fu, Guoxing; Xu, Wei; Bythwood, Tameka; Li, Xu; Wang, Jianxin; Song, Qing

2014-01-01

Background The use of DNA from archival formalin and paraffin embedded (FFPE) tissue for genetic and epigenetic analyses may be problematic, since the DNA is often degraded and only limited amounts may be available. Thus, it is currently not known whether genome-wide methylation can be reliably assessed in DNA from archival FFPE tissue. Methodology/Principal Findings Ovarian tissues, which were obtained and formalin-fixed and paraffin-embedded in either 1999 or 2011, were sectioned and stained with hematoxylin-eosin (H&E).Epithelial cells were captured by laser micro dissection, and their DNA subjected to whole genomic bisulfite conversion, whole genomic polymerase chain reaction (PCR) amplification, and purification. Sequencing and software analyses were performed to identify the extent of genomic methylation. We observed that 31.7% of sequence reads from the DNA in the 1999 archival FFPE tissue, and 70.6% of the reads from the 2011 sample, could be matched with the genome. Methylation rates of CpG on the Watson and Crick strands were 32.2% and 45.5%, respectively, in the 1999 sample, and 65.1% and 42.7% in the 2011 sample. Conclusions/Significance We have developed an efficient method that allows DNA methylation to be assessed in archival FFPE tissue samples. PMID:25133528

The histology of ovarian cancer: worldwide distribution and implications for international survival comparisons (CONCORD-2).

PubMed

Matz, Melissa; Coleman, Michel P; Sant, Milena; Chirlaque, Maria Dolores; Visser, Otto; Gore, Martin; Allemani, Claudia

2017-02-01

Ovarian cancers comprise several histologically distinct tumour groups with widely different prognosis. We aimed to describe the worldwide distribution of ovarian cancer histology and to understand what role this may play in international variation in survival. The CONCORD programme is the largest population-based study of global trends in cancer survival. Data on 681,759 women diagnosed during 1995-2009 with cancer of the ovary, fallopian tube, peritoneum and retroperitonum in 51 countries were included. We categorised ovarian tumours into six histological groups, and explored the worldwide distribution of histology. During 2005-2009, type II epithelial tumours were the most common. The proportion was much higher in Oceania (73.1%), North America (73.0%) and Europe (72.6%) than in Central and South America (65.7%) and Asia (56.1%). By contrast, type I epithelial tumours were more common in Asia (32.5%), compared with only 19.4% in North America. From 1995 to 2009, the proportion of type II epithelial tumours increased from 68.6% to 71.1%, while the proportion of type I epithelial tumours fell from 23.8% to 21.2%. The proportions of germ cell tumours, sex cord-stromal tumours, other specific non-epithelial tumours and tumours of non-specific morphology all remained stable over time. The distribution of ovarian cancer histology varies widely worldwide. Type I epithelial, germ cell and sex cord-stromal tumours are generally associated with higher survival than type II tumours, so the proportion of these tumours may influence survival estimates for all ovarian cancers combined. The distribution of histological groups should be considered when comparing survival between countries and regions. Copyright © 2016. Published by Elsevier Inc.

Polymorphisms in Stromal Genes and Susceptibility to Serous Epithelial Ovarian Cancer: A Report from the Ovarian Cancer Association Consortium

PubMed Central

Amankwah, Ernest K.; Wang, Qinggang; Schildkraut, Joellen M.; Tsai, Ya-Yu; Ramus, Susan J.; Fridley, Brooke L.; Beesley, Jonathan; Johnatty, Sharon E.; Webb, Penelope M.; Chenevix-Trench, Georgia; Dale, Laura C.; Lambrechts, Diether; Amant, Frederic; Despierre, Evelyn; Vergote, Ignace; Gayther, Simon A.; Gentry-Maharaj, Aleksandra; Menon, Usha; Chang-Claude, Jenny; Wang-Gohrke, Shan; Anton-Culver, Hoda; Ziogas, Argyrios; Dörk, Thilo; Dürst, Matthias; Antonenkova, Natalia; Bogdanova, Natalia; Brown, Robert; Flanagan, James M.; Kaye, Stanley B.; Paul, James; Bützow, Ralf; Nevanlinna, Heli; Campbell, Ian; Eccles, Diana M.; Karlan, Beth Y.; Gross, Jenny; Walsh, Christine; Pharoah, Paul D. P.; Song, Honglin; Krüger Kjær, Susanne; Høgdall, Estrid; Høgdall, Claus; Lundvall, Lene; Nedergaard, Lotte; Kiemeney, Lambertus A. L. M.; Massuger, Leon F. A. G.; van Altena, Anne M.; Vermeulen, Sita H. H. M.; Le, Nhu D.; Brooks-Wilson, Angela; Cook, Linda S.; Phelan, Catherine M.; Cunningham, Julie M.; Vachon, Celine M.; Vierkant, Robert A.; Iversen, Edwin S.; Berchuck, Andrew; Goode, Ellen L.; Sellers, Thomas A.; Kelemen, Linda E.

2011-01-01

Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among Caucasians were estimated with odds ratios (OR) among 397 cases and 920 controls in two U.S.-based studies (discovery set), 436 cases and 1,098 controls in Australia (replication set 1) and a consortium of 15 studies comprising 1,668 cases and 4,249 controls (replication set 2). The discovery set and replication set 1 (833 cases and 2,013 controls) showed statistically homogeneous (Pheterogeneity≥0.48) decreased risks of sEOC at four variants: DCN rs3138165, rs13312816 and rs516115, and LUM rs17018765 (OR = 0.6 to 0.9; Ptrend = 0.001 to 0.03). Results from replication set 2 were statistically homogeneous (Pheterogeneity≥0.13) and associated with increased risks at DCN rs3138165 and rs13312816, and LUM rs17018765: all ORs = 1.2; Ptrend≤0.02. The ORs at the four variants were statistically heterogeneous across all 18 studies (Pheterogeneity≤0.03), which precluded combining. In post-hoc analyses, interactions were observed between each variant and recruitment period (Pinteraction≤0.003), age at diagnosis (Pinteraction = 0.04), and year of diagnosis (Pinteraction = 0.05) in the five studies with available information (1,044 cases, 2,469 controls). We conclude that variants in DCN and LUM are not directly associated with sEOC, and that confirmation of possible effect modification of the variants by non-genetic factors is required. PMID:21637745

Targeting Serous Epithelial Ovarian Cancer with Designer Zinc Finger Transcription Factors*

PubMed Central

Lara, Haydee; Wang, Yuhua; Beltran, Adriana S.; Juárez-Moreno, Karla; Yuan, Xinni; Kato, Sumie; Leisewitz, Andrea V.; Cuello Fredes, Mauricio; Licea, Alexei F.; Connolly, Denise C.; Huang, Leaf; Blancafort, Pilar

2012-01-01

Ovarian cancer is the leading cause of death among gynecological malignancies. It is detected at late stages when the disease is spread through the abdominal cavity in a condition known as peritoneal carcinomatosis. Thus, there is an urgent need to develop novel therapeutic interventions to target advanced stages of ovarian cancer. Mammary serine protease inhibitor (Maspin) represents an important metastasis suppressor initially identified in breast cancer. Herein we have generated a sequence-specific zinc finger artificial transcription factor (ATF) to up-regulate the Maspin promoter in aggressive ovarian cancer cell lines and to interrogate the therapeutic potential of Maspin in ovarian cancer. We found that although Maspin was expressed in some primary ovarian tumors, the promoter was epigenetically silenced in cell lines derived from ascites. Transduction of the ATF in MOVCAR 5009 cells derived from ascitic cultures of a TgMISIIR-TAg mouse model of ovarian cancer resulted in tumor cell growth inhibition, impaired cell invasion, and severe disruption of actin cytoskeleton. Systemic delivery of lipid-protamine-RNA nanoparticles encapsulating a chemically modified ATF mRNA resulted in inhibition of ovarian cancer cell growth in nude mice accompanied with Maspin re-expression in the treated tumors. Gene expression microarrays of ATF-transduced cells revealed an exceptional specificity for the Maspin promoter. These analyses identified novel targets co-regulated with Maspin in human short-term cultures derived from ascites, such as TSPAN12, that could mediate the anti-metastatic phenotype of the ATF. Our work outlined the first targeted, non-viral delivery of ATFs into tumors with potential clinical applications for metastatic ovarian cancers. PMID:22782891

Dihydroartemisinin induces apoptosis and sensitizes human ovarian cancer cells to carboplatin therapy.

PubMed

Chen, Tao; Li, Mian; Zhang, Ruiwen; Wang, Hui

2009-07-01

The present study was designed to determine the effects of artemisinin (ARS) and its derivatives on human ovarian cancer cells, to evaluate their potential as novel chemotherapeutic agents used alone or in combination with a conventional cancer chemotherapeutic agent, and to investigate their underlying mechanisms of action. Human ovarian cancer cells (A2780 and OVCAR-3), and immortalized non-tumourigenic human ovarian surface epithelial cells (IOSE144), were exposed to four ARS compounds for cytotoxicity testing. The in vitro and in vivo antitumour effects and possible underlying mechanisms of action of dihydroartemisinin (DHA), the most effective compound, were further determined in ovarian cancer cells. ARS compounds exerted potent cytotoxicity to human ovarian carcinoma cells, with minimal effects on non-tumourigenic ovarian surface epithelial (OSE) cells. DHA inhibited ovarian cancer cell growth when administered alone or in combination with carboplatin, presumably through the death receptor- and, mitochondrion-mediated caspase-dependent apoptotic pathway. These effects were also observed in in vivo ovarian A2780 and OVCAR-3 xenograft tumour models. In conclusion, ARS derivatives, particularly DHA, exhibit significant anticancer activity against ovarian cancer cells in vitro and in vivo, with minimal toxicity to non-tumourigenic human OSE cells, indicating that they may be promising therapeutic agents for ovarian cancer, either used alone or in combination with conventional chemotherapy.

Dihydroartemisinin induces apoptosis and sensitizes human ovarian cancer cells to carboplatin therapy

PubMed Central

Chen, Tao; Li, Mian; Zhang, Ruiwen; Wang, Hui

2009-01-01

The present study was designed to determine the effects of artemisinin (ARS) and its derivatives on human ovarian cancer cells, to evaluate their potential as novel chemotherapeutic agents used alone or in combination with a conventional cancer chemotherapeutic agent, and to investigate their underlying mechanisms of action. Human ovarian cancer cells (A2780 and OVCAR-3), and immortalized non-tumourigenic human ovarian surface epithelial cells (IOSE144), were exposed to four ARS compounds for cytotoxicity testing. The in vitro and in vivo antitumour effects and possible underlying mechanisms of action of dihydroartemisinin (DHA), the most effective compound, were further determined in ovarian cancer cells. ARS compounds exerted potent cytotoxicity to human ovarian carcinoma cells, with minimal effects on non-tumourigenic ovarian surface epithelial (OSE) cells. DHA inhibited ovarian cancer cell growth when administered alone or in combination with carboplatin, presumably through the death receptor- and, mitochondrion-mediated caspase-dependent apoptotic pathway. These effects were also observed in in vivo ovarian A2780 and OVCAR-3 xenograft tumour models. In conclusion, ARS derivatives, particularly DHA, exhibit significant anticancer activity against ovarian cancer cells in vitro and in vivo, with minimal toxicity to non-tumourigenic human OSE cells, indicating that they may be promising therapeutic agents for ovarian cancer, either used alone or in combination with conventional chemotherapy. PMID:18466355

Generation of monoclonal antibodies reacting with human epithelial ovarian cancer.

PubMed

Tagliabue, E; Mènard, S; Della Torre, G; Barbanti, P; Mariani-Costantini, R; Porro, G; Colnaghi, M I

1985-01-01

Fusion of the murine myeloma line P3-X63-Ag8-U1 with spleen cells from a mouse immunized with a membrane preparations (CM) of a mucinous ovarian cystoadenocarcinoma yielded two monoclonal antibodies, MOv1 and MOv2, which reacted by solid-phase radioimmunoassay with immunizing tumor CM but were unreactive with normal kidney CM as well as with plasma proteins and peripheral blood cells from the immunizing carcinoma patient. MOv1 and MOv2 were further tested by solid-phase radioimunoassay on a panel of different CM from fresh surgical specimens of ovarian and nonovarian carcinomas, benign ovarian tumors, normal ovary and kidney tissues, and on various tumor cell lines. In addition, the antibodies were characterized by immunofluorescence on live cells from cell lines and surgical specimens, and on frozen sections of benign and malignant ovarian tumors, of nonovarian tumors, and of normal tissues. The results obtained indicate that MOv1 and MOv2 recognize two different epitopes on molecules present on malignant and benign ovarian mucinous tumors and colonic glands. In addition, the antigen recognized by MOv2 was also detected in carcinmas of lung, colon, stomach, and breast; in gastrointestinal glands; and in the glandular lumina of normal lactating breast.

Everolimus exhibits anti-tumorigenic activity in obesity-induced ovarian cancer.

PubMed

Guo, Hui; Zhong, Yan; Jackson, Amanda L; Clark, Leslie H; Kilgore, Josh; Zhang, Lu; Han, Jianjun; Sheng, Xiugui; Gilliam, Timothy P; Gehrig, Paola A; Zhou, Chunxiao; Bae-Jump, Victoria L

2016-04-12

Everolimus inhibits mTOR kinase activity and its downstream targets by acting on mTORC1 and has anti-tumorigenic activity in ovarian cancer. Clinical and epidemiologic data find that obesity is associated with worse outcomes in ovarian cancer. In addition, obesity leads to hyperactivation of the mTOR pathway in epithelial tissues, suggesting that mTOR inhibitors may be a logical choice for treatment in obesity-driven cancers. However, it remains unclear if obesity impacts the effect of everolimus on tumor growth in ovarian cancer. The present study was aimed at evaluating the effects of everolimus on cytotoxicity, cell metabolism, apoptosis, cell cycle, cell stress and invasion in human ovarian cancer cells. A genetically engineered mouse model of serous ovarian cancer fed a high fat diet or low fat diet allowed further investigation into the inter-relationship between everolimus and obesity in vivo. Everolimus significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, reduced invasion and caused cellular stress via inhibition of mTOR pathways in vitro. Hypoglycemic conditions enhanced the sensitivity of cells to everolimus through the disruption of glycolysis. Moreover, everolimus was found to inhibit ovarian tumor growth in both obese and lean mice. This reduction coincided with a decrease in expression of Ki-67 and phosphorylated-S6, as well as an increase in cleaved caspase 3 and phosphorylated-AKT. Metabolite profiling revealed that everolimus was able to alter tumor metabolism through different metabolic pathways in the obese and lean mice. Our findings support that everolimus may be a promising therapeutic agent for obesity-driven ovarian cancers.

Estrogen receptor beta, a possible tumor suppressor involved in ovarian carcinogenesis

PubMed Central

Lazennec, Gwendal

2006-01-01

Ovarian cancer is one of the leading cause of death from gynecological tumors in women. Several lines of evidence suggest that estrogens may play an important role in ovarian carcinogenesis, through their receptors, ERα and ERβ. Interestingly, malignant ovarian tumors originating from epithelial surface constitute about 90% of ovarian cancers and expressed low levels of ERβ, compared to normal tissues. In addition, restoration of ERβ in ovarian cancer cells, leads to strong inhibition of their proliferation and invasion, while apoptosis is enhanced. In this manuscript, recent data suggesting a possible tumor-suppressor role for ERβ in ovarian carcinogenesis are discussed. PMID:16399219

Ascites-induced shift along epithelial-mesenchymal spectrum in ovarian cancer cells: enhancement of their invasive behavior partly dependant on αv integrins.

PubMed

Carduner, L; Leroy-Dudal, J; Picot, C R; Gallet, O; Carreiras, F; Kellouche, S

2014-08-01

At least one-third of patients with epithelial ovarian cancer (OC) present ascites at diagnosis and almost all have ascites at recurrence. The presence of ascites, which acts as a dynamic reservoir of active molecules and cellular components, correlates with the OC peritoneal metastasis and is associated with poor prognosis. Since epithelial-mesenchymal transition (EMT) is involved in different phases of OC progression, we have investigated the effect of the unique ascitic tumor microenvironment on the EMT status and the behavior of OC cells. The exposure of three OC cell lines to ascites leads to changes in cellular morphologies. Within ascites, OC cells harboring an initial intermediate epithelial phenotype are characterized by marked dislocation of epithelial markers (E-cadherin, ZO-1 staining) while OC cells initially harboring an intermediate mesenchymal phenotype strengthen their mesenchymal markers (N-cadherin, vimentin). Ascites differentially triggers a dissemination phenotype related to the initial cell features by either allowing the proliferation and the formation of spheroids and the extension of colonies for cells that present an initial epithelial intermediate phenotype, or favoring the migration of cells with a mesenchymal intermediate phenotype. In an ascitic microenvironment, a redeployment of αv integrins into cells was observed and the ascites-induced accentuation of the two different invasive phenotypes (i.e. spheroids formation or migration) was shown to involve αv integrins. Thus, ascites induces a shift toward an unstable intermediate state of the epithelial-mesenchymal spectrum and confers a more aggressive cell behavior that takes on a different pathway based on the initial epithelial-mesenchymal cell features.

KRAS mutation testing in borderline ovarian tumors and low-grade ovarian carcinomas with a rapid, fully integrated molecular diagnostic system.

PubMed

Sadlecki, Pawel; Antosik, Paulina; Grzanka, Dariusz; Grabiec, Marek; Walentowicz-Sadlecka, Malgorzata

2017-10-01

Epithelial ovarian neoplasms are a heterogeneous group of tumors, including various malignancies with distinct clinicopathologic and molecular features. Mutations in BRAF and KRAS genes are the most frequent genetic aberrations found in low-grade serous ovarian carcinomas and serous and mucinous borderline tumors. Implementation of targeted therapeutic strategies requires access to highly specific and highly sensitive diagnostic tests for rapid determination of mutation status. One candidate for such test is fully integrated, real-time polymerase chain reaction-based Idylla™ system for quick and simple detection of KRAS mutations in formaldehyde fixed-paraffin embedded tumor samples. The primary aim of this study was to verify whether fully integrated real-time polymerase chain reaction-based Idylla system may be useful in determination of KRAS mutation status in patients with borderline ovarian tumors and low-grade ovarian carcinomas. The study included tissue specimens from 37 patients with histopathologically verified ovarian masses, operated on at the Department of Obstetrics and Gynecology, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz (Poland) between January 2009 and June 2012. Based on histopathological examination of surgical specimens, 30 lesions were classified as low-grade ovarian carcinomas and 7 as borderline ovarian tumors. Seven patients examined with Idylla KRAS Mutation Test tested positive for KRAS mutation. No statistically significant association was found between the incidence of KRAS mutations and histopathological type of ovarian tumors. Mean survival of the study subjects was 48.51 months (range 3-60 months). Presence of KRAS mutation did not exert a significant effect on the duration of survival in our series. Our findings suggest that Idylla KRAS Mutation Test may be a useful tool for rapid detection of KRAS mutations in ovarian tumor tissue.

Long non-coding RNAs, ASAP1-IT1, FAM215A, and LINC00472, in epithelial ovarian cancer.

PubMed

Fu, Yuanyuan; Biglia, Nicoletta; Wang, Zhanwei; Shen, Yi; Risch, Harvey A; Lu, Lingeng; Canuto, Emilie Marion; Jia, Wei; Katsaros, Dionyssios; Yu, Herbert

2016-12-01

Long non-coding RNAs (lncRNAs) are a class of non-protein coding transcripts that has gained significant attention lately due to their important biological actions and potential involvement in cancer. Ovarian cancer is a devastating disease with poor prognosis, and our understanding of lncRNA's involvement in the malignancy is limited. To further our knowledge, we measured the expression of three lncRNAs, ASAP1-IT1, FAM215A, and LINC00472, in tumor samples, and analyzed their associations with disease characteristics and patient survival. Two hundred sixty-six patients diagnosed with primary epithelial ovarian cancers were recruited for the study. Fresh-frozen tumor samples were obtained from the patients at tumor resection and analyzed by RT-qPCR for expression of ASAP1-IT1, FAM215A, and LINC00472. Associations of lncRNA expression with patient survival were determined using Cox proportional hazards regression models. We observed high expression of ASAP1-IT1, FAM215A and LINC00472 more frequently in low grade tumors and early stage disease compared to high grade tumors and late stage disease, respectively. High expression of ASAP1-IT1 and FAM215A were associated with favorable overall survival, and the survival association with ASAP1-IT1 was independent of tumor grade and disease stage. Analyses of online data also demonstrated similar survival associations with ASAP1-IT1 and FAM215A, suggesting that these lncRNAs may be involved in ovarian cancer progression. LncRNAs may play appreciable roles in ovarian cancer and more research is needed to elucidate their biological mechanisms and clinical implications in tumor characterization as well as disease prognosis and treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

Current status and future prospects of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) clinical trials in ovarian cancer.

PubMed

Cowan, Renee A; O'Cearbhaill, Roisin E; Zivanovic, Oliver; Chi, Dennis S

2017-08-01

The natural history of advanced-stage epithelial ovarian cancer is one of clinical remission after surgery and platinum/taxane-based intravenous (IV) and/or intraperitoneal (IP) chemotherapy followed by early or late recurrence in the majority of patients. Prevention of progression and recurrence remains a major hurdle in the management of ovarian cancer. Recently, many investigators have evaluated the use of normothermic and hyperthermic intraoperative IP drug delivery as a management strategy. This is a narrative review of the current status of clinical trials of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) in ovarian cancer and the future directions for this treatment strategy. The existing studies on HIPEC in patients with epithelial ovarian cancer are mostly retrospective in nature, are heterogeneous with regards to combined inclusion of primary and recurrent disease and lack unbiased data. Until data are available from evidence-based trials, it is reasonable to conclude that surgical cytoreduction and HIPEC is a rational and interesting, though still investigative, approach in the management of epithelial ovarian cancer, whose use should be employed within prospective clinical trials.

Inflammatory breast metastases of ovarian cancer: a case report.

PubMed

Kayikçioğlu, F; Boran, N; Ayhan, A; Güler, N

2001-12-01

Metastasis to the breast from extramammary malignancies is rare. A 35-year-old woman presented with bilaterally inflammatory breast involvement, 2 years after the diagnosis of stage IIIC epithelial ovarian cancer. Neoplastic tissue was immunohistochemically positive using antibodies against OC125 and negative for gross cystic disease fluid protein-15 (BRST-2) and estrogen receptor in biopsy material in the breast. Combination chemotherapy consisting of paclitaxel, cisplatin, and anthracycline was started. She died 18 months after the breast metastasis. Ovarian carcinoma usually presents with signs and symptoms related to the tumor burden within the abdominal cavity. The finding of isolated, distant metastases such as breast involvement without intraabdominal disease is extremely rare. Determining the origin of the primary tumor is important in directing the actual therapy. (c)2001 Elsevier Science.

Apolipoprotein concentrations are elevated in malignant ovarian cyst fluids suggesting that lipoprotein metabolism is dysregulated in epithelial ovarian cancer.

PubMed

Podzielinski, Iwona; Saunders, Brook A; Kimbler, Kimberly D; Branscum, Adam J; Fung, Eric T; DePriest, Paul D; van Nagell, John R; Ueland, Frederick R; Baron, Andre T

2013-05-01

SELDI-TOF MS analysis of ovarian cyst fluids revealed that peaks m/z 8696 and 8825 discriminate malignant, borderline, and benign tumors. These peaks correspond to isoforms of apoA2. ELISA demonstrates that apoA1, A2, B, C2, C3, and E cyst fluid concentrations are uncorrelated and higher in malignant ovarian tumors, but only apoA2, apoE, and age are independent classifiers of malignant ovarian tumors, yielding 55.1% sensitivity, 95% specificity, and 88.1% accuracy to discern malignant from benign and borderline tumors. These data suggest that lipoprotein metabolism is dysregulated in ovarian cancer and that apoA2 and apoE warrant further investigation as ovarian tumor biomarkers.

CT and US findings of ovarian torsion within an incarcerated inguinal hernia.

PubMed

Hyun, Park Mee; Jung, Ah Young; Lee, Yul; Yang, Ik; Yang, Dae Hyun; Hwang, Ji-Young

2015-02-01

Inguinal hernia is relatively common in children. Although inguinal hernia is not frequently encountered in girls in comparison to boys, there are occasional cases of uterine or ovarian herniation in female indirect inguinal hernia. Incarcerated ovary in hernia sac has the risk of torsion and strangulation. We present an 8-year-old girl with painful mass in her left groin. With computed tomography (CT) and ultrasonography (US), we made the diagnosis of ovarian strangulation within an incarcerated inguinal hernia. Since ultrasound is primarily used for evaluation of groin mass, CT findings of an incarcerated inguinal hernia is rarely reported.

Dihydroartiminisin inhibits the growth and metastasis of epithelial ovarian cancer.

PubMed

Wu, Buchu; Hu, Ke; Li, Shu; Zhu, Jing; Gu, Liying; Shen, Haoran; Hambly, Brett D; Bao, Shisan; Di, Wen

2012-01-01

Dihydroartiminisin (DHA), the active component of a Chinese herb (Artemisia annua), has been utilised as an anti-malarial drug since ancient China. DHA has also been shown to inhibit proliferation of cancer in vitro. However, the capacity of DHA to inhibit the development of ovarian cancer is still unclear. The adhesion, invasion, and migration of human ovarian cancer cell line (HO8910PM) was determined following DHA treatment in vitro, using Matrigel coated plate, transwell membrane chamber, and wound healing models, respectively. A mouse ovarian cancer model was established by orthotopic inoculation of HO8910PM cell line in nude mice. The growth and metastasis in vivo was determined 8 weeks post-implantation in response to DHA treatment. The expression of phosphorylated focal adhesion kinase (pFAK) and matrix metalloproteinases (MMP-2 and MMP-9) was evaluated using Western blotting. The expression of Von Willebrand factor (vWF) and infiltration of macrophages were determined, using immunohistochemistry. DHA inhibits ovarian cancer cell proliferation, adhesion, migration and invasion in vitro in a dose-dependent manner, consistent with decreased expression of pFAK and MMP-2, but not MMP-9. DHA inhibited metastasis significantly in vivo, associated with reduced vWF expression and macrophage infiltration. In conclusion, DHA inhibits the development of ovarian cancer, in part via down-regulating pFAK, MMP-2, vWF and macrophage infiltration.

Re-purposing of curcumin as an anti-metastatic agent for the treatment of epithelial ovarian cancer: in vitro model using cancer stem cell enriched ovarian cancer spheroids.

PubMed

He, Misi; Wang, Dong; Zou, Dongling; Wang, Chen; Lopes-Bastos, Bruno; Jiang, Wen G; Chester, John; Zhou, Qi; Cai, Jun

2016-12-27

Malignant epithelial ovarian cancer (EOC) spheroids high frequently are detected in the malignant ascites of the patients with the extensive peritoneal metastasis of ovarian cancer, which represent a significant obstacle to efficacious treatment. Clinical data also suggested that EOC spheroids play a putative role in the development of chemoresistance. Since standard surgery and conventional chemotherapy is the only available treatment, there is an urgent need to identify a more effective therapeutic strategy. Recent studies demonstrated that curcumin exerts an anticancer effect in a variety of human cancers including ovarian cancer. This study evaluates anti-peritoneal metastasis and chemoresistance of curcumin related to the EOC spheroids. In this study, we confirm that the high invasive EOC cells forming the spheroids express a high level of a cancer stem cell (CSC) marker, aldehyde dehydrogenase 1 family member A1 (ALDH1A1), which was significantly down-regulated by curcumin treatment. Curcumin treatment markedly enhances the sensitivity of EOC spheroids to cisplatin in a dose-dependent manner. Our experiments provided evidence that curcumin could abolish the sphere-forming capacity of EOC cells in a dose-dependent manner. Moreover, curcumin substantially suppressed the growth of the pre-existed EOC spheroids, inhibited the adhesion of EOC spheroids to ECM as well as the invasion of EOC spheroids to the mesothelial monolayers. We propose to re-purpose curcumin as anti-metastatic and chemoresistant agent for EOC management in combination with conventional regimen. Further preclinical studies are necessary to validate the anti-cancer effect of curcumin in patients with EOC.

Investigation of mammographic breast density as a risk factor for ovarian cancer.

PubMed

Wernli, Karen J; O'Meara, Ellen S; Kerlikowske, Karla; Miglioretti, Diana L; Muller, Carolyn Y; Onega, Tracy; Sprague, Brian L; Henderson, Louise M; Buist, Diana S M

2014-01-01

Endogenous hormones and growth factors that increase mammographic breast density could increase ovarian cancer risk. We examined whether high breast density is associated with ovarian cancer risk. We conducted a cohort study of 724,603 women aged 40 to 79 years with 2,506,732 mammograms participating in the Breast Cancer Surveillance Consortium from 1995 to 2009. Incident epithelial ovarian cancer was diagnosed in 1373 women. We used partly conditional Cox regression to estimate the association between breast density and 5-year risk of incident epithelial ovarian cancer overall and stratified by 10-year age group. All statistical tests were two-sided. Compared with women with scattered fibroglandular densities, women with heterogeneously dense and extremely dense breast tissue had 20% and 18% increased 5-year risk of incident epithelial ovarian cancer (hazard ratio [HR] = 1.20, 95% confidence interval [CI] = 1.06 to 1.36; HR = 1.18, 95% CI = 0.93 to 1.50, respectively; P(trend) = .01). Among women aged 50 to 59 years, we observed a trend in elevated risk associated with increased breast density (P(trend) = .02); women with heterogeneously and extremely dense breast tissue had 30% (HR = 1.30; 95% CI = 1.03 to 1.64) and 65% (HR = 1.65; 95% CI = 1.12 to 2.44) increased risk, respectively, compared with women with scattered fibroglandular densities. The pattern was similar but not statistically significant at age 40 to 49 years. There were no consistent patterns of breast density and ovarian cancer risk at age 60 to 79 years. Dense breast tissue was associated with a modest increase in 5-year ovarian cancer risk in women aged 50 to 59 years but was not associated with ovarian cancer at ages 40 to 49 or 60 to 79 years.

Incidence and mortality in epithelial ovarian cancer by family history of any cancer.

PubMed

Hemminki, Kari; Sundquist, Jan; Brandt, Andreas

2011-09-01

Practically all data on familial risk in ovarian and other cancers are based on incident cancer, whereas familiality in cancer mortality is largely unknown. If fatal forms of cancer are a highly familial subtype, then familial risk for mortality may exceed that of incidence, which is relevant for clinical decision making and counseling. Ovarian cancer patients in the nationwide Swedish Family Cancer Database were classified according to fatal and nonfatal (incident) family history. Familial risks for incident and fatal ovarian cancer were calculated for offspring based on their parental or sibling family history of any cancer using standardized incidence ratios (SIRs) for incidence and standardized mortality ratios (SMRs) for mortality. Offspring without family history were referents. The database included 24,757 mothers and 8138 daughters with ovarian cancer. When a mother had ovarian cancer, the SIR for incident ovarian cancer in daughters was 2.69, and when a sister had ovarian cancer it was 3.49. The SMRs for fatal cancer by fatal cancer in probands were 3.39 and 5.80, respectively. For fatal serous cancers among siblings, the SMR was 6.16, compared with 10.01 for the endometrioid type. Ovarian cancer was associated with maternal (SIR, 1.22; SMR, 1.56) and sororal breast cancer (SIR, 1.27). Another discordant association was between ovarian and paternal prostate cancer (SIR, 1.12; SMR, 1.66). Fatal familial risks were higher for concordant ovarian, ovarian-breast, and ovarian-prostate cancers than the corresponding incident risks. This may suggest that highly fatal subtypes exist for these cancers, calling for genetic dissection. Cancer 2011 © 2011 American Cancer Society.

Solitomab, an epithelial cell adhesion molecule/CD3 bispecific antibody (BiTE), is highly active against primary chemotherapy-resistant ovarian cancer cell lines in vitro and fresh tumor cells ex vivo.

PubMed

English, Diana P; Bellone, Stefania; Schwab, Carlton L; Roque, Dana M; Lopez, Salvatore; Bortolomai, Ileana; Cocco, Emiliano; Bonazzoli, Elena; Chatterjee, Sudeshna; Ratner, Elena; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E; Rutherford, Thomas J; Santin, Alessandro D

2015-02-01

Solitomab is a novel, bispecific, single-chain antibody that targets epithelial cell adhesion molecule (EpCAM) on tumor cells and also contains a cluster of differentiation 3 (CD3) (T-cell coreceptor) binding region. The authors evaluated the in vitro activity of solitomab against primary chemotherapy-resistant epithelial ovarian carcinoma cell lines as well as malignant cells in ascites. EpCAM expression was evaluated by flow cytometry in 5 primary ovarian cancer cell lines and in 42 fresh ovarian tumor cell cultures in ascites from patients with mainly advanced or recurrent, chemotherapy-resistant disease. The potential activity of solitomab against EpCAM-positive tumor cells was evaluated by flow cytometry, proliferation, and 4-hour chromium-release, cell-mediated cytotoxicity assays. EpCAM expression was detected by flow cytometry in approximately 80% of the fresh ovarian tumors and primary ovarian tumor cell lines tested. EpCAM-positive, chemotherapy-resistant cell lines were identified as resistant to natural killer cell-mediated or T-cell-mediated killing after exposure to peripheral blood lymphocytes in 4-hour chromium-release assays (mean±standard error of the mean, 3.6%±0.7% of cells killed after incubation of EpCAM-positive cell lines with control bispecific antibody). In contrast, after incubation with solitomab, EpCAM-positive, chemotherapy-resistant cells became highly sensitive to T-cell cytotoxicity (mean±standard error of the mean, 28.2%±2.05% of cells killed; P<.0001) after exposure to peripheral blood lymphocytes. Ex vivo incubation of autologous tumor-associated lymphocytes with EpCAM-expressing malignant cells in ascites with solitomab resulted in a significant increase in T-cell activation markers and a reduction in the number of viable ovarian tumor cells in ascites (P<.001). Solitomab may represent a novel, potentially effective agent for the treatment of chemotherapy-resistant ovarian cancers that overexpress EpCAM. © 2014 American

Oncofertility in patients with stage I epithelial ovarian cancer: fertility-sparing surgery in young women of reproductive age.

PubMed

Jiang, Xuan; Yang, Jiaxin; Yu, Mei; Xie, Weimin; Cao, Dongyan; Wu, Ming; Pan, Lingya; Huang, Huifang; You, Yan; Shen, Keng

2017-08-15

Fertility-sparing surgery is indicated for patients with stage I epithelial ovarian cancers. We sought to evaluate the clinical outcomes and oncofertility in a cohort of patients of reproductive age with stage I epithelial ovarian cancer (EOC). Overall, 108 patients of reproductive age (≤ 40 years) diagnosed with stage I EOC who were treated at Peking Union Medical College Hospital between 1999 and 2013 were included in the study. The Kaplan-Meier model and Cox regression analyses were used for the survival analysis. The type of surgery included fertility-sparing surgery (FSS) (48.1%) and radical surgery (RS) (51.9%). After a median follow-up of 83 months, we observed that grade 3 or clear-cell carcinoma was the only independent risk factor for disease-free survival and tumor-specific survival in the multivariate analysis. Patients with grade 3 or clear-cell carcinoma tended to be older than 30 years, have endometriosis, and undergo RS (p < 0.05). Fertility-sparing surgery did not affect disease-free survival or tumor-specific survival among patients of reproductive age with stage I EOC and among high-risk patients with stage IC2-3, grade 3, or clear-cell carcinoma. Thirty-four out of 52 (65.4%) FSS patients attempted to get pregnant. Twenty-eight (82.4%) achieved a successful pregnancy with a full-term delivery. Grade 3 or clear-cell carcinoma was the only independent risk factor for survival of patients of reproductive age with stage I EOC. FSS can be safely performed on patients of reproductive age with grade 1-2, stage I EOC. The safety of FSS for grade 3 and clear-cell carcinoma warrants further investigation.

MUC4 mucin-induced epithelial to mesenchymal transition: a novel mechanism for metastasis of human ovarian cancer cells.

PubMed

Ponnusamy, M P; Lakshmanan, I; Jain, M; Das, S; Chakraborty, S; Dey, P; Batra, S K

2010-10-21

The acquisition of invasiveness in ovarian cancer (OC) is accompanied by the process of epithelial-to-mesenchymal transition (EMT). The MUC4 mucin is overexpressed in ovarian tumors and has a role in the invasiveness of OC cells. The present study was aimed at evaluating the potential involvement of MUC4 in the metastasis of OC cells by inducing EMT. Ectopic overexpression of MUC4 in OC cells (SKOV3-MUC4) resulted in morphological alterations along with a decreased expression of epithelial markers (E-cadherin and cytokeratin (CK)-18) and an increased expression of mesenchymal markers (N-cadherin and vimentin) compared with the control cells (SKOV3-vector). Also, pro-EMT transcription factors TWIST1, TWIST2 and SNAIL showed an upregulation in SKOV3-MUC4 cells. We further investigated the pathways upstream of N-cadherin, such as focal adhesion kinase (FAK), MKK7, JNK1/2 and c-Jun, which were also activated in the SKOV3-MUC4 cells compared with SKOV3-vector cells. Inhibition of phospho-FAK (pFAK) and pJNK1/2 decreased N-cadherin expression in the MUC4-overexpressing cells, which further led to a significant decrease in cellular motility. Knockdown of N-cadherin decreased the activation of extracellular signal-regulated kinase-1/2 (ERK1/2), AKT and matrix metalloproteinase 9 (MMP9), and inhibited the motility in the SKOV3-MUC4 cells. Upon in vivo tumorigenesis and metastasis analysis, the SKOV3-MUC4 cells produced significantly larger tumors and demonstrated a higher incidence of metastasis to distance organs (peritoneal wall, colon, intestine, stomach, lymph nodes, liver and diaphragm). Taken together, our study reveals a novel role for MUC4 in inducing EMT through the upregulation of N-cadherin and promoting metastasis of OC cells.

18F-FDG PET/CT as predictor of tumour biology and prognosis in epithelial ovarian carcinoma.

PubMed

González García, B; García Vicente, A M; Jiménez Londoño, G A; Pena Pardo, F J; Bellón Guardia, M E; Talavera Rubio, M P; Palomar Muñoz, A; Gómez Herrero, P; Soriano Castrejón, Á M

To investigate the relationship between maximum standardised uptake value (SUVmax) of ovarian lesions and histopathology subtypes, and their involvement in the response and prognosis of patients with epithelial ovarian carcinoma (EOC). A retrospective analysis of 31 patients with EOC and 18 F-FDG-PET/CT before treatment, including an assessment of the SUVmax of ovarian lesion. Histopathological diagnosis and follow-up was performed. A study was made on the relationship between the SUVmax and histological type (type I and II) and tumour stage, as well as the role of various parameters (SUVmax, histology, stage) on the patient outcomes (complete response [CR], overall survival [OS], disease-free survival [DFS], and disease-free [DF] status, at 12 and 24 months). The medium SUVmax in type I lesions was lower than in type II (6.3 and 9.3, respectively; P=.03). A 7.1 cut-off was set for SUVmax in order to identify type II EOC (sensitivity: 77.8%, specificity: 69.2%; AUC=0.748; P=.02). No significant relationship was found between tumour stage and SUVmax. CR was more common in early stages; relative risk (RR) of 1.64; P=.003, as well as in type I tumours and a lower SUVmax. Tumour stage was decisive in DFS (P=.04), LE24m (0.07) and OS (P=.08). Longer DFS and a higher percentage of DF 24m were observed in type I tumours (RR: 1.32; P=.26). SUVmax was related to EOC histology, so could predict the response and prognosis of these patients. No association was found between glycolytic activity of the primary tumor with the response and prognosis. Copyright © 2017 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

Allelic imbalance on chromosome 17p13 in borderline (low malignant potential) epithelial ovarian tumors.

PubMed

Zanotti, K M; Hart, W R; Kennedy, A W; Belinson, J L; Casey, G

1999-07-01

Borderline epithelial ovarian tumors (BEOTs) possess clinical and pathologic features intermediate between cystadenomas and cystadenocarcinomas. Although the clinical and pathologic characteristics of BEOTs are well described, the molecular aspects are poorly understood. Three regions of loss of heterozygosity (often referred to as allelic imbalance [AI] when identified by polymerase chain reaction) on chromosome 17p13, one of which includes the p53 gene, have been implicated in the development of ovarian and breast cancers. To provide evidence that genes in these regions also may be involved in the development of BEOTs, we undertook a detailed analysis of AI at all three loci in BEOTs from 21 patients. Seventeen of the BEOTs were serous and four were mucinous. Five of 21 tumors (24%) had AI at one or more loci. Four tumors had AI using the D17S695 marker, two of which showed AI only at this locus. In addition, three tumors exhibited AI at the D17S654 locus, one of which showed AI only at this locus. These data suggest that there may be two tumor suppressor genes distal to p53 involved in the development of at least a subset of BEOTs. Peritoneal implants from a subset of serous BEOTs also were evaluated for AI and were found to be concordant with the primary tumor in all cases. Their genetic similarity is consistent with the implantation theory of peritoneal spread of serous BEOTs in these cases.

Exosomes derived from hypoxic epithelial ovarian cancer deliver microRNA-940 to induce macrophage M2 polarization.

PubMed

Chen, Xin; Ying, Xiang; Wang, Xinjing; Wu, Xiaoli; Zhu, Qinyi; Wang, Xipeng

2017-07-01

Hypoxia is a common feature of solid tumors. It is closely related to tumor progression. Exosomal microRNAs derived from cancers are considered to be mediators between cancer cells and the tumor microenvironment. In addition, the number of tumor-associated macrophages (TAMs) in the tumor microenvironment has also been demonstrated to correlate with tumor development. However, the relationship between tumor-secreted exosomes and TAM polarization under hypoxic conditions during tumor progression is not clear. Herein, we demonstrated that hypoxia induces the high expression of microRNA-940 (miR‑940) in exosomes derived from epithelial ovarian cancer (EOC). We also found that miR‑940 is highly expressed in exosomes isolated from ascites of EOC patients. Moreover, the overexpression of miR‑940 in macrophages delivered by exosomes stimulated M2 phenotype polarization, while the M2 subtype macrophages promoted EOC proliferation and migration. These results highlight the function of hypoxia in enhancing the high level of expression of miR‑940 in tumor exosomes taken up by macrophages. We also showed that the tumor-promoting function of miR‑940 is mediated by TAM polarization in EOC. These findings show that tumor-derived exosomal miR‑940 induced by hypoxia plays an important role in stimulating TAM polarization in the progression of EOC.

Trends in incidence of borderline ovarian tumors in Denmark 1978-2006.

PubMed

Hannibal, Charlotte Gerd; Huusom, Lene Drasbek; Kjaerbye-Thygesen, Anette; Tabor, Ann; Kjaer, Susanne K

2011-04-01

To examine period-, age- and histology-specific trends in the incidence rate of borderline ovarian tumors in Denmark in 1978-2006. Register-based cohort study. Denmark 1978-2006. 5079 women diagnosed with a borderline ovarian tumor in at least one of two nationwide registries (4312 epithelial tumors and 767 non-epithelial/unspecified tumors). Estimation of overall incidence rates and period-, age- and histology-specific incidence rates. Age-adjustment was done using the World Standard POPULATION. To evaluate incidence trends over time, we estimated average annual percentage change and 95% confidence intervals (CI) using log-linear Poisson models. Age-standardized and age-specific incidence rates and average annual percentage change. The incidence of epithelial borderline ovarian tumors increased from 2.6 to 5.5 per 100,000 women-years between 1978 and 2006, with an average annual percentage change of 2.6% (95% CI: 2.2-3.0). The median age at diagnosis was 52 years. Women 40 years or older had a higher average annual percentage change than women younger than 40 years. Most tumors were mucinous (49.9%) and serous tumors (44.4%). Women with mucinous tumors were younger at diagnosis (50 years) compared with women with serous tumors (53 years). Women with serous tumors had a higher average annual percentage incidence change than women with mucinous tumors. The incidence rate of borderline ovarian tumors increased significantly in Denmark in 1978-2006. In line with results for ovarian cancer, Denmark had a higher incidence rate of borderline ovarian tumors compared with the other Nordic countries in 1978-2006. © 2011 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2011 Nordic Federation of Societies of Obstetrics and Gynecology.

Chemoprevention of Ovarian Cancer

DTIC Science & Technology

2005-10-01

cycle," Endocrinology 123, 2896-905 (1988). 31 31. A. G. Hendrickx , W. R. Dukelow, "Reproductive Biology," Chap. 9 in Nonhuman Primates in Biomedical...100 units/ml penicillin , 2 mM L-glutamine, and 100 to explore the effect of 4-HPR on normal ovarian epithelial [ig/ml streptomycin. Six different NOE

SERPINB3 in the chicken model of ovarian cancer: a prognostic factor for platinum resistance and survival in patients with epithelial ovarian cancer.

PubMed

Lim, Whasun; Kim, Hee Seung; Jeong, Wooyoung; Ahn, Suzie E; Kim, Jinyoung; Kim, Yong Beom; Kim, Min A; Kim, Mi-Kyung; Chung, Hyun Hoon; Song, Yong Sang; Bazer, Fuller W; Han, Jae Yong; Song, Gwonhwa

2012-01-01

Serine protease inhibitors (SERPINs) appear to be ubiquitously expressed in a variety of species and play important roles in pivotal physiological processes such as angiogenesis, immune responses, blood coagulation and fibronolysis. Of these, squamous cell carcinoma antigen 1 (SCCA1), also known as a SERPINB3, was first identified in squamous cell carcinoma tissue from the cervix of women. However, there is little known about the SERPINB3 expression in human epithelial ovarian cancer (EOC). Therefore, in the present study, we investigated the functional role of SERPINB3 gene in human EOC using chickens, the most relevant animal model. In 136 chickens, EOC was found in 10 (7.4%). SERPINB3 mRNA was induced in cancerous, but not normal ovaries of chickens (P<0.01), and it was abundant only in the glandular epithelium of cancerous ovaries of chickens. Further, several microRNAs, specifically miR-101, miR-1668 and miR-1681 were discovered to influence SERPINB3 expression via its 3'-UTR which suggests that post-transcriptional regulation influences SERPINB3 expression in chickens. SERPINB3 protein was localized predominantly to the glandular epithelium in cancerous ovaries of chickens, and it was abundant in the nucleus of both chicken and human ovarian cancer cell lines. In 109 human patients with EOC, 15 (13.8%), 66 (60.6%) and 28 (25.7%) patients showed weak, moderate and strong expression of SERPINB3 protein, respectively. Strong expression of SERPINB3 protein was a prognostic factor for platinum resistance (adjusted OR; odds ratio, 5.94; 95% Confidence Limits, 1.21-29.15), and for poor progression-free survival (PFS; adjusted HR; hazard ratio, 2.07; 95% CI; confidence interval, 1.03-4.41). Therefore, SERPINB3 may play an important role in ovarian carcinogenesis and be a novel biomarker for predicting platinum resistance and a poor prognosis for survival in patients with EOC.

SERPINB3 in the Chicken Model of Ovarian Cancer: A Prognostic Factor for Platinum Resistance and Survival in Patients with Epithelial Ovarian Cancer

PubMed Central

Jeong, Wooyoung; Ahn, Suzie E.; Kim, Jinyoung; Kim, Yong Beom; Kim, Min A.; Kim, Mi-Kyung; Chung, Hyun Hoon; Song, Yong Sang; Bazer, Fuller W.; Han, Jae Yong; Song, Gwonhwa

2012-01-01

Serine protease inhibitors (SERPINs) appear to be ubiquitously expressed in a variety of species and play important roles in pivotal physiological processes such as angiogenesis, immune responses, blood coagulation and fibronolysis. Of these, squamous cell carcinoma antigen 1 (SCCA1), also known as a SERPINB3, was first identified in squamous cell carcinoma tissue from the cervix of women. However, there is little known about the SERPINB3 expression in human epithelial ovarian cancer (EOC). Therefore, in the present study, we investigated the functional role of SERPINB3 gene in human EOC using chickens, the most relevant animal model. In 136 chickens, EOC was found in 10 (7.4%). SERPINB3 mRNA was induced in cancerous, but not normal ovaries of chickens (P<0.01), and it was abundant only in the glandular epithelium of cancerous ovaries of chickens. Further, several microRNAs, specifically miR-101, miR-1668 and miR-1681 were discovered to influence SERPINB3 expression via its 3′-UTR which suggests that post-transcriptional regulation influences SERPINB3 expression in chickens. SERPINB3 protein was localized predominantly to the glandular epithelium in cancerous ovaries of chickens, and it was abundant in the nucleus of both chicken and human ovarian cancer cell lines. In 109 human patients with EOC, 15 (13.8%), 66 (60.6%) and 28 (25.7%) patients showed weak, moderate and strong expression of SERPINB3 protein, respectively. Strong expression of SERPINB3 protein was a prognostic factor for platinum resistance (adjusted OR; odds ratio, 5.94; 95% Confidence Limits, 1.21–29.15), and for poor progression-free survival (PFS; adjusted HR; hazard ratio, 2.07; 95% CI; confidence interval, 1.03–4.41). Therefore, SERPINB3 may play an important role in ovarian carcinogenesis and be a novel biomarker for predicting platinum resistance and a poor prognosis for survival in patients with EOC. PMID:23185467

Tumour-specific HMG-CoAR is an independent predictor of recurrence free survival in epithelial ovarian cancer.

PubMed

Brennan, Donal J; Brändstedt, Jenny; Rexhepaj, Elton; Foley, Michael; Pontén, Fredrik; Uhlén, Mathias; Gallagher, William M; O'Connor, Darran P; O'Herlihy, Colm; Jirstrom, Karin

2010-04-01

Our group previously reported that tumour-specific expression of the rate-limiting enzyme in the mevalonate pathway, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) is associated with more favourable tumour parameters and a good prognosis in breast cancer. In the present study, the prognostic value of HMG-CoAR expression was examined in tumours from a cohort of patients with primary epithelial ovarian cancer. HMG-CoAR expression was assessed using immunohistochemistry (IHC) on tissue microarrays (TMA) consisting of 76 ovarian cancer cases, analysed using automated algorithms to develop a quantitative scoring model. Kaplan Meier analysis and Cox proportional hazards modelling were used to estimate the risk of recurrence free survival (RFS). Seventy-two tumours were suitable for analysis. Cytoplasmic HMG-CoAR expression was present in 65% (n = 46) of tumours. No relationship was seen between HMG-CoAR and age, histological subtype, grade, disease stage, estrogen receptor or Ki-67 status. Patients with tumours expressing HMG-CoAR had a significantly prolonged RFS (p = 0.012). Multivariate Cox regression analysis revealed that HMG-CoAR expression was an independent predictor of improved RFS (RR = 0.49, 95% CI (0.25-0.93); p = 0.03) when adjusted for established prognostic factors such as residual disease, tumour stage and grade. HMG-CoAR expression is an independent predictor of prolonged RFS in primary ovarian cancer. As HMG-CoAR inhibitors, also known as statins, have demonstrated anti-neoplastic effects in vitro, further studies are required to evaluate HMG-CoAR expression as a surrogate marker of response to statin treatment, especially in conjunction with current chemotherapeutic regimens.

Tumour-specific HMG-CoAR is an independent predictor of recurrence free survival in epithelial ovarian cancer

PubMed Central

2010-01-01

Background Our group previously reported that tumour-specific expression of the rate-limiting enzyme in the mevalonate pathway, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) is associated with more favourable tumour parameters and a good prognosis in breast cancer. In the present study, the prognostic value of HMG-CoAR expression was examined in tumours from a cohort of patients with primary epithelial ovarian cancer. Methods HMG-CoAR expression was assessed using immunohistochemistry (IHC) on tissue microarrays (TMA) consisting of 76 ovarian cancer cases, analysed using automated algorithms to develop a quantitative scoring model. Kaplan Meier analysis and Cox proportional hazards modelling were used to estimate the risk of recurrence free survival (RFS). Results Seventy-two tumours were suitable for analysis. Cytoplasmic HMG-CoAR expression was present in 65% (n = 46) of tumours. No relationship was seen between HMG-CoAR and age, histological subtype, grade, disease stage, estrogen receptor or Ki-67 status. Patients with tumours expressing HMG-CoAR had a significantly prolonged RFS (p = 0.012). Multivariate Cox regression analysis revealed that HMG-CoAR expression was an independent predictor of improved RFS (RR = 0.49, 95% CI (0.25-0.93); p = 0.03) when adjusted for established prognostic factors such as residual disease, tumour stage and grade. Conclusion HMG-CoAR expression is an independent predictor of prolonged RFS in primary ovarian cancer. As HMG-CoAR inhibitors, also known as statins, have demonstrated anti-neoplastic effects in vitro, further studies are required to evaluate HMG-CoAR expression as a surrogate marker of response to statin treatment, especially in conjunction with current chemotherapeutic regimens. PMID:20359358

Epidemiological overview, advances in diagnosis, prevention, treatment and management of epithelial ovarian cancer in Mexico.

PubMed

Gallardo-Rincón, Dolores; Espinosa-Romero, Raquel; Muñoz, Wendy Rosemary; Mendoza-Martínez, Roberto; Villar-Álvarez, Susana Del; Oñate-Ocaña, Luis; Isla-Ortiz, David; Márquez-Manríquez, Juan Pablo; Apodaca-Cruz, Ángel; Meneses-García, Abelardo

2016-04-01

The epithelial ovarian cancer (EOC) has been underdiagnosed because it does not have a specific clinical presentation, and the signs and symptoms are similar to the irritable bowel syndrome and pelvic inflammatory disease. EOC is less common than breast and cervical cancer, but it is more lethal. On the whole, EOC has an early dissemination to peritoneal cavity, which delays a timely diagnosis and increases the rate of advanced diagnosed disease. The diagnosis usually surprises the women and the primary care physician. Therefore, it is necessary to count on prevention and early diagnosis programs. EOC has 80% response to surgical treatment, but nearly 70% of the patients may relapse in five years. The objectives of this document are presenting a summary of the EOC epidemiology and comment about advancements in prevention, diagnosis, and treatment of this cancer. That will raise awareness about the importance of this disease.

The rise of genomic profiling in ovarian cancer

PubMed Central

Previs, Rebecca A.; Sood, Anil K.; Mills, Gordon B.; Westin, Shannon N.

2017-01-01

Introduction Next-generation sequencing and advances in ‘omics technology have rapidly increased our understanding of the molecular landscape of epithelial ovarian cancers. Areas covered Once characterized only by histologic appearance and clinical behavior, we now understand many of the molecular phenotypes that underlie the different ovarian cancer subtypes. While the current approach to treatment involves standard cytotoxic therapies after cytoreductive surgery for all ovarian cancers regardless of histologic or molecular characteristics, focus has shifted beyond a ‘one size fits all’ approach to ovarian cancer. Expert commentary Genomic profiling offers potentially ‘actionable’ opportunities for development of targeted therapies and a more individualized approach to treatment with concomitant improved outcomes and decreased toxicity. PMID:27828713

The origin of ovarian carcinomas: a unifying hypothesis.

PubMed

Auersperg, Nelly

2011-01-01

It is currently a controversial issue whether epithelial ovarian cancers arise in the ovarian surface epithelium (OSE) or the fimbrial epithelium of the oviduct. The hypothesis presented here aims to reconcile these 2 views and provides a possible explanation for 2 questions arising: first, why tumors originating in the fimbriae and OSE, which are parts of different organs, express common features; second, why these epithelia are prone to neoplastic transformation whereas the remaining oviduct and the extraovarian mesothelium are not. We hypothesize that these questions relate to the common origin of the OSE and fimbriae in that region of the embryonic coelomic epithelium, which will eventually link the extraovarian mesothelium to the epithelium of the oviductal ampulla. OSE and fimbriae become separated during embryonic development but, like other transitional, interepithelial junctions in adults, this region might remain incompletely committed and thus prone to neoplastic progression. To define differentiation at the OSE-tubal junction, salpingo-oophorectomy specimens were stained immunohistochemically for mesenchymal differentiation markers of OSE and for epithelial markers and Pax8, characterizing oviductal fimbriae and ampullae. OSE and ampullae were distinctly different, but there was no sharp boundary between OSE and fimbriae. Rather, both mesenchymal and epithelial markers overlapped, and Pax8 and fimbrial epithelial markers diminished distally, near the OSE. The results support the hypothesis that the OSE and fimbriae are parts of a transitional epithelium of common origin rather than 2 independent sources of ovarian cancer, and suggest that their immature, incompletely determined phenotype contributes to their propensity to neoplastic transformation.

Expression and Functional Pathway Analysis of Nuclear Receptor NR2F2 in Ovarian Cancer

PubMed Central

Hawkins, Shannon M.; Loomans, Holli A.; Wan, Ying-Wooi; Ghosh-Choudhury, Triparna; Coffey, Donna; Xiao, Weimin; Liu, Zhandong; Sangi-Haghpeykar, Haleh

2013-01-01

Context: Recent evidence implicates the orphan nuclear receptor, nuclear receptor subfamily 2, group F, member 2 (NR2F2; chicken ovalbumin upstream promoter-transcription factor II) as both a master regulator of angiogenesis and an oncogene in prostate and other human cancers. Objective: The objective of the study was to determine whether NR2F2 plays a role in ovarian cancer and dissect its potential mechanisms of action. Design, Setting, and Patients: We examined NR2F2 expression in healthy ovary and ovarian cancers using quantitative PCR and immunohistochemistry. NR2F2 expression was targeted in established ovarian cancer cell lines to assess the impact of dysregulated NR2F2 expression in the epithelial compartment of ovarian cancers. Results: Our results indicate that NR2F2 is robustly expressed in the stroma of healthy ovary with little or no expression in epithelia lining the ovarian surface, clefts, or crypts. This pattern of NR2F2 expression was markedly disrupted in ovarian cancers, in which decreased levels of stromal expression and ectopic epithelial expression were frequently observed. Ovarian cancers with the most disrupted patterns of NR2F2 were associated with significantly shorter disease-free interval by Kaplan-Meier analysis. Targeting NR2F2 expression in established ovarian cancer cell lines enhanced apoptosis and increased proliferation. In addition, we found that NR2F2 regulates the expression of NEK2, RAI14, and multiple other genes involved in the cell cycle, suggesting potential pathways by which dysregulated expression of NR2F2 impacts ovarian cancer. Conclusions: These results uncover novel roles for NR2F2 in ovarian cancer and point to a unique scenario in which a single nuclear receptor plays potentially distinct roles in the stromal and epithelial compartments of the same tissue. PMID:23690307

Association of the AA genotype of the BCL2 (-938C>A) promoter polymorphism with better survival in ovarian cancer.

PubMed

Heubner, Martin; Wimberger, Pauline; Otterbach, Friedrich; Kasimir-Bauer, Sabine; Siffert, Winfried; Kimmig, Rainer; Nückel, Holger

2009-01-01

Bcl-2 plays a key role in the regulation of apoptosis. Recently, a novel regulatory single nucleotide polymorphism (-938C>A) in the inhibitory P2 BCL2 promoter was described. In this study we investigated its potential association with survival in epithelial ovarian cancer. Patients (n=110) with primary epithelial ovarian cancer were retrospectively genotyped by pyrosequencing. Genotype distribution was not significantly different between 110 ovarian cancer patients and 120 healthy controls, suggesting that genotypes of this polymorphism do not increase the susceptibility to ovarian cancer. Kaplan-Meier curves showed a significant association of the AA genotype with increased survival (p=0.002). Multivariate analysis revealed that the BCL2-938AC/CC genotype (hazard ratio 4.5; p=0.003) was an independent prognostic factor compared to other prognostic factors such as age, histological grade or tumor stage. The results suggest a role for the BCL2-938C>A polymorphism as a marker for survival in patients with epithelial ovarian cancer.

[Correlation between bacterial L-form infection, expression of HIF-1α/MMP-9 and vasculogenic mimicry in epithelial ovarian cancer].

PubMed

Yu, Lan; Wu, Shi-Wu; Zhou, Lei; Song, Wen-Qing

2012-12-25

The aim of the present study is to explore whether vasculogenic mimicry (VM) and bacterial L-form infection exist in human epithelial ovarian cancer (EOC) or not and to elucidate the correlation of L-form infection, expression of hypoxia inducible factor 1α (HIF-1α)/MMP-9 and VM. In 87 specimens of EOC and 20 specimens of ovarian benign epithelial tumor tissues, L-form infection was detected by Gram's staining, expression of HIF-1α/MMP-9 and VM were detected by immunohistochemical and histochemical staining. The results showed that the positive rates of HIF-1α and MMP-9 protein in EOC were 52.9% and 66.7%, while in benign epithelial tumor tissues, the positive rates were 10.0% and 10.0% respectively, and there were significant differences between them (P < 0.05). In EOC and benign epithelial tumor tissues, L-form infections ratios were 24.1% and 0, respectively, and the difference was also significant (P < 0.01). Expression of VM, HIF-1α and MMP-9 in EOC was significantly related to differentiation, abdominal implantation and lymph node metastasis and FIGO stage (P < 0.01). L-form infection had relationship with abdominal implantation, lymph node metastasis and FIGO stage (P < 0.01 or 0.05). The expression of HIF-1α had positive relationship with expression of MMP-9 and VM (r = 0.505, 0.585, respectively, P < 0.01); there was also a positive relationship between MMP-9 expression and VM (r = 0.625, P < 0.01). Overexpression of VM, HIF-1α and MMP-9 were related to poor prognosis: the survival rates were significantly lower in positive patients than those in negative patients (P < 0.05). And the group with L-form infection also had poor prognosis: the survival rates were lower than those in group without infection (P < 0.05). FIGO stage, expression of VM, HIF-1α and MMP-9 were independent prognosis factors of EOC (P < 0.05). The results suggest that L-form infection, the expression of HIF-1α, MMP-9 and VM in EOC are related to differentiation, lymph node

BRCA1/2 genetic background-based therapeutic tailoring of human ovarian cancer: hope or reality?

PubMed Central

Tagliaferri, Pierosandro; Ventura, Monica; Baudi, Francesco; Cucinotto, Iole; Arbitrio, Mariamena; Di Martino, Maria Teresa; Tassone, Pierfrancesco

2009-01-01

Ovarian epithelial tumors are an hallmark of hereditary cancer syndromes which are related to the germ-line inheritance of cancer predisposing mutations in BRCA1 and BRCA2 genes. Although these genes have been associated with multiple different physiologic functions, they share an important role in DNA repair mechanisms and therefore in the whole genomic integrity control. These findings have risen a variety of issues in terms of treatment and prevention of breast and ovarian tumors arising in this context. Enhanced sensitivity to platinum-based anticancer drugs has been related to BRCA1/2 functional loss. Retrospective studies disclosed differential chemosensitivity profiles of BRCA1/2-related as compared to "sporadic" ovarian cancer and led to the identification of a "BRCA-ness" phenotype of ovarian cancer, which includes inherited BRCA1/2 germ-line mutations, a serous high grade histology highly sensitive to platinum derivatives. Molecularly-based tailored treatments of human tumors are an emerging issue in the "era" of molecular targeted drugs and molecular profiling technologies. We will critically discuss if the genetic background of ovarian cancer can indeed represent a determinant issue for decision making in the treatment selection and how the provocative preclinical findings might be translated in the therapeutic scenario. The presently available preclinical and clinical evidence clearly indicates that genetic background has an emerging role in treatment individualization for ovarian cancer patients. PMID:19825178

Pros and cons of intraperitoneal chemotherapy in the treatment of epithelial ovarian cancer.

PubMed

Zeimet, Alain G; Reimer, Daniel; Radl, Alice C; Reinthaller, Alexander; Schauer, Christian; Petru, Edgar; Concin, Nicole; Braun, Stephan; Marth, Christian

2009-07-01

Development of the pros and cons of intraperitoneal (IP) chemotherapy in the treatment of epithelial ovarian cancer based on the most prominent data published on the evolution of IP chemotherapy and on experience with this therapeutic strategy in clinical routine. The literature published on IP chemotherapy in ovarian cancer between 1970 and 2008 was identified systematically by computer-based searches in MEDLINE and the Cochrane Library. Furthermore, a preliminary analysis of data recorded during an observational nationwide multicenter study of the Austrian AGO on IP-IV chemotherapy using the GOG-172 treatment regimen was performed. The literature review unequivocally revealed a significantly greater toxicity for IP than for intravenous (IV) cisplatin-based chemotherapy. However, according to a Cochrane meta-analysis, IP-IV administration of chemotherapy is associated with a 21.6% decrease in the risk for death. In agreement with earlier reports, the most frequently mentioned side-effects in the Austria-wide observational study were long-lasting neurotoxicity, abdominal pain, fatigue, gastrointestinal and metabolic toxicities, and catheter-related complications. Most of these toxicities were identified as mirroring the toxicity profile of high-dose IV cisplatin (>or=100 mg/m(2)). In some patients, the classic IP-IV regimen with cisplatin/paclitaxel was changed to an alternative schedule comprising carboplatin AUC 5 (d1) and weekly paclitaxel 60 mg/m(2) (d1, 8, 15) completely administered via the IP route. This treatment was better tolerated and quality of life was significantly less compromised. However, neutropenia and thrombocytopenia were the limiting side-effects of this IP regimen. In cases where optimal cytoreduction with residual disease

Outcomes of laparoscopic fertility-sparing surgery in clinically early-stage epithelial ovarian cancer.

PubMed

Park, Jin-Young; Heo, Eun Jin; Lee, Jeong-Won; Lee, Yoo-Young; Kim, Tae-Joong; Kim, Byoung-Gie; Bae, Duk-Soo

2016-03-01

Fertility-sparing surgery (FSS) is becoming an important technique in the surgical management of young women with early-stage epithelial ovarian cancer (EOC). We retrospectively evaluated the outcome of laparoscopic FSS in presumed clinically early-stage EOC. We retrospectively searched databases of patients who received laparoscopic FSS for EOC between January 1999 and December 2012 at Samsung Medical Center. Women aged ≤40 years were included. The perioperative, oncological, and obstetric outcomes of these patients were evaluated. A total of 18 patients was evaluated. The median age of the patients was 33.5 years (range, 14 to 40 years). The number of patients with clinically stage IA and IC was 6 (33.3%) and 12 (66.7%), respectively. There were 7 (38.9%), 5 (27.8%), 3 (16.7%), and 3 patients (16.7%) with mucinous, endometrioid, clear cell, and serous tumor types, respectively. Complete surgical staging to preserve the uterus and one ovary with adnexa was performed in 4 patients (22.2%). Two out of them were upstaged to The International Federation of Gynecology and Obstetrics stage IIIA1. During the median follow-up of 47.3 months (range, 11.5 to 195.3 months), there were no perioperative or long term surgical complications. Four women (22.2%) conceived after their respective ovarian cancer treatments. Three (16.7%) of them completed full-term delivery and one is expecting a baby. One patient had disease recurrence. No patient died of the disease. FSS in young patients with presumed clinically early-stage EOC is a challenging and cautious procedure. Further studies are urgent to determine the safety and feasibility of laparoscopic FSS in young patients with presumed clinically early-stage EOC.

Outcomes of laparoscopic fertility-sparing surgery in clinically early-stage epithelial ovarian cancer

PubMed Central

Park, Jin-Young; Lee, Yoo-Young; Kim, Tae-Joong; Kim, Byoung-Gie; Bae, Duk-Soo

2016-01-01

Objective Fertility-sparing surgery (FSS) is becoming an important technique in the surgical management of young women with early-stage epithelial ovarian cancer (EOC). We retrospectively evaluated the outcome of laparoscopic FSS in presumed clinically early-stage EOC. Methods We retrospectively searched databases of patients who received laparoscopic FSS for EOC between January 1999 and December 2012 at Samsung Medical Center. Women aged ≤40 years were included. The perioperative, oncological, and obstetric outcomes of these patients were evaluated. Results A total of 18 patients was evaluated. The median age of the patients was 33.5 years (range, 14 to 40 years). The number of patients with clinically stage IA and IC was 6 (33.3%) and 12 (66.7%), respectively. There were 7 (38.9%), 5 (27.8%), 3 (16.7%), and 3 patients (16.7%) with mucinous, endometrioid, clear cell, and serous tumor types, respectively. Complete surgical staging to preserve the uterus and one ovary with adnexa was performed in 4 patients (22.2%). Two out of them were upstaged to The International Federation of Gynecology and Obstetrics stage IIIA1. During the median follow-up of 47.3 months (range, 11.5 to 195.3 months), there were no perioperative or long term surgical complications. Four women (22.2%) conceived after their respective ovarian cancer treatments. Three (16.7%) of them completed full-term delivery and one is expecting a baby. One patient had disease recurrence. No patient died of the disease. Conclusion FSS in young patients with presumed clinically early-stage EOC is a challenging and cautious procedure. Further studies are urgent to determine the safety and feasibility of laparoscopic FSS in young patients with presumed clinically early-stage EOC. PMID:26768783

Prognostic impact of marital status on survival of women with epithelial ovarian cancer.

PubMed

Mahdi, Haider; Kumar, Sanjeev; Munkarah, Adnan R; Abdalamir, Moshrik; Doherty, Mark; Swensen, Ron

2013-01-01

The objective of this study is to examine the impact of marital status on survival of patients with epithelial ovarian cancer (EOC). Patients with a diagnosis of EOC were identified from the Surveillance, Epidemiology, and End Results Program for the period 1988-2006 and divided into married and unmarried groups. Statistical analysis using Student's t-test, Kaplan-Meier, and Cox regression proportional hazards was performed. In 49,777 patients with EOC, 51.2% were married and 48.8% were unmarried. White women were likely to be married compared with African Americans (52.0% vs 32.4%, p < 0.05). Younger age (63.9% vs 43.4%, p < 0.001) and early stage disease (37.5% vs 33.8%, p < 0.001) were more prominent in married patients compared with unmarried patients. Staging lymphadenectomy was performed more frequently in married than unmarried patients (39.9% vs 29.8%, p < 0.001). Overall 5-year survival was 45.0% for married patients and 33.1% for unmarried patients, p < 0.001. Married patients had a better survival compared with unmarried patients within each racial subgroup: 44.5% vs 33.3% for White women (p < 0.001), 36.9% vs 24.9% for African Americans (p < 0.001), and 53.7% vs 42.7% for others (p < 0.001), respectively. In a model that controlled for age, race, histology, stage, grade, and surgical treatment, married patients had a significantly improved survival compared with unmarried patients (HR 0.8, 95% CI 0.78-0.83, p < 0.001). In this epidemiologic study, the social institution of marriage is associated with improved survival in women with ovarian cancer. Copyright © 2011 John Wiley & Sons, Ltd.

[A prospective study of adenosine triphosphate-tumor chemosensitivity assay directed chemotherapy in patients with recurrent ovarian cancer].

PubMed

Gao, Yu-tao; Wu, Ling-ying; Zhang, Wei; Zhao, Dan; Li, Ning; Tian, Hai-mei; Wang, Xiao-bing; Li, Mo; Sun, Yang-chun; Li, Nan; Li, Xiao-guang

2013-05-01

To investigate the efficacy of adenosine triphosphate (ATP)-tumor chemosensitivity assay (TCA) directed chemotherapy in patients with recurrent epithelial ovarian cancer. From August 2010 to June 2012, recurrent epithelial ovarian cancer patients were prospectively enrollmented in Cancer Hospital, Peking Union Medical College,Chinese Academy of Medical Sciences.The entry criteria are as follows: (1) Histologically proven to be epithelial ovarian cancer. (2) Patients of recurrent ovarian cancer with bidimensionally measurable tumor, or ascitic or pleural fluid for testing. (3) Karnofsky performance status > 60. (4) A life expectancy of at least more than 6 months.According to patients desires, they were assigned into two groups: assay-directed therapy group and physician's-choice therapy group, patients' clinical and pathological characteristics, response rate to chemotherapy and progression-free survival (PFS) were compared between two groups. A total of 113 patients with recurrent epithelial ovarian cancer were prospectively enrollmented to assay-directed chemotherapy (n = 56) or physician's-choice chemotherapy (n = 57).There was no difference in median age,types of recurrence, surgical-pathological stage, pathological type, tumor grade, times of recurrence, residual disease at secondary cytoreductive surgery between assay-directed group and physician's-choice group. The overall response rate (ORR) and median PFS in the ATP-TCA group was 66% (37/56) and 7 months, while the ORR in the control group was 46% (26/57, P = 0.037), the median PFS was 4 months (P = 0.040). For platinum-resistant patients, the ORR between ATP-TCA directed chemotherapy 59% (16/27) and control group 25% (7/28) were significantly different (P = 0.010), and the median PFS between two groups were also significantly different (5 months and 2 months, respectively, P = 0.003). ATP-TCA directed chemotherapy could improve ORR and PFS in patients with recurrent epithelial ovarian cancer, especially

Spontaneous rupture of ovarian cystadenocarcinoma: pre- and post-rupture computed tomography evaluation*

PubMed Central

Salvadori, Priscila Silveira; Bomfim, Lucas Novais; von Atzingen, Augusto Castelli; D’Ippolito, Giuseppe

2015-01-01

Epithelial ovarian tumors are the most common malignant ovarian neoplasms and, in most cases, eventual rupture of such tumors is associated with a surgical procedure. The authors report the case of a 54-year-old woman who presented with spontaneous rupture of ovarian cystadenocarcinoma documented by computed tomography, both before and after the event. In such cases, a post-rupture staging tends to be less favorable, compromising the prognosis. PMID:26543286

Inhibition of gamma-secretase in Notch1 signaling pathway as a novel treatment for ovarian cancer.

PubMed

Feng, Zhaoyi; Xu, Wandong; Zhang, Chenguang; Liu, Mengran; Wen, Hongwu

2017-01-31

Epithelial ovarian cancer (EOC) is the leading cause of death for gynecological cancer. Most patients are not diagnosed until the cancer is at an advanced stage with poor prognosis. Notch1 signaling pathway plays an oncogenic role in EOC. There have been few studies on enzymatic activity of γ-secretase and the mechanism of how γ-secretase inhibitor works on cancer cell. Here, we show that Jagged1 and NICD were highly expressed in ovarian carcinoma. The expressions of Notch1, Jagged1 and NICD in Notch1 pathway did not correlate with outcome in ovarian cancer. The enzymatic activity of γ-secretase in ovarian cancer cell lines SKOV3, CAOV3 and ES2 is significantly higher than in normal ovarian epithelial cell line T29. DAPT (a γ-secretase inhibitor) reduced the enzymatic activity of γ-secretase, inhibited the proliferation, and increased the apoptosis in ovarian cancer cell lines. Hence, γ-secretase inhibitor may become a highly promising novel therapeutic strategy against ovarian cancer in the field of precision medicine.

New perspectives on targeted therapy in ovarian cancer

PubMed Central

Coward, Jermaine IG; Middleton, Kathryn; Murphy, Felicity

2015-01-01

Epithelial ovarian cancer remains the most lethal gynecologic malignancy. During the last 15 years, there has been only marginal improvement in 5 year overall survival. These daunting statistics are compounded by the fact that despite all subtypes exhibiting striking heterogeneity, their systemic management remains identical. Although changes to the scheduling and administration of chemotherapy have improved outcomes to a degree, a therapeutic ceiling is being reached with this approach, resulting in a number of trials investigating the efficacy of targeted therapies alongside standard treatment algorithms. Furthermore, there is an urge to develop subtype-specific studies in an attempt to improve outcomes, which currently remain poor. This review summarizes the key studies with antiangiogenic agents, poly(adenosine diphosphate [ADP]-ribose) inhibitors, and epidermal growth factor receptor/human epidermal growth factor receptor family targeting, in addition to folate receptor antagonists and insulin growth factor receptor inhibitors. The efficacy of treatment paradigms used in non-ovarian malignancies for type I tumors is also highlighted, in addition to recent advances in appropriate patient stratification for targeted therapies in epithelial ovarian cancer. PMID:25678824

[Effects of dihydroartiminisin on the adhesion, migration, and invasion of epithelial ovarian cancer cells].

PubMed

Tan, Xian-Jie; Lang, Jing-He; Plouet, Jean; Wu, Ming; Shen, Keng

2008-10-14

To investigate the effects of dihydroartiminisin (DHA) on the adhesion, migration, and invasion ovarian cancer cells. Human ovarian cancer cells of the lines SKOV3 and OVCAR3 were cultured. Suspensions of SKOV3 and OVCAR3 cells were treated with DHA of the concentrations of 0.5, 2.5, 12.5, and 62.5 micromol/L respectively, and then inoculated on the plate coated with Matrigel. MTT method was used to -determine the adhesion rate. Transwell membrane chamber model was used to evaluate the effect of DHA on the migration and invasion of the SKOV3 and OVCAR3 cells. Western blotting and reverse transcriptase polymerase chain reaction were used to detect the effect of DHA on the phosphorylation of focal adhesion kinase (FAK) and on the effect of expression of metal matrix proteinases (MMPs) and their tissue inhibitors (TIMPs) respectively. (1) Compared to the cells without DHA treatment, the cell adhesion ability levels of the SKOV3 and OVCAR3 cells treated with 12.5 micromol/L DHA decreased by 76.1% and 57.9% respectively (P < 0.05), while their migration ability levels decreased by 59.3% and 69.7% respectively (P < 0.05). (2) Both SKOV3 and OVCAR3 showed weak invasion ability, and DHA only showed a slight inhibitory effect on the cell invasion of these 2 lines (both P > 0.05). (3) Compared to the cells without DHA treatment, the phosphorylation level of FAK of the SKOV3 and OVCAR3 cells treated with 12.5 micromol/L DHA decreased by 42.9% and 44.8% respectively (both P < 0.05). (4) RT-PCR showed mRNA expression of MMP2, TIMP1, and TIMP2, but not mRNA expression of MMP9 in both SKOV3 and OVCAR3 cells. The mRNA expression levels of the SKOV3 and OVCAR3 cells treated with 12.5 micromol/L DHA increased by 1.5 and 2.6 times respectively (both P < 0.05). DHA has inhibitory effects on the adhesion and migration of epithelial ovarian cancer cells, which may be related to its down-regulation of the phosphorylation of FAK in these cells.

Coffee, tea, and caffeine consumption and risk of epithelial ovarian cancer and borderline ovarian tumors: Results from a Danish case-control study.

PubMed

Gosvig, Camilla F; Kjaer, Susanne K; Blaakær, Jan; Høgdall, Estrid; Høgdall, Claus; Jensen, Allan

2015-01-01

Epidemiological studies that have investigated the association between coffee, tea and caffeine consumption and ovarian cancer risk have produced conflicting results. Furthermore, only few studies have examined the role of coffee and tea consumption separately for borderline ovarian tumors. By use of data from a large Danish population-based case-control study, we examined the risk of ovarian tumors associated with coffee, tea, and caffeine consumption with a particular focus on characterizing risks by tumor behavior and histology. From 1995 through 1999, we included 267 women with ovarian cancer, 115 women with borderline ovarian tumors and 911 randomly selected control women. All women completed a beverage frequency questionnaire with detailed information on coffee and tea consumption. Analyses were performed using multiple logistic regression models. Both coffee (OR = 0.90; 95% CI 0.84-0.97 per cup/day) and total caffeine consumption from coffee and tea combined (OR = 0.93; 95% CI 0.88-0.98 per 100 mg/day) decreased the risk of ovarian cancer. These associations were significant only for the serous and "other" subtypes of ovarian cancer. No relation between tea consumption and ovarian cancer risk was observed. The risk estimates for borderline ovarian tumors resembled those observed for ovarian cancer, but did not reach statistical significance. Our results indicate that coffee consumption and total caffeine consumption from coffee and tea combined is associated with a modest decreased risk of ovarian cancer. However, more biological studies are needed to identify bioactive chemical compounds in coffee that potentially could affect ovarian cancer development.

The role of oxidative stress in the development of cisplatin resistance in epithelial ovarian cancer.

PubMed

Belotte, Jimmy; Fletcher, Nicole M; Awonuga, Awoniyi O; Alexis, Mitchell; Abu-Soud, Husam M; Saed, Mohammed G; Diamond, Michael P; Saed, Ghassan M

2014-04-01

To investigate the role of oxidative stress in the development of cisplatin resistance in epithelial ovarian cancer (EOC). Two parent EOC cell lines (MDAH-2774 and SKOV-3) and their chemoresistant counterparts (cisplatin, 50 µmol/L) were used. Total RNA was extracted and subjected to real-time reverse transcriptase polymerase chain reaction to evaluate the expression of glutathione reductase (GSR) and inducible nitric oxide synthase (iNOS), as well as nitrate/nitrite levels. Analysis of variance was used for main effects and Tukey for post hoc analysis at P < .05 for statistical significance. Both cisplatin resistant cell lines displayed a significant decrease in GSR messenger RNA (mRNA) levels and activity (P < .01). As compared to sensitive controls, nitrate/nitrite levels were significantly higher in SKOV-3 cisplatin resistant cells while iNOS mRNA levels were significantly higher in MDAH-2774 cisplatin resistant cells (P < .05). Our data suggest that the development of cisplatin resistance tilts the balance toward a pro-oxidant state in EOC.

Prognostic and clinicopathological significance of Cacna2d1 expression in epithelial ovarian cancers: a retrospective study

PubMed Central

Yu, Dandan; Holm, Ruth; Goscinski, Mariusz Adam; Trope, Claes G; Nesland, Jahn M; Suo, Zhenhe

2016-01-01

Ovarian cancer is the most lethal gynecologic malignancy, in which cancer stem cells (CSC) have been reported to be the driving force of relapse and therapy-resistance. It is therefore important to explore CSC markers in ovarian cancer. This project aimed to explore the correlation between the expression of potential CSC maker Cacna2d1 and clinicopathological parameters in 238 epithelial ovarian cancer (EOC) samples. Immunohistochemically, positive Cacna2d1 expression was observed in 83.6% (199/238) of the EOC tumors, among which 107 tumors (44.9%) were highly positive and 92 (38.7%) tumors were weakly positive for the Cacna2d1 protein expression. Among the 158 serous carcinomas, the Cacna2d1 positivity was 148 (93.7%), in which 88 (55.7%) were highly positive, and 60 (38.0%) were weakly positive for the Cacna2d1 protein expression. Most strikingly, the Cacna2d1 was specifically expressed in the infiltration front areas of the EOC tumors. Statistical analyses showed that positive expression of Cacna2d1 was significantly associated with advanced FIGO stage (P<0.001), histological subtype (P=0.017) and tumor differentiation (P=0.015). Positive Cacna2d1 protein expression was significantly associated with poor overall survival (OS) and shorter progression free survival (PFS) in both total EOCs and serous carcinomas, although multivariate analyses did not reach statistical significance. In summary, our results suggest Cacna2d1 protein may play a crucial role in promoting aggressive EOC behavior and progression, and Cacna2d1 may serve as a novel predictive prognostic marker and a potential target for therapeutic intervention in EOCs. PMID:27725913

Somatostatin receptors in differentiated ovarian tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reubi, J.C.; Horisberger, U.; Klijn, J.G.

1991-05-01

The presence of somatostatin receptors was investigated in 57 primary human ovarian tumors using in vitro receptor autoradiography with three different somatostatin radioligands, {sup 125}I-(Tyr11)-somatostatin-14, {sup 125}I-(Leu8, D-Trp22, Tyr25)-somatostatin-28, or {sup 125}I-(Tyr3)-SMS 201-995. Three cases, all belonging to epithelial tumors, were receptor positive; specifically 1 of 42 adenocarcinomas, 1 of 3 borderline malignancies, and 1 of 2 cystadenomas. Four other epithelial tumors (3 fibroadenomas, 1 Brenner tumor), 4 sex cord-stromal tumors (2 fibrothecomas, 2 granulosa cell tumors), and 2 germ cell tumors (1 dysgerminoma, 1 teratoma) were receptor negative. In the positive cases, the somatostatin receptors were localized on epithelialmore » cells exclusively, were of high affinity (KD = 4.6 nmol/l (nanomolar)), and specific for somatostatin analogs. These receptors bound somatostatin-14 and somatostatin-28 radioligands with a higher affinity than the octapeptide (Tyr3)-SMS 201-995. Healthy ovarian tissue had no somatostatin receptors. A subpopulation of relatively well-differentiated ovarian tumors, therefore, was identified pathobiochemically on the basis of its somatostatin receptor content. This small group of somatostatin receptor-positive tumors may be a target for in vivo diagnostic imaging with somatostatin ligands.« less

Ovarian cancer and smoking: individual participant meta-analysis including 28 114 women with ovarian cancer from 51 epidemiological studies

PubMed Central

2012-01-01

Summary Background Smoking has been linked to mucinous ovarian cancer, but its effects on other ovarian cancer subtypes and on overall ovarian cancer risk are unclear, and the findings from most studies with relevant data are unpublished. To assess these associations, we review the published and unpublished evidence. Methods Eligible epidemiological studies were identified by electronic searches, review articles, and discussions with colleagues. Individual participant data for 28 114 women with and 94 942 without ovarian cancer from 51 epidemiological studies were analysed centrally, yielding adjusted relative risks (RRs) of ovarian cancer in smokers compared with never smokers. Findings After exclusion of studies with hospital controls, in which smoking could have affected recruitment, overall ovarian cancer incidence was only slightly increased in current smokers compared with women who had never smoked (RR 1·06, 95% CI 1·01–1·11, p=0·01). Of 17 641 epithelial cancers with specified histology, 2314 (13%) were mucinous, 2360 (13%) endometrioid, 969 (5%) clear-cell, and 9086 (52%) serous. Smoking-related risks varied substantially across these subtypes (pheterogeneity<0·0001). For mucinous cancers, incidence was increased in current versus never smokers (1·79, 95% CI 1·60–2·00, p<0·0001), but the increase was mainly in borderline malignant rather than in fully malignant tumours (2·25, 95% CI 1·91–2·65 vs 1·49, 1·28–1·73; pheterogeneity=0·01; almost half the mucinous tumours were only borderline malignant). Both endometrioid (0·81, 95% CI 0·72–0·92, p=0·001) and clear-cell ovarian cancer risks (0·80, 95% CI 0·65–0·97, p=0·03) were reduced in current smokers, and there was no significant association for serous ovarian cancers (0·99, 95% CI 0·93–1·06, p=0·8). These associations did not vary significantly by 13 sociodemographic and personal characteristics of women including their body-mass index, parity, and use of

Fertility sparing treatment in borderline ovarian tumours

PubMed Central

Alvarez, Rosa Maria; Vazquez-Vicente, Daniel

2015-01-01

Borderline ovarian tumours are low malignant potential tumours. They represent 10–15% of all epithelial ovarian malignancies. Patients with this type of tumour are younger at the time of diagnosis than patients with invasive ovarian cancer. Most of them are diagnosed in the early stages and have an excellent prognosis. It has been quite clearly established that the majority of borderline ovarian tumours should be managed with surgery alone. Because a high proportion of women with this malignancy are young and the prognosis is excellent, the preservation of fertility is an important issue in the management of these tumours. In this systemic review of the literature, we have evaluated in-depth oncological safety and reproductive outcomes in women with borderline ovarian tumours treated with fertility-sparing surgery, reviewing the indications, benefits, and disadvantages of each type of conservative surgery, as well as new alternative options to surgery to preserve fertility. PMID:25729420

[Studies of prognostic factor and chemotherapeutic effect of epithelial ovarian cancer using Cox's proportional hazard model].

PubMed

Umesaki, N; Sugawa, T; Yajima, A; Satoh, S; Terashima, Y; Ochiai, K; Tomoda, Y; Kanoh, T; Noda, K; Yakushiji, M

1993-12-01

To make clear the prognostic factor and chemotherapeutic effect of epithelial ovarian cancer, a multiple-center study involving 22 hospitals in Japan was conducted using Cox's proportional hazard model. A total of 1,181 cases were reviewed. Clinical stage, histologic type, and residual tumor diameter were significant prognostic factors, but the degree of tissue differentiation was not. The effect of remission induction chemotherapy was assessed with or without CDDP, and a distinct prognostic difference was noted. Among the patients receiving CDDP + ADM + other chemotherapeutic agents (PA group), CDDP + other chemotherapeutic agents (PO group) and CDDP only (P group), the prognosis of the PO group was better than for the P group. The long-term prognosis improving effect of chemotherapy was assessed. Neither maintenance chemotherapy based on oral administration of pyrimidine fluoride nor immunotherapy had any long-term prognosis improving effect, while intermittent chemotherapy based on CDDP resulted in improved prognosis.

Erlotinib in Treating Patients With Advanced Non-Small Cell Lung Cancer, Ovarian Cancer, or Squamous Cell Carcinoma of the Head and Neck

ClinicalTrials.gov

2013-01-08

Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage IIIA Non-small Cell Lung Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IIIB Ovarian Epithelial Cancer; Stage IIIC Ovarian Epithelial Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx

Distribution of OV-TL 3 and MOv18 in normal and malignant ovarian tissue.

PubMed

Buist, M R; Molthoff, C F; Kenemans, P; Meijer, C J

1995-07-01

To analyse the distribution of OV-TL 3 and MOv18 in normal ovarian tissue to determine which antibody is most suitable for (radio)immunotherapy of ovarian carcinoma. The distribution of OV-TL 3 and MOv18 was determined using immunohistochemistry and flow cytometry. Epithelial and other cells in many tissues, and leucocytes in peripheral blood, bone marrow and spleen stained positively with OV-TL 3. The staining pattern of MOv18 in normal tissues was more restricted and was confined to epithelial cells in the lung, kidney, pancreas, salivary gland, ovary, Fallopian tubes, and cervix. Reactivity was also observed with pneumocytes in the lung, tubuli in the kidney, acinar cells in the salivary gland and pancreas, in the placenta, and with Kupffer cells in the liver. The staining pattern of chimeric MOv18 was identical with the murine form. OV-TL 3 and MOv18 reacted with 100% and 98% (45/46) of the 46 tested epithelial ovarian cancers, respectively. In ovarian carcinoma tissue homogeneous staining of epithelial cells was observed with OV-TL 3 and more heterogeneous staining with MOv18. In 12 and nine patients, respectively, a difference in staining intensity for OV-TL 3 and MOv18 was observed between various tumour samples from the same patient. MOv18 has greater therapeutic potential because of its restricted reactivity with normal tissues and especially, in contrast to OV-TL 3, its lack of reactivity with haematopoietic cells.

Ovarian Brenner tumour: a morphologic and immunohistochemical analysis suggesting an origin from fallopian tube epithelium.

PubMed

Kuhn, Elisabetta; Ayhan, Ayse; Shih, Ie-Ming; Seidman, Jeffrey D; Kurman, Robert J

2013-12-01

Brenner tumours (BTs), like other epithelial ovarian tumours, are thought to develop from the ovarian surface epithelium. We hypothesised that BTs arise from transitional metaplasia near the tuboperitoneal junction which, when embedded in the ovary as Walthard cell nests, may progress to BTs. The aim of this study was to validate this hypothesis by a morphologic and immunohistochemical (IHC) analysis. The IHC analysis revealed that fallopian tube secretory cells, transitional metaplasia, Walthard cell nests and the epithelial component of BTs shared a similar IHC profile, consistently expressing AKR1C3 (an enzyme involved in androgen biosynthesis) and androgen receptor, but not calretinin. The tumour stromal cells that immediately surrounded the epithelial nests showed strong expression of calretinin, inhibin and steroidogenic factor 1 (markers of steroidogenic cells) in the majority of BTs. Using a highly sensitive immunofluorescent staining method, we detected small groups of cilia in transitional metaplasia and Walthard cell nests, multifocal stretches of cilia and/or ciliated vacuoles in benign BTs and well-developed cilia in atypical proliferative BTs. Our findings suggest a tubal origin of BTs through transitional metaplasia and Walthard cell nests, based on their anatomic proximity, similar IHC profile and the presence of cilia. In addition, we hypothesise a role of androgenic stimulation in the pathogenesis of BT, based on the IHC staining pattern of calretinin, inhibin and steroidogenic factor 1 expressed in the luteinised stromal cells surrounding the epithelial nests of the tumours, and AKR1C3 and androgen receptor expressed in both the epithelial and stromal components. Copyright © 2013 Elsevier Ltd. All rights reserved.

Increased expression of Nlp, a potential oncogene in ovarian cancer, and its implication in carcinogenesis.

PubMed

Qu, Danni; Qu, Hongyan; Fu, Ming; Zhao, Xuelian; Liu, Rong; Sui, Lihua; Zhan, Qimin

2008-08-01

Nlp (Ninein-like protein), a novel centrosome protein involved in microtubule nucleation, has been studied extensively in our laboratory, and its overexpression has been found in some human tumors. To understand the role of Nlp in human ovarian cancer development, we studied the correlation of Nlp expression with clinicopathological parameters and survival in epithelial ovarian cancer, and the impact of Nlp overexpression on ovarian cancer cells. Nlp expression in normal, borderline, benign and malignant epithelial ovarian tissues was examined by immunohistochemistry. The correlation between Nlp expression and tumor grade, FIGO stage and histological type was also evaluated. Survival was calculated using Kaplan-Meier estimates. Cell proliferation and apoptosis were assayed after stable transfection of pEGFP-C3-Nlp or empty vector in human ovarian cancer cell line SKOV3. Nlp was positive in 1 of 10 (10%) normal ovarian tissues, 5 of 34 (14.7%) benign tumors, 9 of 26 (34.6%) borderline tumors and 73 of 131 (56.0%) ovarian tumors. Nlp immunoreactivity intensity significantly correlated with tumor grade, but not with FIGO stage or histological type. Kaplan-Meier curves showed that Nlp overexpression was marginally associated with decreased overall survival. Overexpression of Nlp enhanced proliferation and inhibited apoptosis induced by paclitaxel in the SKOV3 cell line. Overexpression of Nlp in ovarian tumors raises the possibility that Nlp may play a role in ovarian carcinogenesis.

Ovarian and endometrial endometrioid carcinomas have distinct CTNNB1 and PTEN mutation profiles.

PubMed

McConechy, Melissa K; Ding, Jiarui; Senz, Janine; Yang, Winnie; Melnyk, Nataliya; Tone, Alicia A; Prentice, Leah M; Wiegand, Kimberly C; McAlpine, Jessica N; Shah, Sohrab P; Lee, Cheng-Han; Goodfellow, Paul J; Gilks, C Blake; Huntsman, David G

2014-01-01

Ovarian endometrioid carcinomas and endometrial endometrioid carcinomas share many histological and molecular alterations. These similarities are likely due to a common endometrial epithelial precursor cell of origin, with most ovarian endometrioid carcinomas arising from endometriosis. To directly compare the mutation profiles of two morphologically similar tumor types, endometrial endometrioid carcinomas (n=307) and ovarian endometrioid carcinomas (n=33), we performed select exon capture sequencing on a panel of genes: ARID1A, PTEN, PIK3CA, KRAS, CTNNB1, PPP2R1A, TP53. We found that PTEN mutations are more frequent in low-grade endometrial endometrioid carcinomas (67%) compared with low-grade ovarian endometrioid carcinomas (17%) (P<0.0001). By contrast, CTNNB1 mutations are significantly different in low-grade ovarian endometrioid carcinomas (53%) compared with low-grade endometrial endometrioid carcinomas (28%) (P<0.0057). This difference in CTNNB1 mutation frequency may be reflective of the distinct microenvironments; the epithelial cells lining an endometriotic cyst within the ovary are exposed to a highly oxidative environment that promotes tumorigenesis. Understanding the distinct mutation patterns found in the PI3K and Wnt pathways of ovarian and endometrial endometrioid carcinomas may provide future opportunities for stratifying patients for targeted therapeutics.

Lentiviral CRISPR/Cas9 vector mediated miR-21 gene editing inhibits the epithelial to mesenchymal transition in ovarian cancer cells.

PubMed

Huo, Wenying; Zhao, Guannan; Yin, Jinggang; Ouyang, Xuan; Wang, Yinan; Yang, Chuanhe; Wang, Baojing; Dong, Peixin; Wang, Zhixiang; Watari, Hidemichi; Chaum, Edward; Pfeffer, Lawrence M; Yue, Junming

2017-01-01

CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats) mediated genome editing is a powerful approach for loss of function studies. Here we report that lentiviral CRISPR/Cas9 vectors are highly efficient in introducing mutations in the precursor miRNA sequence, thus leading to the loss of miRNA expression and function. We constructed four different lentiviral CRISPR/Cas9 vectors that target different regions of the precursor miR-21 sequence and found that these lentiviral CRISPR/Cas9 miR-21 gRNA vectors induced mutations in the precursor sequences as shown by DNA surveyor mutation assay and Sanger sequencing. Two miR-21 lentiviral CRISPR/Cas9 gRNA vectors were selected to probe miR-21 function in ovarian cancer SKOV3 and OVCAR3 cell lines. Our data demonstrate that disruption of pre-miR-21 sequences leads to reduced cell proliferation, migration and invasion. Moreover, CRISPR/Cas9-mediated miR-21 gene editing sensitizes both SKOV3 and OVCAR3 cells to chemotherapeutic drug treatment. Disruption of miR-21 leads to the inhibition of epithelial to mesenchymal transition (EMT) in both SKOV3 and OVCAR3 cells as evidenced by the upregulation of epithelial cell marker E-cadherin and downregulation of mesenchymal marker genes, vimentin and Snai2. The miR-21 target genes PDCD4 and SPRY2 were upregulated in cells transduced with miR-21gRNAs compared to controls. Our study indicates that lentiviral CRISPR/Cas9-mediated miRNA gene editing is an effective approach to address miRNA function, and disruption of miR-21 inhibits EMT in ovarian cancer cells.

Lentiviral CRISPR/Cas9 vector mediated miR-21 gene editing inhibits the epithelial to mesenchymal transition in ovarian cancer cells

PubMed Central

Huo, Wenying; Zhao, Guannan; Yin, Jinggang; Ouyang, Xuan; Wang, Yinan; Yang, Chuanhe; Wang, Baojing; Dong, Peixin; Wang, Zhixiang; Watari, Hidemichi; Chaum, Edward; Pfeffer, Lawrence M.; Yue, Junming

2017-01-01

CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats) mediated genome editing is a powerful approach for loss of function studies. Here we report that lentiviral CRISPR/Cas9 vectors are highly efficient in introducing mutations in the precursor miRNA sequence, thus leading to the loss of miRNA expression and function. We constructed four different lentiviral CRISPR/Cas9 vectors that target different regions of the precursor miR-21 sequence and found that these lentiviral CRISPR/Cas9 miR-21 gRNA vectors induced mutations in the precursor sequences as shown by DNA surveyor mutation assay and Sanger sequencing. Two miR-21 lentiviral CRISPR/Cas9 gRNA vectors were selected to probe miR-21 function in ovarian cancer SKOV3 and OVCAR3 cell lines. Our data demonstrate that disruption of pre-miR-21 sequences leads to reduced cell proliferation, migration and invasion. Moreover, CRISPR/Cas9-mediated miR-21 gene editing sensitizes both SKOV3 and OVCAR3 cells to chemotherapeutic drug treatment. Disruption of miR-21 leads to the inhibition of epithelial to mesenchymal transition (EMT) in both SKOV3 and OVCAR3 cells as evidenced by the upregulation of epithelial cell marker E-cadherin and downregulation of mesenchymal marker genes, vimentin and Snai2. The miR-21 target genes PDCD4 and SPRY2 were upregulated in cells transduced with miR-21gRNAs compared to controls. Our study indicates that lentiviral CRISPR/Cas9-mediated miRNA gene editing is an effective approach to address miRNA function, and disruption of miR-21 inhibits EMT in ovarian cancer cells. PMID:28123598

[Alterations of c-Myc and c-erbB-2 genes in ovarian tumours].

PubMed

Pastor, Tibor; Popović, Branka; Gvozdenović, Ana; Boro, Aleksandar; Petrović, Bojana; Novaković, Ivana; Puzović, Dragana; Luković, Ljiljana; Milasin, Jelena

2009-01-01

According to clinical and epidemiological studies, ovarian cancer ranks fifth in cancer deaths among women. The causes of ovarian cancer remain largely unknown but various factors may increase the risk of developing it, such as age, family history of cancer, childbearing status etc. This cancer results from a succession of genetic alterations involving oncogenes and tumour suppressor genes, which have a critical role in normal cell growth regulation. Mutations and/or overexpression of three oncogenes, c-erbB-2, c-Myc and K-ras, and of the tumour suppressor gene p53, have been frequently observed in a sporadic ovarian cancer. The aim of the present study was to analyse c-Myc and c-erbB-2 oncogene alterations, specifically amplification, as one of main mechanisms of their activation in ovarian cancers and to establish a possible association with the pathogenic process. DNA was isolated from 15 samples of malignant and 5 benign ovarian tumours, using proteinase K digestion, followed by phenol-chloroform isoamyl extraction and ethanol precipitation. C-Myc and c-erbB-2 amplification were detected by differential PCR. The level of gene copy increase was measured using the Scion image software. The amplification of both c-Myc and c-erbB-2 was detected in 26.7% of ovarian epithelial carcinoma specimens. Only one tumour specimen concomitantly showed increased gene copy number for both studied genes. Interestingly, besides amplification, gene deletion was also detected (26.7% for c-erbB-2). Most of the ovarian carcinomas with alterations in c-Myc and c-erbB-2 belonged to advanced FIGO stages. The amplification of c-Myc and c-erbB-2 oncogenes in ovarian epithelial carcinomas is most probably a late event in the pathogenesis conferring these tumours a more aggressive biological behaviour. Similarly, gene deletions point to genomic instability in epithelial carcinomas in higher clinical stages as the result of clonal evolution and selection.

Monoclonal Antibody Therapy in Treating Patients With Ovarian Epithelial Cancer, Melanoma, Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Non-Small Cell Lung Cancer

ClinicalTrials.gov

2013-01-09

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Melanoma; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer

Variation in NF-κB signaling pathways and survival in invasive epithelial ovarian cancer.

PubMed

Block, Matthew S; Charbonneau, Bridget; Vierkant, Robert A; Fogarty, Zachary; Bamlet, William R; Pharoah, Paul D P; Rossing, Mary Anne; Cramer, Daniel; Pearce, Celeste Leigh; Schildkraut, Joellen; Menon, Usha; Kjaer, Susanne K; Levine, Douglas A; Gronwald, Jacek; Culver, Hoda Anton; Whittemore, Alice S; Karlan, Beth Y; Lambrechts, Diether; Wentzensen, Nicolas; Kupryjanczyk, Jolanta; Chang-Claude, Jenny; Bandera, Elisa V; Hogdall, Estrid; Heitz, Florian; Kaye, Stanley B; Fasching, Peter A; Campbell, Ian; Goodman, Marc T; Pejovic, Tanja; Bean, Yukie T; Hays, Laura E; Lurie, Galina; Eccles, Diana; Hein, Alexander; Beckmann, Matthias W; Ekici, Arif B; Paul, James; Brown, Robert; Flanagan, James M; Harter, Philipp; du Bois, Andreas; Schwaab, Ira; Hogdall, Claus K; Lundvall, Lene; Olson, Sara H; Orlow, Irene; Paddock, Lisa E; Rudolph, Anja; Eilber, Ursula; Dansonka-Mieszkowska, Agnieszka; Rzepecka, Iwona K; Ziolkowska-Seta, Izabela; Brinton, Louise A; Yang, Hannah; Garcia-Closas, Montserrat; Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace; Walsh, Christine S; Lester, Jenny; Sieh, Weiva; McGuire, Valerie; Rothstein, Joseph H; Ziogas, Argyrios; Lubiński, Jan; Cybulski, Cezary; Menkiszak, Janusz; Jensen, Allan; Gayther, Simon A; Ramus, Susan J; Gentry-Maharaj, Aleksandra; Berchuck, Andrew; Wu, Anna H; Pike, Malcolm C; Van Den Berg, David; Terry, Kathryn L; Vitonis, Allison F; Ramirez, Starr M; Rider, David N; Knutson, Keith L; Sellers, Thomas A; Phelan, Catherine M; Doherty, Jennifer A; Johnatty, Sharon E; deFazio, Anna; Song, Honglin; Tyrer, Jonathan; Kalli, Kimberly R; Fridley, Brooke L; Cunningham, Julie M; Goode, Ellen L

2014-07-01

Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10(-5)). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41-2.35; P = 4.13 × 10(-6)] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56-0.82; P = 2.33 × 10(-5)). Other associations of note included TNF receptor-associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77-0.92; P = 6.49 × 10(-5)) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26-0.73; P = 4.56 × 10(-4)). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies. ©2014 American Association for Cancer Research.

[Methylation of selected tumor-supressor genes in benign and malignant ovarian tumors].

PubMed

Cul'bová, M; Lasabová, Z; Stanclová, A; Tilandyová, P; Zúbor, P; Fiolka, R; Danko, J; Visnovský, J

2011-09-01

To evaluate the usefullness of examination of methylation status of selected tumor-supressor genes in early diagnosis of ovarian cancer. Prospective clinical study. Department of Gynecology and Obstetrics, Department of Molecular Biology, Jessenius Medical Faculty, Commenius University, Martin, Slovak Republic. In this study we analyzed hypermethylation of 5 genes RASSF1A, GSTP, E-cadherin, p16 and APC in ovarian tumor samples from 34 patients - 13 patients with epithelial ovarian cancer, 2 patients with border-line ovarian tumors, 12 patients with benign lesions of ovaries and 7 patients with healthy ovarian tissue. The methylation status of promoter region of tumor-supressor genes was determined by Methylation Specific Polymerase Chain Reaction (MSP) using a nested two-step approach with bisulfite modified DNA template and specific primers. Gene methylation analysis revealed hypermethylation of gene RASSF1A (46%) and GSTP (8%) only in malignant ovarian tissue samples. Ecad, p16 and APC genes were methylated both in maignant and benign tissue samples. Methylation positivity in observed genes was present independently to all clinical stages of ovarian cancer and to tumor grades. However, there was observed a trend of increased number and selective involvement of methylated genes with increasing disease stages. Furthermore, there was no association between positive methylation status and histological subtypes of ovarian carcinomas. RASSF1A and GSTP promoter methylation positivity is associated with ovarian cancer. The revealed gene-selective methylation positivity and the increased number of methylated genes with advancing disease stages could be considered as a useful molecular marker for early detection of ovarian cancer. However, there is need to find diagnostic approach of specifically and frequently methylated genes to determining a methylation phenotype for early detection of ovarian malignancies.

Risk factors for ovarian cancers with and without microsatellite instability.

PubMed

Segev, Yakir; Pal, Tuya; Rosen, Barry; McLaughlin, John R; Sellers, Thomas A; Risch, Harvey A; Zhang, Shiyu; Sun, Ping; Narod, Steven A; Schildkraut, Joellen

2014-05-01

In a population-based sample of epithelial ovarian cancers, the objective of this study was to evaluate the association between microsatellite instability (MSI) status and the following factors: (1) ovarian cancer risk factors and (2) the distribution of the specific histologic subtypes. Participants were drawn from 3 population-based studies of primary epithelial ovarian cancer; tumor DNA was analyzed using 5 standardized microsatellite markers to assess the MSI status. Patients were divided into 3 groups (MSI-high, MSI-low, and MSI-stable) according to the National Cancer Institute criteria. We compared the prevalence of specific known risk and protective factors among the 3 subgroups, including body mass index, smoking history, parity, BRCA1 and BRCA2 mutation status, past oral contraceptive use, and tubal ligation. Similarly, we compared the distribution of the histologic subtypes among the 3 subgroups. A total of 917 ovarian cancer patients were included. One hundred twenty-seven cases of cancer (13.8%) were MSI-high. Subgroup analyses according to smoking, body mass index, parity, past oral contraceptive use, and past tubal ligation did not reveal any statistically significance differences among the groups. Among the 29 patients with BRCA1 mutations, 20.7% had MSI-high cancers compared with 5.9% among 17 patients with BRCA2 mutations. The proportions of different ovarian cancer histologies among the various MSI subgroups were similar. The prevalence of risk and protective factors among ovarian cancer patients is similar for cancers with and without MSI. The distributions of MSI do not differ significantly among ovarian cancers with different histologies. Ovarian cancer patients with BRCA1 mutations had a 21% rate of MSI-high tumors compared with 6% among patients with BRCA2 mutations, but this difference was not statistically significant.

Cyclophosphamide or Denileukin Diftitox Followed By Expanding a Patient's Own T Cells in the Laboratory in Treating Patients With HER-2/Neu Overexpressing Metastatic Breast Cancer, Ovarian Cancer, or Non-Small Cell Lung Cancer Previously Treated With HER-2/Neu Vaccine

ClinicalTrials.gov

2014-11-07

HER2-positive Breast Cancer; Recurrent Breast Cancer; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Stage IV Breast Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor

Serum agonistic autoantibodies against type-1 angiotensin II receptor titer in patients with epithelial ovarian cancer: a potential role in tumor cell migration and angiogenesis

PubMed Central

2013-01-01

Background Although agonistic autoantibodies against type-1 angiotensin-II receptor (AT1-AA) are frequently detected in women with preeclampsia, the clinical significance of AT1-AA in association with epithelial ovarian cancer (EOC) has not been identified. Methods In an attempt to clarify this issue, we measured serum AT1-AA titer from EOC patients (n = 89) and healthy normal subjects (n = 55), correlated AT1-AA titer with EOC stage and grade, and demonstrated the effects of purified AT1-AA on migration of ovarian cancer cells and angiogenesis of chick embryo chorioallantoic membrane. Results We found that the AT1-AA titer was significantly higher in EOC patients compared with healthy control subjects (1.77 ± 0.28 vs. 0.35 ± 0.05, P < 0.01). The positive rate was averaged by 72.1±2.5% in EOC patients and 15.5 ±1.5% in control (P < 0.01). Increased AT1-AA titer in EOC patients was associated with advanced stages and grades of EOC, and positively correlated with level of vascular endothelial growth factor (r = 0.855, P < 0.01). Furthermore, AT1-AA directly stimulated migration of ovarian cancer cells and enhanced microvascular density of chick embryo chorioallantoic membrane. These AT1-AA-mediated effects were significantly blocked either by an autoantibody-neutralizing peptide or an angiotensin II type I receptor antagonist, losartan. Conclusion Taken together, we found that a higher serum AT1-AA titer may be associated with advanced progression of EOC in patients and play an important role in development of EOC by promoting cancer cell migration and angiogenesis. These findings implicate that AT1-AA might be selected as a detectable biomarker and potential therapeutic target in diagnosis and treatment of EOC patients. PMID:23561060

Novel paradigm for immunotherapy of ovarian cancer by engaging prophylactic immunity against hepatitis B virus.

PubMed

Malecki, Marek; Putzer, Emily; Quach, Caroline; Dodivenaka, Chaitanya; Tombokan, Xenia

2016-12-01

Only eight women out of one hundred diagnosed with ovarian epithelial cancers, which progressed to the clinical stage IV, survive 10 years. First line therapies: surgery, chemotherapy, and radiation therapy inflict very serious iatrogenic consequences. Passive immunotherapy of ovarian cancers offers only low efficacy. Prophylactic and therapeutic vaccines for ovarian cancers are not available. Interestingly, prophylactic vaccines for Hepatitis B Viruses (HBV) are very effective. The specific aim of this work was to design, synthesize, and administer biomolecules, which would engage prophylactic, vaccination-induced immunity for HBV towards killing of ovarian cancer cells with high specificity and efficacy. Tissue biopsies, ascites, and blood were acquired from the patients, whose identities were entirely concealed in accordance with the Declaration of Helsinki, pursuant to the Institutional Review Board approval, and with the Patients' informed consent. By biomolecular engineering, we have created a novel family of biomolecules: antibody × vaccine engineered constructs (AVEC: anti-HER-2 × HBsAg). We have collected the blood from the volunteers, and measured the titers of anti-HBV antibodies resulting from the FDA approved and CDC scheduled HBV vaccinations. We have acquired tumor biopsies, ascites, and blood from patients suffering from the advanced ovarian cancers. We have established cultures of HER-2 over-expressing epithelial ovarian cancers: OV-90, TOC-112D, SKOV-3, as well as human ovary surface epithelial (HOSE) and human artery endothelial (HAE) cells. Treatment of the HER-2+ ovarian cancer cells with AVEC: anti-HER-2 × HBsAg, accompanied by administration of blood drawn from patients with high titers of the anti-HBV antibodies, resulted in much higher therapeutic efficacy as compared to treatment with the naked anti-HER-2 antibodies alone and/or with the relevant isotype antibodies. This treatment had practically no effect upon the HOSE and HAE

Ginger inhibits cell growth and modulates angiogenic factors in ovarian cancer cells

PubMed Central

Rhode, Jennifer; Fogoros, Sarah; Zick, Suzanna; Wahl, Heather; Griffith, Kent A; Huang, Jennifer; Liu, J Rebecca

2007-01-01

Background Ginger (Zingiber officinale Rosc) is a natural dietary component with antioxidant and anticarcinogenic properties. The ginger component [6]-gingerol has been shown to exert anti-inflammatory effects through mediation of NF-κB. NF-κB can be constitutively activated in epithelial ovarian cancer cells and may contribute towards increased transcription and translation of angiogenic factors. In the present study, we investigated the effect of ginger on tumor cell growth and modulation of angiogenic factors in ovarian cancer cells in vitro. Methods The effect of ginger and the major ginger components on cell growth was determined in a panel of epithelial ovarian cancer cell lines. Activation of NF-κB and and production of VEGF and IL-8 was determined in the presence or absence of ginger. Results Ginger treatment of cultured ovarian cancer cells induced profound growth inhibition in all cell lines tested. We found that in vitro, 6-shogaol is the most active of the individual ginger components tested. Ginger treatment resulted in inhibition of NF-kB activation as well as diminished secretion of VEGF and IL-8. Conclusion Ginger inhibits growth and modulates secretion of angiogenic factors in ovarian cancer cells. The use of dietary agents such as ginger may have potential in the treatment and prevention of ovarian cancer. PMID:18096028

Suppression of epithelial ovarian cancer invasion into the omentum by 1α,25-dihydroxyvitamin D3 and its receptor.

PubMed

Lungchukiet, Panida; Sun, Yuefeng; Kasiappan, Ravi; Quarni, Waise; Nicosia, Santo V; Zhang, Xiaohong; Bai, Wenlong

2015-04-01

Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer death in women, mainly because it has spread to intraperitoneal tissues such as the omentum in the peritoneal cavity by the time of diagnosis. In the present study, we established in vitro assays, ex vivo omental organ culture system and syngeneic animal tumor models using wild type (WT) and vitamin D receptor (VDR) null mice to investigate the effects of 1α,25-dihydroxyvitamin D3 (1,25D3) and VDR on EOC invasion. Treatment of human EOC cells with 1,25D3 suppressed their migration and invasion in monolayer scratch and transwell assays and ability to colonize the omentum in the ex vivo system, supporting a role for epithelial VDR in interfering with EOC invasion. Furthermore, VDR knockdown in OVCAR3 cells increased their ability to colonize the omentum in the ex vivo system in the absence of 1,25D3, showing a potential ligand-independent suppression of EOC invasion by epithelial VDR. In syngeneic models, ID8 tumors exhibited an increased ability to colonize omenta of VDR null over that of WT mice; pre-treatment of WT, not VDR null, mice with EB1089 reduced ID8 colonization, revealing a role for stromal VDR in suppressing EOC invasion. These studies are the first to demonstrate a role for epithelial and stromal VDR in mediating the activity of 1,25D3 as well as a 1,25D3-independent action of the VDR in suppressing EOC invasion. The data suggest that VDR-based drug discovery may lead to the development of new intervention strategies to improve the survival of patients with EOC at advanced stages. This article is part of a Special Issue entitled "Vitamin D Workshop". Copyright © 2014 Elsevier Ltd. All rights reserved.

Rare ATAD5 missense variants in breast and ovarian cancer patients.

PubMed

Maleva Kostovska, Ivana; Wang, Jing; Bogdanova, Natalia; Schürmann, Peter; Bhuju, Sabin; Geffers, Robert; Dürst, Matthias; Liebrich, Clemens; Klapdor, Rüdiger; Christiansen, Hans; Park-Simon, Tjoung-Won; Hillemanns, Peter; Plaseska-Karanfilska, Dijana; Dörk, Thilo

2016-06-28

ATAD5/ELG1 is a protein crucially involved in replication and maintenance of genome stability. ATAD5 has recently been identified as a genomic risk locus for both breast and ovarian cancer through genome-wide association studies. We aimed to investigate the spectrum of coding ATAD5 germ-line mutations in hospital-based series of patients with triple-negative breast cancer or serous ovarian cancer compared with healthy controls. The ATAD5 coding and adjacent splice site regions were analyzed by targeted next-generation sequencing of DNA samples from 273 cancer patients, including 114 patients with triple-negative breast cancer and 159 patients with serous epithelial ovarian cancer, and from 276 healthy females. Among 42 different variants identified, twenty-two were rare missense substitutions, of which 14 were classified as pathogenic by at least one in silico prediction tool. Three of four novel missense substitutions (p.S354I, p.H974R and p.K1466N) were predicted to be pathogenic and were all identified in ovarian cancer patients. Overall, rare missense variants with predicted pathogenicity tended to be enriched in ovarian cancer patients (14/159) versus controls (11/276) (p = 0.05, 2df). While truncating germ-line variants in ATAD5 were not detected, it remains possible that several rare missense variants contribute to genetic susceptibility toward epithelial ovarian carcinomas. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The impact of ultra-radical surgery in the management of patients with stage IIIC and IV epithelial ovarian, fallopian tube, and peritoneal cancer.

PubMed

Turnbull, Hilary L; Akrivos, Nikolaos; Wemyss-Holden, Simon; Maiya, Balachandra; Duncan, Timothy J; Nieto, Joaquin J; Burbos, Nikolaos

2017-03-01

The aim of this study is to estimate the percentage of patients with metastatic ovarian, fallopian tube, and primary peritoneal cancer requiring ultra-radical surgery to achieve cytoreduction to less than 1 cm (optimal) or no macroscopic residual disease (complete). Perioperative data were collected prospectively on consecutive patients undergoing elective cytoreductive surgery for metastatic epithelial ovarian, fallopian tube, or primary peritoneal cancer at the Norfolk and Norwich University Hospital, a tertiary referral cancer centre in the United Kingdom from November 2012 to June 2016. Over a 42-month period, 135 consecutive patients underwent cytoreductive surgery for stage IIIC and IV ovarian, fallopian tube, or primary peritoneal cancer. The median age of the patients was 69 years. 47.4% of the patients underwent diaphragmatic peritonectomy and/or resection, 20% underwent splenectomy, 14.1% had excision of disease from porta hepatis and celiac axis, and 5.2% of the patients had gastrectomy. Cytoreduction to no macroscopic visible disease (complete) and to disease with greater tumour diameter of less than 1 cm (optimal) was achieved in 54.1 and 34.1% of the cases, respectively. Without incorporating surgical procedures in the upper abdomen ('ultra-radical'), the combined rate of complete and optimal cytoreduction would be only 33.3%. Up to 50.4% of the patients in this study required at least one surgical procedure classified as ultra-radical, emphasizing the importance of cytoreductive surgery in the upper abdomen in management of women with stage IIIC and IV ovarian, fallopian tube, and primary peritoneal cancer.

The thrombospondin-1 mimetic ABT-510 increases the uptake and effectiveness of cisplatin and paclitaxel in a mouse model of epithelial ovarian cancer.

PubMed

Campbell, Nicole E; Greenaway, James; Henkin, Jack; Moorehead, Roger A; Petrik, Jim

2010-03-01

Epithelial ovarian cancer (EOC) comprises approximately 90% of ovarian cancers and arises from the surface epithelium. Typical treatment of EOC involves cytoreductive surgery combined with chemotherapy. More recent therapies have targeted the tumor vasculature using antiangiogenic compounds such as thrombospondin-1 (TSP-1). TSP-1 mimetic peptides such as ABT-510 have been created and have been in various clinical trials. We have previously shown that ABT-510 reduces abnormal vasculature associated with tumor tissue and increases the presence of mature blood vessels. It has been hypothesized that treatment with antiangiogenic compounds would allow increased delivery of cytotoxic agents and enhance treatment. In this study, we evaluated the potential role of ABT-510 and various chemotherapeutics (cisplatin and paclitaxel) on tumor progression, angiogenesis, and the benefits of combinational treatments on tissue uptake and perfusion using an orthotopic syngeneic mouse model of EOC. Animals were treated with ABT-510 (100 mg/kg per day) alone or in combination with cisplatin (2 mg/kg per 3 days) or paclitaxel (10 mg/kg per 2 days) at 60 days after tumor induction. Radiolabeled and fluorescently labeled paclitaxel demonstrated a significant increase in tumor uptake after ABT-510 treatment. Combined treatment with ABT-510 and cisplatin or paclitaxel resulted in a significant increase in tumor cell and tumor endothelial cell apoptosis and a resultant decrease in ovarian tumor size. Combined treatment also regressed secondary lesions and eliminated the presence of abdominal ascites. The results from this study show that through vessel normalization, ABT-510 increases uptake of chemotherapy drugs and can induce regression of advanced ovarian cancer.

The prediction of progression-free and overall survival in women with an advanced stage of epithelial ovarian carcinoma.

PubMed

Gerestein, C G; Eijkemans, M J C; de Jong, D; van der Burg, M E L; Dykgraaf, R H M; Kooi, G S; Baalbergen, A; Burger, C W; Ansink, A C

2009-02-01

Prognosis in women with ovarian cancer mainly depends on International Federation of Gynecology and Obstetrics stage and the ability to perform optimal cytoreductive surgery. Since ovarian cancer has a heterogeneous presentation and clinical course, predicting progression-free survival (PFS) and overall survival (OS) in the individual patient is difficult. The objective of this study was to determine predictors of PFS and OS in women with advanced stage epithelial ovarian cancer (EOC) after primary cytoreductive surgery and first-line platinum-based chemotherapy. Retrospective observational study. Two teaching hospitals and one university hospital in the south-western part of the Netherlands. Women with advanced stage EOC. All women who underwent primary cytoreductive surgery for advanced stage EOC followed by first-line platinum-based chemotherapy between January 1998 and October 2004 were identified. To investigate independent predictors of PFS and OS, a Cox' proportional hazard model was used. Nomograms were generated with the identified predictive parameters. The primary outcome measure was OS and the secondary outcome measures were response and PFS. A total of 118 women entered the study protocol. Median PFS and OS were 15 and 44 months, respectively. Preoperative platelet count (P = 0.007), and residual disease <1 cm (P = 0.004) predicted PFS with a optimism corrected c-statistic of 0.63. Predictive parameters for OS were preoperative haemoglobin serum concentration (P = 0.012), preoperative platelet counts (P = 0.031) and residual disease <1 cm (P = 0.028) with a optimism corrected c-statistic of 0.67. PFS could be predicted by postoperative residual disease and preoperative platelet counts, whereas residual disease, preoperative platelet counts and preoperative haemoglobin serum concentration were predictive for OS. The proposed nomograms need to be externally validated.

Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk.

PubMed

Chornokur, Ganna; Lin, Hui-Yi; Tyrer, Jonathan P; Lawrenson, Kate; Dennis, Joe; Amankwah, Ernest K; Qu, Xiaotao; Tsai, Ya-Yu; Jim, Heather S L; Chen, Zhihua; Chen, Ann Y; Permuth-Wey, Jennifer; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V; Bean, Yukie T; Beckmann, Matthias W; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Bunker, Clareann H; Butzow, Ralf; Campbell, Ian G; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; du Bois, Andreas; Despierre, Evelyn; Dicks, Ed; Doherty, Jennifer A; Dörk, Thilo; Dürst, Matthias; Easton, Douglas F; Eccles, Diana M; Edwards, Robert P; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Goodman, Marc T; Gronwald, Jacek; Harrington, Patricia; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hillemanns, Peter; Hogdall, Claus K; Hogdall, Estrid; Hosono, Satoyo; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kelemen, Linda E; Kellar, Mellissa; Kiemeney, Lambertus A; Krakstad, Camilla; Kjaer, Susanne K; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lim, Boon Kiong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; McNeish, Iain; Menon, Usha; Milne, Roger L; Modugno, Francesmary; Moysich, Kirsten B; Ness, Roberta B; Nevanlinna, Heli; Eilber, Ursula; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Paul, James; Pearce, Celeste L; Pejovic, Tanja; Pelttari, Liisa M; Pike, Malcolm C; Poole, Elizabeth M; Risch, Harvey A; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Schernhammer, Eva; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C; Spiewankiewicz, Beata; Sucheston, Lara; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Thomsen, Lotte; Tangen, Ingvild L; Tworoger, Shelley S; van Altena, Anne M; Vierkant, Robert A; Vergote, Ignace; Walsh, Christine S; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Wu, Anna H; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Hasmad, Hanis N; Berchuck, Andrew; Iversen, Edwin S; Schildkraut, Joellen M; Ramus, Susan J; Goode, Ellen L; Monteiro, Alvaro N A; Gayther, Simon A; Narod, Steven A; Pharoah, Paul D P; Sellers, Thomas A; Phelan, Catherine M

2015-01-01

Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons. The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). These results, generated on a large cohort of women, revealed associations between inherited cellular transport

UPLC-MS/MS based diagnostics for epithelial ovarian cancer using fully sialylated C4-binding protein.

PubMed

Tanabe, Kazuhiro; Matsuo, Koji; Miyazawa, Masaki; Hayashi, Masaru; Ikeda, Masae; Shida, Masako; Hirasawa, Takeshi; Sho, Ryuichiro; Mikami, Mikio

2018-05-01

Serum levels of fully sialylated C4-binding protein (FS-C4BP) are remarkably elevated in patients with epithelial ovarian cancer (EOC) and can be used as a marker to distinguish ovarian clear cell carcinoma from endometrioma. This study aimed to develop a stable, robust and reliable liquid chromatography-hybrid mass spectrometry (UPLC-MS/MS) based diagnostic method that would generalize FS-C4BP as a clinical EOC biomarker. Glycopeptides derived from 20 μL of trypsin-digested serum glycoprotein were analyzed via UPLC equipped with an electrospray ionization time-of-flight mass spectrometer. This UPLC-MS/MS-based diagnostic method was optimized for FS-C4BP and validated using sera from 119 patients with EOC and 127 women without cancer. A1958 (C4BP peptide with two fully sialylated biantennary glycans) was selected as a marker of FS-C4BP because its level in serum was highest among FS-C4BP family members. Preparation and UPLC-MS/MS were optimized for A1958, and performance and robustness were significantly improved relative to our previous method. An area under the curve analysis of the FS-C4BP index receiver operating characteristic curve revealed that the ratio between A1958 and A1813 (C4BP peptide with two partially sialylated biantennary glycans) reached 85%. A combination of the FS-C4BP index and carbohydrate antigen-125 levels further enhanced the sensitivity and specificity. © 2017 The Authors. Biomedical Chromatography published by John Wiley & Sons Ltd.

A Model System to Investigate the Effect of BRCA1 and/or p53 Inactivation in the Ovarian Stroma on Growth and Transformation Potential of the Ovarian Epithelium

DTIC Science & Technology

2009-10-01

Effect of BRCA1 and/or p53 Inactivation in the Ovarian Stroma on Growth and Transformation Potential of the Ovarian Epithelium PRINCIPAL...AND SUBTITLE 5a. CONTRACT NUMBER A Model System To Investigate the Effect of BRCA1 and/or p53 Inactivation in the Ovarian Stroma on Growth and... effects of loss of function of BRCA1 or BRCA1 and Trp53 in the stroma on the growth and neoplastic transformation of epithelial cells using 2D and 3D in

Dihydroartemisinin selectively inhibits PDGFRα-positive ovarian cancer growth and metastasis through inducing degradation of PDGFRα protein.

PubMed

Li, Xiaoguang; Ba, Qian; Liu, Yanling; Yue, Qingxi; Chen, Peizhan; Li, Jingquan; Zhang, Haibing; Ying, Hao; Ding, Qiurong; Song, Haiyun; Liu, Hong; Zhang, Ruiwen; Wang, Hui

2017-01-01

To develop traditional medicines as modern pharmacotherapies, understanding their molecular mechanisms of action can be very helpful. We have recently reported that Artemisinin and its derivatives, which are clinically used anti-malarial drugs, have significant effects against ovarian cancer, but the direct molecular targets and related combination therapy have been unclear. Herein, we report that dihydroartemisinin, one of the most active derivatives of Artemisinin, directly targets platelet-derived growth factor receptor-alpha (PDGFRα) to inhibit ovarian cancer cell growth and metastasis. Dihydroartemisinin directly binds to the intercellular domain of PDGFRα, reducing its protein stability by accelerating its ubiquitin-mediated degradation, which further inactivates downstream phosphoinositide 3-Kinase and mitogen-activated protein kinase pathways and subsequently represses epithelial-mesenchymal transition, inhibiting cell growth and metastasis of PDGFRα-positive ovarian cancer in vitro and in vivo . A combinational treatment reveals that dihydroartemisinin sensitizes ovarian cancer cells to PDGFR inhibitors. Our clinical study also finds that PDGFRα is overexpressed and positively correlated with high grade and metastasis in human ovarian cancer. Considering that Artemisinin compounds are currently clinically used drugs with favorable safety profiles, the results from this study will potentiate their use in combination with clinically used PDGFRα inhibitors, leading to maximal therapeutic efficacy with minimal adverse effects in PDGFRα-positive cancer patients. These findings also shed high light on future development of novel Artemisinin-based targeted therapy.

Progesterone signaling mediated through progesterone receptor membrane component-1 in ovarian cells with special emphasis on ovarian cancer.

PubMed

Peluso, John J

2011-08-01

Various ovarian cell types including granulosa cells and ovarian surface epithelial cells express the progesterone (P4) binding protein, progesterone receptor membrane component-1 (PGRMC1). PGRMC1 is also expressed in ovarian tumors. PGRMC1 plays an essential role in promoting the survival of both normal and cancerous ovarian cell in vitro. Given the clinical significance of factors that regulate the viability of ovarian cancer, this review will focus on the role of PGRMC1 in ovarian cancer, while drawing insights into the mechanism of PGRMC1's action from cell lines derived from healthy ovaries as well as ovarian tumors. Studies using PGRMC1siRNA demonstrated that P4's ability to inhibit ovarian cells from undergoing apoptosis in vitro is dependent on PGRMC1. To confirm the importance of PGRMC1, the ability of PGRMC1-deplete ovarian cancer cell lines to form tumors in intact nude mice was assessed. Compared to PGRMC1-expressing ovarian cancer cells, PGRMC1-deplete ovarian cancer cells formed tumors in fewer mice (80% compared to 100% for controls). Moreover, the number of tumors derived from PGRMC1-deplete ovarian cancer cells was 50% of that observed in controls. Finally, the tumors that formed from PGRMC1-deplete ovarian cancer cells were about a fourth the size of tumors derived from ovarian cancer cells with normal levels of PGRMC1. One reason for PGRMC1-deplete tumors being smaller is that they had a poorly developed microvasculature system. How PGRMC1 regulates cell viability and in turn tumor growth is not known but part of the mechanism likely involves the regulation of genes that promote cell survival and inhibit apoptosis. Copyright © 2011 Elsevier Inc. All rights reserved.

Low-grade serous ovarian cancer: A review.

PubMed

Kaldawy, Anis; Segev, Yakir; Lavie, Ofer; Auslender, Ron; Sopik, Victoria; Narod, Steven A

2016-11-01

Epithelial ovarian cancers can be divided into the more common, aggressive type II cancers and the less common, slow-growing type I cancers. Under this model, serous ovarian carcinomas can be subdivided into high-grade (type II) and low-grade (type I) tumours. The two-tier system for grading serous ovarian carcinomas is superior to more detailed grading systems in terms of predicting survival. Low-grade serous carcinomas typically present in young women and have a relatively good prognosis, despite being resistant to chemotherapy. Low-grade serous cancers have a high prevalence of KRAS and BRAF mutations, but a low prevalence of TP53 mutations (which are characteristic of high-grade serous cancers). Among women with low-grade serous ovarian cancer, the presence of a KRAS/BRAF mutation is a favorable prognostic factor. Studies of the mitogen-activated protein kinase (MAPK) inhibitor in low-grade serous ovarian cancer suggest that identifying MAPK mutations might eventually be useful in guiding treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

Improvement of hyperandrogenism, oligo-ovulation, and ovarian morphology in a patient with polycystic ovary syndrome: possible role of ovarian wedge resection.

PubMed

Zhang, YuanYuan; Luo, SuiYu; Gong, ZhiQuan; Feng, XiaoYa; Wang, ZiYi; Zhu, HaoHui; Wang, Yu

2018-06-01

Polycystic ovary syndrome (PCOS) is an endocrinological abnormality which typically presents as hormones disorder and/or infertility. It has received more and more attention in recent years though its pathogenesis is still unclear. Ovarian mucinous adenoma is a rarely pathological type which generates from epithelial cell of ovary. Here we present a patient with PCOS and ovarian mucinous tumor (occasionally discovered by cesarean section) receiving a complete relief after benign ovarian tumor excision. In this case, tumor excision played as a partial resection of ovary which might result in the normalized concentration level of hormones and morphology of ovary. This report suggests that therapeutic strategies for PCOS should be considered more carefully and individually.

Acrylamide Hemoglobin Adduct Levels and Ovarian Cancer Risk: a nested case-control study

PubMed Central

Xie, Jing; Terry, Kathryn L.; Poole, Elizabeth M.; Wilson, Kathryn M.; Rosner, Bernard A.; Willett, Walter C.; Vesper, Hubert W.; Tworoger, Shelley S.

2013-01-01

Background Acrylamide is a probable human carcinogen formed during cooking of starchy foods. Two large prospective cohort studies of dietary acrylamide intake and ovarian cancer risk observed a positive association, although two other studies reported no association. Methods We measured acrylamide exposure using red blood cell acrylamide and glycidamide hemoglobin adducts among women in two large prospective cohorts: the Nurses’ Health Study and Nurses’ Health Study II. Between blood collection and 2010, we identified 263 incident cases of epithelial ovarian cancer, matching two controls per case. We used logistic regression models to examine the association between acrylamide exposure and ovarian cancer risk, adjusting for matching factors, family history of ovarian cancer, tubal ligation, oral contraceptive use, body mass index (BMI), parity, alcohol intake, smoking, physical activity, and caffeine intake. Results The multivariate-adjusted relative risk (RR) of ovarian cancer comparing the highest versus lowest tertile of total acrylamide adducts was 0.79 (95% CI: 0.50–1.24, P trend = 0.08). The comparable RR of ovarian cancer among non-smokers at blood draw was 0.85 (95% CI: 0.57–1.27, P trend =0.14). The association did not differ by tumor histology (serous invasive versus not), P for heterogeneity=0.41. Individual adduct types (acrylamide or glycidamide) were not associated with risk. Conclusions We observed no evidence that acrylamide exposure as measured by adducts to hemoglobin is associated with an increased risk of ovarian cancer. Impact Our finding indicates that acrylamide intake may not increase risk of ovarian cancer. PMID:23417989

Wine drinking and epithelial ovarian cancer risk: a meta-analysis

PubMed Central

Kim, Hee Seung; Shouten, Leo J.; Larsson, Susanna C.; Chung, Hyun Hoon; Kim, Yong Beom; Ju, Woong; Park, Noh Hyun; Song, Yong Sang; Kim, Seung Cheol; Kang, Soon-Beom

2010-01-01

Objective Wine has been the focus in the prevention of epithelial ovarian cancer (EOC) development because resveratrol abundant in wine has anti-carcinogenic properties. However, epidemiologic results have been heterogenous in the chemopreventive effect of wine on the development of EOC. Thus, we performed a meta-analysis for comparing EOC risk between wine and never drinkers using previous related studies. Methods After extensive search of the literature between January 1986 and December 2008, we analyzed 10 studies (3 cohort and 7 case control studies) with 135,871 women, who included 65,578 of wine and 70,293 of never drinkers. Results In all studies, there was no significant difference in EOC risk between wine and never drinkers (odds ratio [OR], 1.13; 95% confidence interval [CI], 0.92 to 1.38; random effects). When we performed re-analysis according to the study design, 3 cohort and 7 case control studies showed that there were also no significant differences in EOC risk between wine and never drinkers, respectively (OR, 1.44 and 1.04; 95% CI, 0.74 and 2.82 and 0.88 to 1.22; random effects). In sub-analyses using 2 case-control studies, EOC risk was not different between former and never drinkers (OR, 1.12; 95% CI, 0.87 to 1.44; fixed effect), and between current and former drinkers (OR, 0.74; 95% CI, 0.41 to 1.34; random effects). Conclusion Although resveratrol, abundantly found in wine, is a promising naturally occurring compound with chemopreventive properties on EOC in preclinical studies, this meta-analysis suggests the epidemiologic evidence shows no association between wine drinking and EOC risk. PMID:20613902

Predictive markers of chemoresistance in advanced stages epithelial ovarian carcinoma.

PubMed

Bonneau, Claire; Rouzier, Roman; Geyl, Caroline; Cortez, Annie; Castela, Mathieu; Lis, Raphael; Daraï, Emile; Touboul, Cyril

2015-01-01

DNA repair mechanisms, environment-mediated drug resistance and cancer initiating cells (CIC) are three major research concepts that can explain the chemoresistance of epithelial ovarian cancer (EOC). The objective was to test if changes in the expression of potential markers associated with drug resistance before and after chemotherapy would correlate with platinum resistance, defined as a recurrence within the first year after chemotherapy cessation, and with survival, in advanced EOC. We included 32 patients with stage IIIC-IV EOC who underwent laparoscopy to evaluate the extent of carcinomatosis, neoadjuvant chemotherapy (carboplatin/taxol) and interval surgery. Biopsies taken during the initial laparoscopies and interval surgeries were evaluated using immunohistochemistry for the expression of 7 proteins: CD117, CD44 and ALDH1 to evaluate CIC; IL-6, IL-8 and BMP2 to evaluate environment-mediated drug resistance; and ERCC1 to evaluate DNA repair. Expression measurements were correlated with platin resistance and survival. The markers' relevance was confirmed in vitro using chemoresistance tests and flow cytometric measurements of the proportion of CD44+ cells. 17 patients were chemoresistant and 15 patients were chemosensitive. We observed increases in CD44, IL-6 and ERCC1 expression and stable ALDH1, CD117, IL-8, and BMP2 expression. Reduced expression of cancer initiating cell markers and increased expression of environment-mediated drug resistance markers were associated with poor prognosis. We also demonstrated that CD44+ cells had survival advantages in vitro. Changes in CD44 and IL-8 expression on tumor cells appeared to correlate with overall survival and should be further tested as predictors of chemoresistance using larger cohort. Copyright © 2014 Elsevier Inc. All rights reserved.

Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

PubMed Central

Schildkraut, Joellen M.; Goode, Ellen L; Clyde, Merlise A.; Iversen, Edwin S.; Moorman, Patricia G.; Berchuck, Andrew; Marks, Jeffrey R.; Lissowska, Jolanta; Brinton, Louise; Peplonska, Beata; Cunningham, Julie M.; Vierkant, Robert A.; Rider, David N.; Chenevix-Trench, Georgia; Webb, Penelope M.; Beesley, Jonathan; Chen, Xiaoqing; Phelan, Catherine; Sutphen, Rebecca; Sellers, Thomas A.; Pearce, Leigh; Wu, Anna H.; Van Den Berg, David; Conti, David; Elund, Christopher K.; Anderson, Rebecca; Goodman, Marc T.; Lurie, Galina; Carney, Michael E.; Thompson, Pamela J.; Gayther, Simon A.; Ramus, Susan J.; Jacobs, Ian; Kjaer, Susanne Krüger; Hogdall, Estrid; Blaakaer, Jan; Hogdall, Claus; Easton, Douglas F.; Song, Honglin; Pharoah, Paul D.P.; Whittemore, Alice S.; McGuire, Valerie; Quaye, Lydia; Anton-Culver, Hoda; Ziogas, Argyrios; Terry, Kathryn L.; Cramer, Daniel W.; Hankinson, Susan E.; Tworoger, Shelley S.; Calingaert, Brian; Chanock, Stephen; Sherman, Mark; Garcia-Closason, Montserrat

2009-01-01

The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNPs) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (ORs), 95% probability intervals (PIs) and Bayes factors (BFs) for genotype associations. Five SNPs showed significant associations with risk in one or more of the discovery investigations and were followed up by OCAC. Mixed effects analysis confirmed associations with serous invasive cancers for two correlated (r2 = 0.62) SNPs: rs2287498 (median per allele OR = 1.30; 95% PI = 1.07-1.57) and rs12951053 (median per allele OR = 1.19; 95% PI = 1.01 - 1.38). Analyses of other histological subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated with common variants in the TP53 region. PMID:19276375

Analysis of patients with epithelial ovarian cancer or fallopian tube carcinoma retreated with cisplatin after the development of a carboplatin allergy.

PubMed

Dizon, Don S; Sabbatini, Paul J; Aghajanian, Carol; Hensley, Martee L; Spriggs, David R

2002-03-01

We report the outcome of seven patients treated for recurrent ovarian cancer with cisplatin after an allergic reaction to carboplatin. One case is presented in which a heavily pretreated patient suffered a severe anaphylactic reaction, which was refractory to standard resuscitative measures and resulted in her death. Six further patients who received cisplatin after documentation of an allergic reaction to carboplatin (CBDCA) for the treatment of recurrent epithelial ovarian cancer between 1993 and 2000 were identified from the MSKCC database. Electronic medical records were reviewed for relevant treatment and outcome data. Five of six of these patients were successfully treated without further allergic reactions. One patient with platinum-refractory disease had an allergic reaction to carboplatin and subsequently to cisplatin. Few patients with a carboplatin allergy are subsequently treated with cisplatin at our center. One patient suffered a serious hypersensitivity reaction following retreatment and died. Based on this limited experience, cross allergy can exist although the true incidence is not known. Routine retreatment of carboplatin-allergic patients with cisplatin in the relapsed setting cannot be recommended without careful consideration of potential risks and benefits.

Epithelial Ovarian Cancer Metastatic to the Central Nervous System and a Family History Concerning for Hereditary Breast and Ovarian Cancer--A Potential Relationship.

PubMed

Jernigan, Amelia M; Mahdi, Haider; Rose, Peter G

2015-09-01

To estimate the frequency of hereditary breast and ovarian cancer (HBOC) in women with central nervous system (CNS) metastasis from epithelial ovarian cancer (EOC) and to evaluate for a potential relationship between HBOC status and survival. A total of 1240 cases of EOC treated between 1995 and 2014 were reviewed to identify CNS metastasis. Demographics, treatment, family history, genetic testing, and survival outcomes were recorded. Women were then classified as HBOC+ or HBOC- based on histories and genetic testing results. Kaplan-Meier survival curves and univariable Cox proportional hazards models were used. Of 1240 cases, 32 cases of EOC with CNS metastasis were identified (2.58%). Median age was 52.13 (95% confidence interval [CI], 40.56-78.38) years, and 87.10% had stage III to IV disease. Among those with documented personal and family history, 66.7% (20/30) were suspicious for HBOC syndrome. Among those who underwent germline testing, 71.43% (5/7) had a pathogenic BRCA mutation. The median time from diagnosis to CNS metastasis was 29.17 (95% CI, 0-187.91) months. At a median survival of 5.97 (95% CI, 0.20-116.95) months from the time of CNS metastasis and 43.76 (95% CI, 1.54-188.44) months from the time of EOC diagnosis, 29 women died of disease. Univariate Cox proportional hazard models were used to compare HBOC- to HBOC+ women and did not reveal a significant difference for survival outcomes. Confirmed BRCA mutations and histories concerning for HBOC syndrome are common in women with EOC metastatic to the CNS. We did not demonstrate a relationship between HBOC status and survival outcomes, but were not powered to do so.

Prediction of polycystic ovarian syndrome based on ultrasound findings and clinical parameters.

PubMed

Moschos, Elysia; Twickler, Diane M

2015-03-01

To determine the accuracy of sonographic-diagnosed polycystic ovaries and clinical parameters in predicting polycystic ovarian syndrome. Medical records and ultrasounds of 151 women with sonographically diagnosed polycystic ovaries were reviewed. Sonographic criteria for polycystic ovaries were based on 2003 Rotterdam European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine guidelines: at least one ovary with 12 or more follicles measuring 2-9 mm and/or increased ovarian volume >10 cm(3) . Clinical variables of age, gravidity, ethnicity, body mass index, and sonographic indication were collected. One hundred thirty-five patients had final outcomes (presence/absence of polycystic ovarian syndrome). Polycystic ovarian syndrome was diagnosed if a patient had at least one other of the following two criteria: oligo/chronic anovulation and/or clinical/biochemical hyperandrogenism. A logistic regression model was constructed using stepwise selection to identify variables significantly associated with polycystic ovarian syndrome (p < .05). The validity of the model was assessed using receiver operating characteristics and Hosmer-Lemeshow χ(2) analyses. One hundred twenty-eight patients met official sonographic criteria for polycystic ovaries and 115 (89.8%) had polycystic ovarian syndrome (p = .009). Lower gravidity, abnormal bleeding, and body mass index >33 were significant in predicting polycystic ovarian syndrome (receiver operating characteristics curve, c = 0.86). Pain decreased the likelihood of polycystic ovarian syndrome. Polycystic ovaries on ultrasound were sensitive in predicting polycystic ovarian syndrome. Ultrasound, combined with clinical parameters, can be used to generate a predictive index for polycystic ovarian syndrome. © 2014 Wiley Periodicals, Inc.

The latest animal models of ovarian cancer for novel drug discovery.

PubMed

Magnotti, Elizabeth; Marasco, Wayne A

2018-03-01

Epithelial ovarian cancer is a heterogeneous disease classified into five subtypes, each with a different molecular profile. Most cases of ovarian cancer are diagnosed after metastasis of the primary tumor and are resistant to traditional platinum-based chemotherapeutics. Mouse models of ovarian cancer have been utilized to discern ovarian cancer tumorigenesis and the tumor's response to therapeutics. Areas covered: The authors provide a review of mouse models currently employed to understand ovarian cancer. This article focuses on advances in the development of orthotopic and patient-derived tumor xenograft (PDX) mouse models of ovarian cancer and discusses current humanized mouse models of ovarian cancer. Expert opinion: The authors suggest that humanized mouse models of ovarian cancer will provide new insight into the role of the human immune system in combating and augmenting ovarian cancer and aid in the development of novel therapeutics. Development of humanized mouse models will take advantage of the NSG and NSG-SGM3 strains of mice as well as new strains that are actively being derived.

The role of the fallopian tube in the origin of ovarian cancer

PubMed Central

Erickson, Britt K.; Conner, Michael G.; Landen, Charles N.

2014-01-01

Advanced cases of epithelial ovarian, primary peritoneal, and primary tubal malignancies have a relatively poor prognosis and collectively remain the most deadly of all gynecologic malignancies. Although traditionally thought of as one disease process, ongoing research suggests that there is not 1 single site or cell type from which these cancers arise. A majority of the serous tumors appear to originate from dysplastic lesions in the distal fallopian tube. Therefore, what we have traditionally considered “ovarian” cancer may in fact be tubal in origin. In this article, we will review epithelial ovarian cancer classification and genetics, theories regarding cells of origin with a focus on tubal intraepithelial carcinoma, and implications for prevention and screening. PMID:23583217

Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium.