Clinical Outcome In Ovarian Cancer Research Articles

Distinct fibroblast functional states drive clinical outcomes in ovarian cancer and are regulated by TCF21.

Recent studies indicate that cancer-associated fibroblasts (CAFs) are phenotypically and functionally heterogeneous. However, little is known about CAF subtypes, the roles they play in cancer progression, and molecular mediators of the CAF "state." Here, we identify a novel cell surface pan-CAF marker, CD49e, and demonstrate that two distinct CAF states, distinguished by expression of fibroblast activation protein (FAP), coexist within the CD49e+ CAF compartment in high-grade serous ovarian cancers. We show for the first time that CAF state influences patient outcomes and that this is mediated by the ability of FAP-high, but not FAP-low, CAFs to aggressively promote proliferation, invasion and therapy resistance of cancer cells. Overexpression of the FAP-low-specific transcription factor TCF21 in FAP-high CAFs decreases their ability to promote invasion, chemoresistance, and in vivo tumor growth, indicating that it acts as a master regulator of the CAF state. Understanding CAF states in more detail could lead to better patient stratification and novel therapeutic strategies.

BRCA1 Promoter Methylation and Clinical Outcomes in Ovarian Cancer: An Individual Patient Data Meta-Analysis.

BRCA1 methylation has been associated with homologous recombination deficiency, a biomarker of platinum sensitivity. Studies evaluating BRCA1-methylated tubal and ovarian cancer (OC) do not consistently support improved survival following platinum chemotherapy. We examine the characteristics of BRCA1-methylated OC in a meta-analysis of individual participant data. Data of 2636 participants across 15 studies were analyzed. BRCA1-methylated tumors were defined according to their original study. Associations between BRCA1 methylation and clinicopathological characteristics were evaluated. The effects of methylation on overall survival (OS) and progression-free survival (PFS) were examined using mixed-effects models. All statistical tests were 2-sided. 430 (16.3%) tumors were BRCA1-methylated. BRCA1 methylation was associated with younger age and advanced-stage, high-grade serous OC. There were no survival differences between BRCA1-methylated and non-BRCA1-methylated OC (median PFS = 20.0 vs 18.5 months, hazard ratio [HR] = 1.01, 95% CI = 0.87 to 1.16; P = .98; median OS = 46.6 vs 48.0 months, HR = 1.02, 95% CI = 0.87 to 1.18; P = .96). Where BRCA1/2 mutations were evaluated (n = 1248), BRCA1 methylation displayed no survival advantage over BRCA1/2-intact (BRCA1/2 wild-type non-BRCA1-methylated) OC. Studies used different methods to define BRCA1 methylation. Where BRCA1 methylation was determined using methylation-specific polymerase chain reaction and gel electrophoresis (n = 834), it was associated with improved survival (PFS: HR = 0.80, 95% CI = 0.66 to 0.97; P = .02; OS: HR = 0.80, 95% CI = 0.63 to 1.00; P = .05) on mixed-effects modeling. BRCA1-methylated OC displays similar clinicopathological features to BRCA1-mutated OC but is not associated with survival. Heterogeneity within BRCA1 methylation assays influences associations. Refining these assays may better identify cases with silenced BRCA1 function and improved patient outcomes.

Ascites-derived ALDH+CD44+ tumour cell subsets endow stemness, metastasis and metabolic switch via PDK4-mediated STAT3/AKT/NF-\u03baB/IL-8 signalling in ovarian cancer

BackgroundOvarian cancer is characterised by frequent recurrence due to persistent presence of residual cancer stem cells (CSCs). Here, we identify and characterise tumour subsets from ascites-derived tumour cells with stemness, metastasis and metabolic switch properties and to delineate the involvement of pyruvate dehydrogenase kinase 4 (PDK4) in such process.MethodsOvarian cancer cells/cell lines derived from ascites were used for tumourspheres/ALDH+CD44+ subset isolation. The functional roles and downstream signalling of PDK4 were explored. Its association with clinical outcome of ovarian cancer was analysed.ResultsWe demonstrated enhanced CSC characteristics of tumour cells derived from ovarian cancer ascites, concomitant with ALDH and CD44 subset enrichment and high PDK4 expression, compared to primary tumours. We further showed tumourspheres/ALDH+CD44+ subsets from ascites-derived tumour cells/cell lines with CSC properties and enhanced glycolysis. Clinically, PDK4 expression was correlated with aggressive features. Notably, blockade of PDK4 in tumourspheres/ALDH+CD44+ subsets led to inhibition of CSC characteristics, glycolysis and activation of STAT3/AKT/NF-κB/IL-8 (signal transducer and activator of transcription 3/protein kinases B/nuclear factor-κB/interleukin-8) signalling. Conversely, overexpression of PDK4 in ALDH−CD44– subsets exerted the opposite effects.ConclusionAscites-derived ALDH+CD44+ tumour cell subsets endow stemness, metastatic and metabolic switch properties via PDK4-mediated STAT3/AKT/NF-κB/IL-8 signalling, suggesting PDK4 as a viable therapeutic molecular target for ovarian cancer management.

Clonal tumor mutations in homologous recombination genes predict favorable clinical outcome in ovarian cancer treated with platinum-based chemotherapy

ObjectivePlatinum-based chemotherapy remains the first-line treatment for ovarian carcinoma by inducing DNA damage. The therapeutic impact of clonal and subclonal somatic mutations in DNA damage repair (DDR) pathways remains unexplored. MethodsWe performed an integrated analysis to infer the clonality of somatic deleterious mutations in 385 ovarian carcinomas treated with platinum-based chemotherapy. The Kaplan–Meier method was performed for visualization and the differences between survival curves were calculated by log-rank test. Proportional hazards models were used to estimate relative hazards for platinum-free interval (PFI), progression-free survival (PFS) and overall survival (OS). ResultsWe found that somatic deleterious mutations in DDR pathways exhibited widespread clonal heterogeneity, and that patients with DDR clonal mutations exhibited a “hypermutator phenotype”. Clonal somatic mutations in homologous recombination repair (HRR) pathway were significantly associated with better OS (HR = 0.19 (95% CI, 0.06–0.59), P = 0.0044) and PFS (HR = 0.20 (95% CI, 0.08–0.49), P = 0.0005) than HRR wild-type, while HRR subclonal mutations were not associated with prognosis. Moreover, HRR clonal mutations were associated with significantly higher chemotherapy sensitive rate (P = 0.0027) and longer PFI (HR = 0.20 (95% CI, 0.08–0.49), P = 0.0005) than HRR wild-type, while HRR subclonal mutations were not. We validated our findings using an independent cohort of 93 ovarian cancer patients that received platinum-based chemotherapy. ConclusionsHRR clonal mutations, but not subclonal mutations, were associated with improved survival, chemotherapy response, and genome instability compared with HRR wild-type.

Identification of an energy metabolism‑related gene signature in ovarian cancer prognosis.

Changes in energy metabolism may be potential biomarkers and therapeutic targets for cancer as they frequently occur within cancer cells. However, basic cancer research has failed to reach a consistent conclusion on the function(s) of mitochondria in energy metabolism. The significance of energy metabolism in the prognosis of ovarian cancer remains unclear; thus, there remains an urgent need to systematically analyze the characteristics and clinical value of energy metabolism in ovarian cancer. Based on gene expression patterns, the present study aimed to analyze energy metabolism-associated characteristics to evaluate the prognosis of patients with ovarian cancer. A total of 39 energy metabolism-related genes significantly associated with prognosis were obtained, and three molecular subtypes were identified by nonnegative matrix factorization clustering, among which the C1 subtype was associated with poor clinical outcomes of ovarian cancer. The immune response was enhanced in the tumor microenvironment. A total of 888 differentially expressed genes were identified in C1 compared with the other subtypes, and the results of the pathway enrichment analysis demonstrated that they were enriched in the ‘PI3K-Akt signaling pathway’, ‘cAMP signaling pathway’, ‘ECM-receptor interaction’ and other pathways associated with the development and progression of tumors. Finally, eight characteristic genes (tolloid-like 1 gene, type XVI collagen, prostaglandin F2α, cartilage intermediate layer protein 2, kinesin family member 26b, interferon inducible protein 27, growth arrest-specific gene 1 and chemokine receptor 7) were obtained through LASSO feature selection; and a number of them have been demonstrated to be associated with ovarian cancer progression. In addition, Cox regression analysis was performed to establish an 8-gene signature, which was determined to be an independent prognostic factor for patients with ovarian cancer and could stratify sample risk in the training, test and external validation datasets (P<0.01; AUC >0.8). Gene Set Enrichment Analysis results revealed that the 8-gene signature was involved in important biological processes and pathways of ovarian cancer. In conclusion, the present study established an 8-gene signature associated with metabolic genes, which may provide new insights into the effects of energy metabolism on ovarian cancer. The 8-gene signature may serve as an independent prognostic factor for ovarian cancer patients.

ADP-Ribosylation Levels and Patterns Correlate with Gene Expression and Clinical Outcomes in Ovarian Cancers.

Inhibitors of nuclear PARP enzymes (e.g., PARP-1) have improved clinical outcomes in ovarian cancer, especially in patients with BRCA1/2 gene mutations or additional homologous recombination (HR) DNA repair pathway deficiencies. These defects serve as biomarkers for response to PARP inhibitors (PARPi). We sought to identify an additional biomarker that could predict responses to both conventional chemotherapy and PARPi in ovarian cancers. We focused on cellular ADP-ribosylation (ADPRylation), which is catalyzed by PARP enzymes and detected by detection reagents we developed previously. We determined molecular phenotypes of 34 high-grade serous ovarian cancers and associated them with clinical outcomes. We used the levels and patterns of ADPRylation and PARP-1 to distribute ovarian cancers into distinct molecular phenotypes, which exhibit dramatically different gene expression profiles. In addition, the levels and patterns of ADPRylation, PARP-1 protein, and gene expression correlated with clinical outcomes in response to platinum-based chemotherapy, with cancers exhibiting the highest levels of ADPRylation having the best outcomes independent of BRCA1/2 status. Finally, in cell culture-based assays using patient-derived ovarian cancer cell lines, ADPRylation levels correlated with sensitivity to the PARPi, Olaparib, with cell lines exhibiting high levels of ADPRylation having greater sensitivity to Olaparib. Collectively, our study demonstrates that ovarian cancers exhibit a wide range of ADPRylation levels, which correlate with therapeutic responses and clinical outcomes. These results suggest ADPRylation may be a useful biomarker for PARPi sensitivity in ovarian cancers, independent of BRCA1/2 or homologous recombination deficiency status.

Depletion of UBE2C reduces ovarian cancer malignancy and reverses cisplatin resistance via downregulating CDK1

Ovarian cancer is the most lethal gynecological malignancy, but the mechanisms of ovarian cancer progression and cisplatin resistance remain unclear. Emerging evidence suggested that ubiquitin-conjugating enzyme E2C (UBE2C) was highly expressed in a variety of tumors and acted as an oncogene. In our study, we demonstrated that UBE2C was overexpressed in ovarian cancer by immunohistochemistry (IHC) and The Cancer Genome Atlas (TCGA) database analysis. It was also found that high levels of UBE2C expression predicted worse clinical outcomes in ovarian cancer. After knocking down UBE2C, SKOV3 and A2780 cells showed inhibitory cell proliferation, increased apoptosis by blocking G2/M transition in vitro and in vivo. Besides, the downregulation of UBE2C reversed the cisplatin resistance states of SKOV3/DDP and A2780/DDP cells. Interestingly, CDK1 expression was also downregulated in UBE2C depleted ovarian cancer cells. Furthermore, we found that UBE2C expression was highly correlated with CDK1 expression in ovarian cancer tissues and cell lines, indicating that UBE2C might cooperate with CDK1 in ovarian tumorigenesis. Collectively, our findings strongly supported UBE2C as a candidate oncogene and a potential target for the treatment of ovarian cancer.

1875PD - Targeting molecular mediators of T cell exclusion for effective immunotherapy in ovarian cancer

BackgroundClose proximity between cytotoxic T lymphocytes and tumour cells is required for effective immunotherapy. However, what determines the spatial distribution of T cells in the tumour microenvironment is not well understood. Coupling digital pathology and transcriptome analysis on large ovarian tumour cohorts, here we report classification and functionally dissection of tumour-immune contexture in human ovarian cancer. MethodsCD8 IHC and RNAseq analysis were performed on 370 ovarian tumours from the ICON7 phase III clinical trial. Coupling digital pathology with transcriptome analysis, a random forest machine learning algorithm was developed and independently validated for classifying tumour-immune phenotypes in ovarian cancer. Anti-tumour activity of TGFβ blockade in combination with anti-PD-L1 was evaluated in an ovarian cancer mouse model. ResultsWe show the identified tumour-immune phenotypes are of biological and clinical importance with interconnection to molecular subtypes and association with clinical outcome in ovarian cancer. Two important hallmarks of T cell exclusion were identified: 1) loss of antigen presentation on tumour cells and 2) upregulation of TGFβ and activated stroma. We identified TGFβ as a key mediator of T cell exclusion. TGFβ reduced MHC class I expression in ovarian cancer cells and induced extracellular matrix (ECM) production and immunosuppressive molecules in human primary fibroblasts. Finally, we demonstrated that combination of anti-TGFβ and anti-PD-L1 in a mouse ovarian cancer model significantly improved the anti-tumour efficacy and survival. ConclusionsThis study provided the first systematic and in-depth characterization of the molecular features and mechanisms underlying the tumour-immune phenotypes in ovarian cancer. We illuminated a multi-faceted role of TGFβ in mediating consequential crosstalk between tumour cells and cancer associated fibroblasts to shape the tumour-immune contexture. Our findings support that targeting the TGFβ pathway represents a promising therapeutic strategy to overcome T cell exclusion and optimize response to cancer immunotherapy. Legal entity responsible for the studyThe authors. FundingGenentech/Roche. DisclosureAll authors have declared no conflicts of interest.

JS-K, a nitric oxide donor, induces autophagy as a complementary mechanism inhibiting ovarian cancer

BackgroundOvarian cancer (OC) is the second most frequent gynecological cancer and is associated with a poor prognosis because OC progression is often asymptoma-tic and is detected at a late stage. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. As a nitric oxide prodrug, JS-K is reported highly cytotoxic to human cancer cells such as acute myeloid leukemia, multiple myeloma and breast cancer. This study is aim to investigate the influence of JS-K on proliferation and apoptosis in ovarian cancer cells and explored possible autophagy-related mechanisms, which will contribute to future ovarian cancer therapy and supply theory support that JS-K holds great promise as a novel therapeutic agent against ovarian cancer.MethodsThe cytotoxicity, extracellular ROS/RNS activity and apoptotic effect of JS-K and indicated inhibitors on ovarian cancer cells in vitro were evaluated by MTT assay, extracellular ROS/RNS assay, caspases activities assay and western blot. Further autophagy effect of JS-K and indicated inhibitors were examined by MTT assay, cell transfection, immunofluorescence analysis, transmission electron microscopy (TEM) analysis and western blot on ovarian cancer cells in vitro. In vivo, the BALB/c-nude female mice with SKOV3 ovarian cancer cells xenograft were used to examine the efficacy of JS-K treatment on tumor growth. PCNA and p62 proteins were analyzed by immunohistochemistry.ResultsIn vitro, JS-K inhibited the proliferation of ovarian cancer cells, induced apoptosis and cell nucleus shrinkage, enhanced the enzymatic activity of caspase-3/7/8/9, and significantly increased the production of ROS/RNS in ovarian cancer A2780 and SKOV3 cells, these effects were attenuated by inhibition of NAC. In addition, JS-K induced autophagy-related proteins and autophagosomes changes in ovarian cancer A2780 and SKOV3 cells. In vivo, JS-K inhibited tumor growth, decreased p62 protein expression and increased the expression levels of PCNA in xenograft models which were established using SKOV3 ovarian cancer cells.ConclusionTaken together, we demonstrated that ROS/RNS stress-mediated apoptosis and autophagy are mechanisms by which SKOV3 cells undergo cell death after treatment with JS-K in vitro. Moreover, JS-K inhibited SKOV3 tumor growth in vivo. An alternative therapeutic approach for triggering cell death in cancer cells could constitute a useful multimodal therapies for treating ovarian cancer, which is known for its resistance to apoptosis-inducing drugs.

Nutritional Interventions to Improve Clinical Outcomes in Ovarian Cancer: A Systematic Review of Randomized Controlled Trials.

Among all gynaecological neoplasms, ovarian cancer has the highest rate of disease-related malnutrition, representing an important risk factor of postoperative mortality and morbidity. Hence, the importance of finding effective nutritional interventions is crucial to improve ovarian cancer patient’s well-being and survival. This systematic review of randomized controlled trials (RCTs) aims at assessing the effects of nutritional interventions on clinical outcomes such as overall survival, progression-free survival, length of hospital stay (LOS), complications following surgery and/or chemotherapy in ovarian cancer patients. Three electronic bibliographic databases (MEDLINE, Web of Science, and Cochrane Central Register of Controlled Trials) were used to conduct a systematic literature search based on fixed inclusion and exclusion criteria, until December 2018. A total of 14 studies were identified. Several early postoperative feeding interventions studies (n = 8) were retrieved mainly demonstrating a reduction in LOS and an ameliorated intestinal recovery after surgery. Moreover, innovative nutritional approaches such as chewing gum intervention (n = 1), coffee consumption (n = 1), ketogenic diet intervention (n = 2) or fruit and vegetable juice concentrate supplementation diet (n = 1) and short-term fasting (n = 1) have been shown as valid and well-tolerated nutritional strategies improving clinical outcomes. However, despite an acceptable number of prospective trials, there is still a lack of homogeneous and robust endpoints. In particular, there is an urgent need of RCTs evaluating overall survival and progression-free survival during ovarian oncology treatments. Further high-quality studies are warranted, especially prospective studies and large RCTs, with more homogeneous types of intervention and clinical outcomes, including a more specific sampling of ovarian cancer women, to identify appropriate and effective nutritional strategies for this cancer, which is at high risk of malnutrition.

Prognostic value of preoperative dynamic contrast-enhanced magnetic resonance imaging in epithelial ovarian cancer

ObjectivesTo investigate whether semi-quantitative and pharmacokinetic perfusion dynamic contrast-enhanced (DCE) parameters are associated with traditional prognostic factors and can predict clinical outcome in ovarian cancer (OC). MethodsThis prospective study, approved by local ethical committee, enrolled 38 patients with primary OC, 2011–2014. After preoperative DCE-MRI (3.0 T), two observers measured perfusion (Ktrans, Kep, Ve, Vp) and semi-quantitative parameters (area under the curve, peak, time-to-peak) by drawing regions of interest (ROIs) covering the large solid lesion (L-ROI) and the most enhancing small area (S-ROI) (NordicICE platform). Kruskal–Wallis was used to analyze associations between MRI parameters and classified prognostic factors. ResultsMean Ktrans values were higher in high-grade serous OC than in other types (L-ROI, P = 0.041; S-ROI, P = 0.018), and lower mean Ktrans values predicted residual tumor (L-ROI P = 0.030; S-ROI, P = 0.012). Higher minimum Vp values were associated with higher International Federation of Gynecology and Obstetrics (FIGO) stage (S-ROI, P = 0.023).Shorter recurrence-free survival was predicted by higher Ve (minimum L-ROI, P = 0.035; maximum S-ROI, P = 0.046), Vp (maximum S-ROI, P = 0.033), and lower time-to-peak (maximum S-ROI, P = 0.047) in Kaplan–Meier analysis. Multiparametric MRI variables combining DCE and diffusion weighted data were also predictive for survival. ConclusionDCE-MRI parameters may represent imaging biomarkers for predicting tumor aggressiveness and prognosis in OC. Higher Ktrans levels were associated with better results in cytoreductive surgery but with earlier recurrence.

Current state and outlook for drug repositioning anticipated in the field of ovarian cancer.

Ovarian cancer is the seventh most common cancer and the eighth most common cause of cancer mortality in women. Although standard chemotherapy is the established treatment for ovarian cancer, the prognosis remains poor, and it is highly anticipated that new drugs will be developed. New drugs, such as humanized anti-vascular endothelial growth factor monoclonal antibodies and poly ADP-ribose polymerase inhibitors, are expected to improve clinical outcomes of ovarian cancer. However, long-term, costly research is required to develop such new drugs, and soaring national healthcare costs are becoming a concern worldwide. In this social context, drug repositioning, wherein existing drugs are used to develop drugs with new indications for other diseases, has recently gained attention. Because trials have already confirmed the safety in humans and the pharmacokinetics of such drugs, the development period is shorter than the conventional development of a new drug, thereby reducing costs. This review discusses the available basic experimental and clinical data on drugs used for other types of cancer for which drug repositioning is anticipated to repurpose the drug for the treatment of ovarian cancer. These include statins, which are used to treat dyslipidemia; bisphosphonate, which is used to treat osteoporosis; metformin, which is used to treat diabetes; non-steroidal anti-inflammatory drugs; ivermectin, an antiparasitic agent; and itraconazole, an anti-fungal agent. These drugs will play an important role in future drug repositioning strategies for ovarian cancer. Furthermore, drug repositioning is anticipated to extend not only to ovarian cancer treatment but also to ovarian cancer prevention.

PO-110 AKT expression is associated with poor clinical outcome in ovarian cancer

IntroductionOvarian cancer (OC) is the third most common gynaecological cancer among women worldwide and it is associated with the highest mortality rate among gynaecologic malignancies. There is an urgent need to refine classification of ovarian cancer and identify novel targets. The PI3K/AKT/mTOR pathway is an intracellular signalling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation and cancer. We aimed to investigate the prognostic role of AKT in ovarian cancer.Material and methodsInvestigation of the expression of AKT in ovarian epithelial cancer was carried out on tissue microarrays of 525 consecutive ovarian epithelial cancer cases treated at Nottingham University Hospitals (NUH) between 1997 and 2010 and their expression was correlated to clinicopathological outcomes as well as to recurrence free survival (RFS).Results and discussionsHigh cytoplasmic AKT expression was significantly associated with serous type of tumour (p=0.042). Furthermore, High AKT protein expression was correlated with poor outcome in terms of Recurrence Free Survival (RFS) (p=0.034). Moreover, by selecting only stage one disease positive AKT expression showed significantly higher chance of worse RFS.ConclusionAKT protein is a prospectively valuable recurrence predictive biomarker of epithelial ovarian cancer.

Prospects of chimeric antigen receptor T cell therapy in ovarian cancer.

Despite advances in various chemotherapy regimens, current therapeutic options are limited for ovarian cancer patients. Immunotherapy provides a promising and novel treatment option for ovarian cancer. Recently, chimeric antigen receptor (CAR) T cell therapy has shown promising results in hematological tumors and current research is going on in various solid tumors like ovarian cancer. CAR T cells are genetically engineered T cells with major histocompatibility complex-independent, tumor-specific, immune-mediated cytolytic actions against cancer cells. Initial studies of CAR T cell therapy have shown promising results in ovarian cancer, but there are some obstacles like impaired T cell trafficking, lack of antigenic targets, cytokine release syndrome and most important immunosuppressive tumor microenvironment. Optimization of design, improving tumor microenvironment and combinations with other therapies may help us in improving CAR T cell efficacy. In this review article, we highlight the current knowledge regarding CAR T cell therapy in ovarian cancer. We have discussed basic functioning of CAR T cells, their rationale and clinical outcome in ovarian cancer with limitations.

FIH is an oxygen sensor for G9a/GLP‐driven epigenetic regulation of metastasis‐related genes in ovarian cancer

The dioxygenases PHD1‐3 and FIH are the oxygen sensors for hypoxia‐inducible factor (HIF)‐driven transcription of hypoxia‐induced genes. However, little is known about the oxygen sensors responsible for oxygen‐dependent epigenetic regulation. We here show that FIH plays additional roles as an oxygen sensor in G9a‐ and GLP‐driven epigenetic regulation. FIH hydroxylates and inhibits G9a and GLP under normoxia. When the FIH reaction is limited under hypoxia, G9a and GLP are activated and repress the metastasis suppressor genes, thereby triggering cancer cell migration and peritoneal dissemination of ovarian cancer xenografts. FIH and G9a expressions are reciprocally associated with clinical outcomes of ovarian cancer. Mutations of FIH‐target motifs in G9a and GLP were identified in human cancers, and they exhibit excessive H3K9 methylation and facilitate cell invasion. This study provides insight into a new function of FIH as an upstream regulator of oxygen‐dependent chromatin remodeling. It also implies that the FIH‐G9a/GLP pathway could be a potential target for inhibiting hypoxia‐induced cancer metastasis.Support or Funding InformationThis work was supported by a grant from the National Research Foundation of Korea (2017R1A4A1015015 and 2016R1A2A1A05005082 to J.W.P). Kang J received a scholarship from the BK21‐plus education program provided by the National Research Foundation of Korea.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The positivity of estrogen receptor and progesterone receptor may not be associated with metastasis and recurrence in epithelial ovarian cancer

The estrogen (ER) or progesterone receptors (PR) is positively associated with better clinical outcomes in ovarian cancer. Whether metastasis or recurrence of ovarian cancer is correlated with this association has not been investigated. Data on 894 women with epithelial ovarian cancer were collected and the association between ER or PR positivity and peritoneal or lymph node metastases or recurrence was analysed. ER or PR positivity was higher in high-grade, low-grade serous and endometrioid carcinoma, but lower in mucinous and clear-cell carcinoma. Significantly higher ER or PR positivity was seen in endometrioid carcinoma or high-grade serous carcinoma with peritoneal metastases, respectively, but not other subtypes. In addition, there was no significant difference in ER or PR positivity between cases with and without lymph node metastasis in these five subtypes. In recurrent high-grade serous carcinoma with peritoneal metastases (n = 103), the positivity of ER or PR was 86% and 55% respectively. Our data demonstrate that the association between ER or PR positivity and peritoneal metastases was only seen in endometrioid or high grade serous carcinoma, respectively. There was no association of ER or PR positivity and lymph node metastases. The majority of recurrent high-grade serous carcinoma with peritoneal metastases (86%) were ER positive.

Angiogenesis Analysis by In Vitro Coculture Assays in Transwell Chambers in Ovarian Cancer.

Angiogenesis is an important biological process in tumor growth and metastasis of tumor cells, and it has been associated with poor clinical outcomes in ovarian cancer. In vitro assays are useful tools for understanding the complex mechanisms of angiogenesis under a variety of conditions. Capillary-like formation and transwell migration assays are two of the most common techniques used in angiogenesis research. Here, we show an easy coculture model to study the role of microRNAs on angiogenesis that combines tube formation and cell migration assays. Recently, we reported that miR-204 is repressed in breast cancer and restoration in cancer cell lines results in angiogenesis inhibition. Here, we restored the expression of miR-204 by transfection of precursor molecule in the tumorigenic SKOV3 ovarian cancer cell line, and analyzed the effects in cell migration, invasion, and tube formation of endothelial cells using matrigel-coated transwell chambers.

Significant association of the EXO1 rs851797 polymorphism with clinical outcome of ovarian cancer.

BackgroundExonuclease 1 (EXO1), one of DNA mismatch repair pathway genes, functions in maintaining genomic stability and affects tumor progression. We hypothesized that genetic variations in EXO1 may predict clinical outcomes in epithelial ovarian cancer (EOC).MethodsIn this cohort study with 1,030 consecutive EOC patients, we genotyped four potentially functional polymorphisms in EXO1 by the Taqman assay and evaluated their associations with patients’ survival.ResultsUsing multivariate Cox proportional hazards regression models, we found that rs851797AG/GG genotypes were significantly associated with recurrence and cancer death (HR =1.30 and 1.38, 95% CI =1.11–1.52 and 1.02–1.88, respectively). Kaplan–Meier survival estimates showed that patients who carried rs851797AG/GG genotypes had poorer progression-free survival and poorer overall survival, compared with rs851797AA genotype carriers (log-rank test, P=0.002 and 0.025, respectively). Moreover, patients with older age at menophania, advanced stage tumor, or being received incomplete cytoreduction were more likely to be recurrent and dead.ConclusionEXO1 rs851797 polymorphism can predict the clinical outcomes in EOC patients. In addition, age at menophania, FIGO stage, and complete cytoreduction might be independently prognostic factors of ovarian cancer. Large studies with functional experiments are warranted to validate these findings.

Hormone receptors expression in ovarian cancer taking into account menopausal status: a retrospective study in Chinese population.

Ovarian cancer is a major gynaecological cancer with different subtypes and studies have suggested that estrogen receptor (ER) or progesterone receptor (PR) positivity are associated with better clinical outcomes. Furthermore, the clinical outcomes of ovarian cancer are better in Asian compared to Caucasian. To date, studies investigating the ER or PR positivity in all subtypes of ovarian cancer, including borderline epithelial, are limited. In this retrospective study we investigated ER and PR positivity in Chinese women with malignant epithelial ovarian cancer (n=577), sex cord-stromal tumor (n=26) and borderline epithelial ovarian cancer (n=98) taking into account menopausal status. The positivity of ER (>85%) or PR (>58%) was higher in serous and endometrioid carcinoma of malignant epithelial ovarian cancer than that in mucinous and clear-cell carcinoma (<19% of ER or 24% of PR). The majority of serous carcinomas of borderline epithelial ovarian cancerwere ER or PR positive, but in contrast less than 33% of mucinous carcinomas of borderline epithelial ovarian cancerswere ERor PR positive.Furthermore, there was no association between the ER or PR positivity and menopausal status in both malignant and borderline epithelial ovarian cancer. We also found that the age at diagnosis with ovarian cancer was younger in Chinese women. Our data suggest that ER or PR positivity in Chinese women with ovarian cancer is similar to that of other ethnicities reported in literature, suggesting that the better clinical outcomes seen in Asian may be associated with other factors such as age at diagnosis of ovarian cancer.

Mitochondrial mRNA transcripts predict overall survival, tumor recurrence and progression in serous ovarian cancer: Companion diagnostics for cancer therapy.

Here, we performed a systematic analysis to discover new biomarkers of overall survival and tumor progression in ovarian cancer patients. More specifically, we determined whether nuclear-encoded mitochondrial genes related to mitochondrial biogenesis and function are effective in predicting clinical outcome in ovarian cancer. As a consequence, we are able to provide in silico validation of the prognostic value of these mitochondrial markers, in a well-defined population of ovarian cancer patients. Towards this end, we used a group of N=111 ovarian cancer patients (serous type; stage III), with optimal de-bulking. Importantly, in this group of cancer patients, CA125 and PCNA (conventional markers) were associated with poor overall survival, as would be expected. Using this approach, we identified >100 new individual mitochondrial gene probes that effectively predicted significantly reduced overall survival, with hazard-ratios (HR) of up to 3.68 (p < 9.8e-05). These mitochondrial mRNA transcripts included membrane proteins, chaperones, anti-oxidant enzymes, as well as mitochondrial ribosomal proteins (MRPs) and key members of the OXPHOS (I-V) complexes. Based on this bioinformatics analysis and in silico validation, we conclude that mitochondrial biogenesis and OXPHOS should both be considered as new therapeutic targets, for the more effective treatment of human ovarian cancers. The mitochondrial biomarkers that we have identified could also be employed as new companion diagnostics to assist oncologists in: i) more accurately predicting clinical outcomes and ii) improving the response to therapy, in ovarian cancer patients.