Journal of Ovarian Research - Most accessed articles

Role of CA125 in predicting ovarian cancer survival - a review of the epidemiological literature

Digant Gupta — 2009-10-09T00:00:00Z

CA125 is the gold standard tumor marker in ovarian cancer. Serum level of CA125 is used to monitor response to chemotherapy, relapse, and disease progression in ovarian cancer patients. Thus, it is reasonable to investigate whether CA125 may have utility as a prognostic indicator as well in ovarian cancer. A large number of epidemiological studies have been carried out to this effect. This review summarizes all available epidemiological literature on the association between CA125 levels and survival in ovarian cancer. To place these studies in context, we provide some background information on CA125 and its role in ovarian cancer.

Gene Expression and Pathway Analysis of Ovarian Cancer Cells Selected for Resistance to Cisplatin, Paclitaxel, or Doxorubicin

Cheryl Sherman-Baust — 2011-12-05T00:00:00Z

Background: Resistance to current chemotherapeutic agents is a major cause of therapy failure in ovarian cancer patients, but the exact mechanisms leading to the development of drug resistance remain unclear. Methods: To better understand mechanisms of drug resistance, and possibly identify novel targets for therapy, we generated a series of drug resistant ovarian cancer cell lines through repeated exposure to three chemotherapeutic drugs (cisplatin, doxorubicin, or paclitaxel), and identified changes in gene expression patterns using Illumina whole-genome expression microarrays. Validation of selected genes was performed by RT-PCR and immunoblotting. Pathway enrichment analysis using the KEGG, GO, and Reactome databases was performed to identify pathways that may be important in each drug resistance phenotype. Results: A total of 845 genes (p < 0.01) were found altered in at least one drug resistance phenotype when compared to the parental, drug sensitive cell line. Focusing on each resistance phenotype individually, we identified 460, 366, and 337 genes significantly altered in cells resistant to cisplatin, doxorubicin, and paclitaxel, respectively. Of the 845 genes found altered, only 62 genes were simultaneously altered in all three resistance phenotypes. Using pathway analysis, we found many pathways enriched for each resistance phenotype, but some dominant pathways emerged. The dominant pathways included signaling from the cell surface and cell movement for cisplatin resistance, proteasome regulation and steroid biosynthesis for doxorubicin resistance, and control of translation and oxidative stress for paclitaxel resistance. Conclusions: Ovarian cancer cells develop drug resistance through different pathways depending on the drug used in the generation of chemoresistance. A better understanding of these mechanisms may lead to the development of novel strategies to circumvent the problem of drug resistance.

The role of melatonin as an antioxidant in the follicle

Hiroshi Tamura — 2012-01-26T00:00:00Z

Melatonin is secreted during the dark hours at night by pineal gland, and it regulates a variety of important central and peripheral actions related to circadian rhythms and reproduction. It has been believed that melatonin regulates ovarian function by the regulation of gonadotropin release in the hypothalamus-pituitary gland axis via its specific receptors. In addition to the receptor mediated action, the discovery of melatonin as a direct free radical scavenger has greatly broadened the understanding of melatonin's mechanisms which benefit reproductive physiology. Higher concentrations of melatonin have been found in human preovulatory follicular fluid compared to serum, and there is growing evidence of the direct effects of melatonin on ovarian function especially oocyte maturation and embryo development. Many scientists have focused on the direct role of melatonin on oocyte maturation and embryo development as an antioxidant to reduce oxidative stress induced by reactive oxygen species, which are produced during ovulation process. The beneficial effects of melatonin administration on oocyte maturation and embryo development have been confirmed by in vitro and in vivo experiments in animals. This review also discusses the first application of melatonin to the clinical treatment of infertile women and confirms that melatonin administration reduces intrafollicular oxidative damage and increase fertilization rates. This review summarizes our recent works and new findings related to the reported beneficial effects of melatonin on reproductive physiology in its role as a reducer of oxidative stress, especially on oocyte maturation and embryo development.

Curcumin induces chemo/radio-sensitization in ovarian cancer cells and curcumin nanoparticles inhibit ovarian cancer cell growth

Murali Yallapu — 2010-04-29T00:00:00Z

Background: Chemo/radio-resistance is a major obstacle in treating advanced ovarian cancer. The efficacy of current treatments may be improved by increasing the sensitivity of cancer cells to chemo/radiation therapies. Curcumin is a naturally occurring compound with anti-cancer activity in multiple cancers; however, its chemo/radio-sensitizing potential is not well studied in ovarian cancer. Herein, we demonstrate the effectiveness of a curcumin pre-treatment strategy for chemo/radio-sensitizing cisplatin resistant ovarian cancer cells. To improve the efficacy and specificity of curcumin induced chemo/radio sensitization, we developed a curcumin nanoparticle formulation conjugated with a monoclonal antibody specific for cancer cells. Methods: Cisplatin resistant A2780CP ovarian cancer cells were pre-treated with curcumin followed by exposure to cisplatin or radiation and the effect on cell growth was determined by MTS and colony formation assays. The effect of curcumin pre-treatment on the expression of apoptosis related proteins and β-catenin was determined by Western blotting or Flow Cytometry. A luciferase reporter assay was used to determine the effect of curcumin on β-catenin transcription activity. The poly(lactic acid-co-glycolic acid) (PLGA) nanoparticle formulation of curcumin (Nano-CUR) was developed by a modified nano-precipitation method and physico-chemical characterization was performed by transmission electron microscopy and dynamic light scattering methods. Results: Curcumin pre-treatment considerably reduced the dose of cisplatin and radiation required to inhibit the growth of cisplatin resistant ovarian cancer cells. During the 6 hr pre-treatment, curcumin down regulated the expression of Bcl-XL and Mcl-1 pro-survival proteins. Curcumin pre-treatment followed by exposure to low doses of cisplatin increased apoptosis as indicated by annexin V staining and cleavage of caspase 9 and PARP. Additionally, curcumin pre-treatment lowered β-catenin expression and transcriptional activity. Nano-CUR was successfully generated and physico-chemical characterization of Nano-CUR indicated an average particle size of ~70 nm, steady and prolonged release of curcumin, antibody conjugation capability and effective inhibition of ovarian cancer cell growth. Conclusion: Curcumin pre-treatment enhances chemo/radio-sensitization in A2780CP ovarian cancer cells through multiple molecular mechanisms. Therefore, curcumin pre-treatment may effectively improve ovarian cancer therapeutics. A targeted PLGA nanoparticle formulation of curcumin is feasible and may improve the in vivo therapeutic efficacy of curcumin.

Suppression of Cancer Stemness p21-regulating mRNA and microRNA Signatures in Recurrent Ovarian Cancer Patient Samples

Michael Gallagher — 2012-01-19T00:00:00Z

Background: Malignant ovarian disease is characterised by high rates of mortality due to high rates of recurrent chemoresistant disease. Anecdotal evidence indicates this may be due to chemoresistant properties of cancer stem cells (CSCs). However, our understanding of the role of CSCs in recurrent ovarian disease remains sparse. In this study we used gene microarrays and meta-analysis of our previously published microRNA (miRNA) data to assess the involvement of cancer stemness signatures in recurrent ovarian disease. Methods: Microarray analysis was used to characterise early regulation events in an embryonal carcinoma (EC) model of cancer stemness. This was then compared to our previously published microarray data from a study of primary versus recurrent ovarian disease. In parallel, meta-analysis was used to identify cancer stemness miRNA signatures in tumour patient samples. Results: Microarray analysis demonstrated a 90% difference between gene expression events involved in early regulation of differentiation in murine EC (mEC) and embryonic stem (mES) cells. This contrasts the known parallels between mEC and mES cells in the undifferentiated and well-differentiated states. Genelist comparisons identified a cancer stemness signature set of genes in primary versus recurrent data, a subset of which are known p53-p21 regulators. This signature is present in primary and recurrent or in primary alone but essentially never in recurrent tumours specifically. Meta-analysis of miRNA expression showed a much stronger cancer stemness signature within tumour samples. This miRNA signature again related to p53-p21 regulation and was expressed prominently in recurrent tumours. Our data indicate that the regulation of p53-p21 in ovarian cancer involves, at least partially, a cancer stemness component. Conclusion: We present a p53-p21 cancer stemness signature model for ovarian cancer. We propose that this may, at least partially, differentially regulate the p53-p21 mechanism in ovarian disease. Targeting CSCs within ovarian cancer represents a potential therapeutic avenue.

Application of RNA-Seq Transcriptome Analysis: CD151 is an Invasion/Migration Target in All Stages of Epithelial Ovarian Cancer

Rebecca Mosig — 2012-01-24T00:00:00Z

Background: RNA-Seq allows a theoretically unbiased analysis of both genome-wide transcription levels and mutation status of a tumor. Using this technique we sought to identify novel candidate therapeutic targets expressed in epithelial ovarian cancer (EOC). Methods: Specifically, we sought candidate invasion/migration targets based on expression levels across all tumors, novelty of expression in EOC, and known function. RNA-Seq analysis revealed the high expression of CD151, a transmembrane protein, across all stages of EOC. Expression was confirmed at both the mRNA and protein levels using RT-PCR and immunohistochemical staining, respectively. Results: In both EOC tumors and normal ovarian surface epithelial cells we demonstrated CD151 to be localized to the membrane and cell-cell junctions in patient-derived and established EOC cell lines. We next evaluated its role in EOC dissemination using two ovarian cancer-derived cell lines with differential levels of CD151 expression. Targeted antibody-mediated and siRNA inhibition or loss of CD151 in SKOV3 and OVCAR5 cell lines effectively inhibited their migration and invasion. Conclusion: Taken together, these findings provide the first proof-of-principle demonstration for a next generation sequencing approach to identifying candidate therapeutic targets and reveal CD151 to play a role in EOC dissemination.

IGFBP-4 tumor and serum levels are increased across all stages of epithelial ovarian cancer.

Rebecca Mosig — 2012-01-20T00:00:00Z

Background: We sought to identify candidate serum biomarkers for the detection and surveillance of EOC. Based on RNA-Seq transcriptome analysis of patient-derived tumors, highly expressed secreted proteins were identified using a bioinformatic approach. Methods: RNA-Seq was used to quantify papillary serous ovarian cancer transcriptomes. Paired end sequencing of 22 flash frozen tumors was performed. Sequence alignments were processed with the program ELAND, expression levels with ERANGE and then bioinformatically screened for secreted protein signatures. Serum samples from women with benign and malignant pelvic masses and serial samples from women during chemotherapy regimens were measured for IGFBP-4 by ELISA. Student's t Test, ANOVA, and ROC curves were used for statistical analysis. Results: Insulin-like growth factor binding protein (IGFBP-4) was consistently present in the top 7.5% of all expressed genes in all tumor samples. We then screened serum samples to determine if increased tumor expression correlated with serum expression. In an initial discovery set of 21 samples, IGFBP-4 levels were found to be elevated in patients, including those with early stage disease and normal CA125 levels. In a larger and independent validation set (82 controls, 78 cases), IGFBP-4 levels were significantly increased (p < 5 × 10-5). IGFBP-4 levels were ~3× greater in women with malignant pelvic masses compared to women with benign masses. ROC sensitivity was 73% at 93% specificity (AUC 0.816). In women receiving chemotherapy, average IGFBP-4 levels were below the ROC-determined threshold and lower in NED patients compared to AWD patients. Conclusions: This study, the first to our knowledge to use RNA-Seq for biomarker discovery, identified IGFBP-4 as overexpressed in ovarian cancer patients. Beyond this, these studies identified two additional intriguing findings. First, IGFBP-4 can be elevated in early stage disease without elevated CA125. Second, IGFBP-4 levels are significantly elevated with malignant versus benign disease. These findings provide the rationale for future validation studies.

Ovarian cancer mouse models: A summary of current models and their limitations

Miranda Fong — 2009-09-28T00:00:00Z

Development of mouse models representing human spontaneous ovarian cancer has been hampered by the lack of understanding of the etiology of this very complex disease. Mouse models representing the different types of ovarian cancer are needed to understand how epithelial ovarian cancer differs from granulosa cell tumors. Many different methods have been used to generate a viable genetic model with limited success. This review focuses on the methods of various investigators and the limitations of each model in establishing a reproducible and inheritable line to study this disease.

Discovery of Dachshund 2 protein as a novel biomarker of poor prognosis in epithelial ovarian cancer

Bjorn Nodin — 2012-01-27T00:00:00Z

Background: The Dachshund homolog 2 (DACH2) gene has been implicated in development of the female genital tract in mouse models and premature ovarian failure syndrome, but to date, its expression in human normal and cancerous tissue remains unexplored. Using the Human Protein Atlas as a tool for cancer biomarker discovery, DACH2 protein was found to be differentially expressed in epithelial ovarian cancer (EOC). Here, the expression and prognostic significance of DACH2 was further evaluated in ovarian cancer cell lines and human EOC samples. Methods: Immunohistochemical expression of DACH2 was examined in tissue microarrays with 143 incident EOC cases from two prospective, population-based cohorts, including a subset of benign-appearing fallopian tubes (n =32). A nuclear score (NS), i.e. multiplier of staining fraction and intensity, was calculated. For survival analyses, cases were dichotomized into low (NS <=3) and high (NS >3) using classification and regression tree analysis. Kaplan Meier analysis and Cox proportional hazards modelling were used to assess the impact of DACH2 expression on survival. DACH2 expression was analysed in the cisplatin sensitive ovarian cancer cell line A2780 and its cisplatin resistant derivative A2780-Cp70. The specificity of the DACH2 antibody was tested using siRNA-mediated silencing of DACH2 in A2780-Cp70 cells. Results: DACH2 expression was considerably higher in the cisplatin resistant A2780-Cp70 cells compared to the cisplatin-sensitive A2780 cells. While present in all sampled fallopian tubes, DACH2 expression ranged from negative to strong in EOC. In EOC, DACH2 expression correlated with several proteins involved in DNA integrity and repair, and proliferation. DACH2 expression was significantly higher in carcinoma of the serous subtype compared to non-serous carcinoma. In the full cohort, high DACH2 expression was significantly associated with poor prognosis in univariable analysis, and in carcinoma of the serous subtype, DACH2 remained an independent factor of poor prognosis. Conclusions: This study provides a first demonstration of DACH2 protein being expressed in human fallopian tubes and EOC, with the highest expression in serous carcinoma where DACH2 was found to be an independent biomarker of poor prognosis. Future research should expand on the role of DACH2 in ovarian carcinogenesis and chemotherapy resistance.

Endometriosis-associated ovarian cancer: A ten-year cohort study of women living in the Estrie Region of Quebec, Canada

Aziz Aris — 2010-01-19T00:00:00Z

ObjectivesEndometriosis has been believed to increase the risk of developing ovarian cancer, but recent data supporting this hypothesis are lacking. The aim of this study was to verify whether the incidence of endometriosis, ovarian cancer and the both increased during the last 10 years among women living in the Estrie region of Quebec. Methods: We collected data of women diagnosed with endometriosis, ovarian cancer or both, between 1997 and 2006, from a population living in the Estrie region of Quebec. We performed this retrospective cross-sectional study from the CIRESSS (Centre Informatisé de Recherche Évaluative en Services et Soins de Santé) system, the database of the CHUS (Centre Hospitalier Universitaire of Sherbrooke), Sherbrooke, Canada. Results: Among the 2854 identified patients, 2521 had endometriosis, 292 patients had ovarian cancer and 41 patients had both ovarian cancer and endometriosis. We showed a constant increase in the number of ovarian cancer (OC) between 1997 and 2006 (r2 = 0.557, P = 0.013), which is not the case for endometriosis (ENDO) or endometriosis-associated ovarian cancer (EAOC). The mean age ± SD was 40.0 ± 9.9 and 53.9 ± 11.4 for patients having ENDO and OC, respectively. Mean age of women with EAOC was 48.3 ± 10.8, suggesting an early onset of ovarian cancer in women having endometriosis of about 5.5 years average, P = 0.003. Women with ENDO were at increased risk for developing OC (Rate Ratio [RR] = 1.6; 95% Confidence Interval [CI] = 1.12-2.09). Pathological analyses showed the predominance of endometrioid type (24.4%) and clear-cell type (21.9%) types in EAOC compared to OC, P = 0.0070 and 0.0029, respectively. However, the serous type is the most widespread in OC (44.5%) in comparison to EAOC (19.51%), P = 0.0023. Conclusion: Our findings highlight that the number of cases of ovarian cancer is constantly increasing in the last ten years and that endometriosis represents a serious risk factor which accelerates its apparition by about 5.5 years.