The up-regulation of PAK2 indicates unfavorable prognosis in patients with serous epithelial ovarian cancer and contributes to paclitaxel resistance in ovarian cancer cells.

BACKGROUND: The main challenge in treating ovarian cancer is chemotherapy resistance. Previous studies have shown that PAK2 is highly expressed in various cancers. This research investigates whether increased PAK2 expression contributes to chemo-resistance and poor prognosis in ovarian cancer. METHODS: Initially, bioinformatics analysis was used to assess the importance of PAK2 mRNA up-regulation in ovarian cancer. This was then validated using tissue microarray to confirm PAK2 protein expression and localization in clinical samples. Univariate and multivariate logistic regression analyses were carried out to identify potential risk factors for chemo-resistance in serous epithelial ovarian cancer (EOC), while multivariate Cox regression and Kaplan-Meier analysis were conducted to ascertain prognostic factors for overall survival (OS) and disease-free survival (DFS) in patients with serous EOC. In vitro experiments were conducted to verify if inhibiting PAK2 expression could increase A2780/Taxol cells' sensitivity to paclitaxel, as shown by evaluating cell proliferation, apoptosis, transwell, and clone formation. Additionally, the interaction between PAK2, lnc-SNHG1, and miR-216b-5p was verified using RIP and luciferase reporter assays. Rescue experiments were undertaken to examine the influence of the lnc-SNHG1/miR-216b-5p/PAK2 axis on the development of paclitaxel resistance in A2780/Taxol cells. RESULTS: The bioinformatics analysis indicated a notable increase in PAK2 expression in ovarian malignant tumors compared to adjacent tissues, particularly in patients with stage III-IV disease compared to those with stage I-II disease (P = 0.0056). Elevated levels of PAK2 were linked to reduced OS in ovarian cancer patients, although no significant association was observed with DFS. Immunohistochemistry findings further supported these results, showing positive PAK2 protein expression in chemo-resistant serous EOC tissues, predominantly localized in the cytoplasm, which correlated with poorer OS and DFS outcomes. In vitro experiments demonstrated that the downregulation of PAK2 in A2780/Taxol cells led to a reduction in colony formation, an increase in apoptosis, and a diminished capacity for cell invasion. Subsequent analysis confirmed that lnc-SNHG1 functions as a competitive endogenous RNA (ceRNA) by interacting with miR-216b-5p and regulating PAK2 expression. Rescue experiments demonstrated that lnc-SNHG1 induces resistance to paclitaxel in A2780/Taxol cells by modulating the miR-216b-5p/PAK2 axis. CONCLUSIONS: PAK2 shows promise as a predictor of chemotherapy resistance and poor outcomes in ovarian cancer, indicating its potential use as a treatment target to overcome this resistance.

A novel clinical nomogram for predicting cancer-specific survival in patients with non-serous epithelial ovarian cancer: A real-world analysis based on the Surveillance, Epidemiology, and End Results database and external validation in a tertiary center.

BACKGROUND: Currently, there is a lack of prognostic evaluation methods for non-serous epithelial ovarian cancer (EOC). METHOD: We collected patients with non-serous EOC diagnosed between 2010 and 2017 from the Surveillance, Epidemiology, and End Results (SEER) database into a training cohort (n = 2078) and an internal validation cohort (n = 891). Meanwhile, patients meeting the criteria were screened from the Fujian Provincial Maternal and Child Health Hospital from 2013 to 2022 as an external validation cohort (n = 56). Univariate and multivariable logistic regression were used to determine the independent prognostic factors of cancer-specific survival (CSS) to construct the nomogram. The nomogram was validated by the concordance index (C-index), receiver operating characteristics (ROC) curve and calibration curves. RESULT: Age, laterality, preoperative CA125 status, histologic type, tumor grade, AJCC stage, surgery lesion, number of lymph nodes examined, residual lesion size, and bone metastasis were identified as independent prognostic factors to construct the nomogram. The nomogram showed better predictive ability than FIGO stage through internal and external cohorts validation. The C-index of the nomogram in the training cohort, validation cohort, and external validation cohort were 0.831, 0.835 and 0.944 higher than those of the Federation International of Gynecology and Obstetric (FIGO) stage, P<0.05. The Area Under Curve (AUC) values results indicated great clinical usefulness of the nomogram. The calibration curve indicated good agreement between the nomogram prediction and actual survival. CONCLUSION: We developed a nomogram with high predictive accuracy to predict survival in patients with non-serous EOC.

Real-world Study on the Effect of PARPi as Maintenance Therapy on Platinum Sensitivity after First- and Second-line Chemotherapy in Patients with Recurrent High-grade Serous Epithelial Ovarian Cancer.

BACKGROUND: This study investigated the effect of poly(ADP-ribose) polymerase inhibitors (PARPi) as maintenance therapy after first- and second-line chemotherapy on platinum sensitivity in patients with recurrent high-grade serous epithelial ovarian cancer (rHGSOC). METHODS: This study retrospectively analyzed 172 patients with rHGSOC treated at Zhejiang Cancer Hospital and Jiaxing Maternity and Child Health Care Hospital between January 2017 and December 2021. The 1st-PARPi group comprised patients who received a PARPi as maintenance therapy after first-line chemotherapy (n=23), and the 1st-control group comprised those who did not (n = 105). Similarly, the 2nd-PARPi group comprised patients not given a PARPi in their first-line treatment (n = 30), and the 2nd-control group comprised those who were given a PARPi (n = 89). RESULTS: Among the 23 patients in the 1st-PARPi group and the 105 patients in the 1st-control group, nine and 99 were platinum-sensitive, and 14 and six were platinum-resistant, respectively (hazard ratio [HR]: 14.46, P < 0.0001). Among the 30 patients in the 2nd-PARPi group and 89 patients in the 2nd-control group, 10 and 71 were platinum-sensitive, and 20 and 18 were platinumresistant, respectively (HR: 4.37, P < 0.0001). Age, stage, residual tumor, the courses of platinumbased chemotherapy, and breast cancer susceptibility gene mutations were not associated with platinum sensitivity when using a PARPi as maintenance therapy after first- and second-line chemotherapy. CONCLUSION: Patients with rHGSOC using a PARPi were more likely to be platinum-sensitive and develop platinum resistance independent of PARPi duration. Care should be taken when using a PARPi as maintenance therapy after first- and second-line chemotherapy.

Prognostic Significance of HE4 Tissue Expression in Serous Epithelial Ovarian Carcinoma.

Neerja BhatlaBackground Human Epididymis protein 4 (HE4) is expressed in ovarian cancer. Preoperative serum testing is still not widely available. This pilot study aimed to investigate the magnitude of expression of HE4 in tissue sections of serous epithelial ovarian carcinoma, its correlation with clinical outcome, and the feasibility of HE4 immunohistochemistry as a prognostic marker. Materials and Method In this ambispective study, immunohistochemistry (IHC) was used to evaluate tissue sections of ovarian serous epithelial carcinoma at primary cytoreductive surgery. On HE4 immunohistochemistry (IHC), the magnitude of HE4 expression was assessed categorically as high or low HE4 expression and semiquantitatively by the H-score, and correlated with clinical outcome in terms of survival status, progression-free survival, and overall survival. Results Of 32 cases, most ( n = 31, 96.8%) were positive for HE4 IHC. The mean age was 49 ± 8.2 years; 29 (90.6%) patients were in FIGO stage IIIC; 25 (78.9%) had ≥1cm residual disease after surgery; 31 (96.8%) received adjuvant chemotherapy, either 3-weekly ( n = 25, 81.2%) or dose-dense weekly ( n = 6, 18.8%) regimen. The majority ( n = 31, 96.8%) had a high-grade tumor, of whom 19 (59.4%) had high HE4 expression and 13(40.6%) patients had H-score in the range of 5 to 8. The mean H-score was 6.97 ± 3.61 (range 0 to 12). The overall survival of the study population at 64 months was 36.65% (95% CI: 8.59-66.34), with median overall survival of 59 months. A new scoring system was developed combining categorical HE4 expression and serum CA-125 levels; the combination of HE4 expression with postoperative CA-125 levels was found to be the best prognostic marker for overall survival ( p = 0.05). A composite score of 2 identified patients with poor progression-free survival (HR 4.64, p = 0.039) and overall survival (HR 5.45, p = 0.05). Conclusion The new composite scoring system using HE4 IHC with postoperative serum CA-125 levels offers an extremely useful option for prognosticating patients with serous epithelial ovarian carcinoma than serum CA-125 alone. This is useful where preoperative records are not available to the treating clinician.

The Value of Magnetic Resonance Diffusion-Weighted Imaging and Dynamic Contrast Enhancement in the Diagnosis and Prognosis of Treatment Response in Patients with Epithelial Serous Ovarian Cancer.

Background. The aim of our study was to describe the selected parameters of diffusion-weighted imaging (DWI) and perfusion dynamic contrast enhancement (DCE) MRI in primary tumors in patients with serous epithelial ovarian cancer (EOC), as well as in disease course prognosis and treatment response, including bevacizumab maintenance therapy. Materials and Methods. In total, 55 patients with primary serous EOC were enrolled in the study. All patients underwent MR imaging using a 1.5 T clinical whole-body MR system in preoperative DWI and DCE MRI selected parameters: apparent diffusion coefficients (ADC), time to peek (TTP) and perfusion maximum enhancement (Perf. Max. En.) were measured. The data were compared with histopathological and immunochemistry results (with Ki67 and VEGF expression) and clinical outcomes. Results. Higher mean ADC values were found in low-grade EOC compared to high-grade EOC: 1151.27 vs. 894,918 (p < 0.0001). A negative correlation was found between ADC and Ki67 expression (p = 0.027), and between ADC and VEGF expression (p = 0.042). There was a negative correlation between TTP and PFS (p = 0.0019) and Perf. Max. En. and PSF (p = 0.003). In the Kaplan−Meier analysis (log rank), a longer PFS was found in patients with ADC values greater than the median; p = 0.046. The Kaplan−Meier analysis showed a longer PFS (p = 0.0126) in a group with TTP below the mean value for this parameter in patients who received maintenance treatment with bevacizumab. Conclusions. The described relationships between PFS and DCE and DWI allow us to hope to include these parameters in the group of EOC prognostic factors. This aspect seems to be of particular interest in the case of the association of PFS with DCE values in the group of patients treated with bevacizumab.

Liquid Biopsy in the Clinical Management of High-Grade Serous Epithelial Ovarian Cancer-Current Use and Future Opportunities.

The lack of a sensitive and specific biomarker and the limits relating to the single primary tumor sampling make it difficult to monitor high-grade serous epithelial ovarian cancer (HGS-EOC) over time and to capture those alterations that are potentially useful in guiding clinical decisions. To overcome these issues, liquid biopsy has emerged as a very promising tool for HGS-EOC. The analysis of circulating tumor DNA appears to be feasible and studies assessing specific pathogenic mutations (i.e., TP53) or copy number alterations have shown a sufficient degree of sensitivity and specificity to be realistically used to monitor the effectiveness of antitumor therapy. Liquid biopsy can also provide potential important information on the mechanisms of sensitivity and resistance, e.g., by the determination of the reversion of BRCA mutations. Perspective studies are needed to test whether the application of liquid biopsy will significantly improve HGS-EOC management and patients' survival.

Dense hyperthermic intraperitoneal chemotherapy with cisplatin in patients with stage III serous epithelial ovarian cancer: a retrospective study.

BACKGROUND: To investigate the efficacy and safety of interval debulking surgery (IDS) combined with dense hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin in Chinese patients with FIGO stage III serous epithelial ovarian cancer (EOC). METHODS: This retrospective single-center study reviewed the demographic and clinical data of 197 patients with primary FIGO stage III serous EOC who were treated with IDS with (n = 121) or without (n = 76, control group) dense HIPEC between January 2012 and April 2017. The co-primary endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoint was the occurrence of adverse events. RESULTS: The median PFS was 24 months in the IDS plus dense HIPEC group, whereas it was 19 months in the IDS alone group (hazard ratio [HR] 0.46, 95% confidence interval [CI]: 0.33-0.65, p = 0.000). The median OS in patients treated with IDS plus dense HIPEC (51 months) was significantly longer than that in patients treated with IDS alone (40 months, HR 0.52, 95% CI: 0.35-0.78, p = 0.001). The demographic and preoperative clinical characteristics of these two groups were comparable (p > 0.05). In the IDS alone group, no adverse events were recorded in 42 (55.3%) of the 76 patients, and 14 (18.4%) patients were reported to have grade III/IV adverse events. In the IDS plus dense HIPEC group, no adverse events were recorded in 55 (45.5%) of the 121 patients, and 23 (19.0%) patients were reported to have grade III/IV adverse events. No postoperative deaths occurred within 30 days in either group and neither did severe fatal complications in the IDS plus dense HIPEC group. CONCLUSIONS: IDS plus dense HIPEC with cisplatin in Chinese patients with FIGO stage III serous EOC is associated with improved survival and is reasonably well tolerated by patients.

Dysregulation of lnc-SNHG1 and miR-216b-5p correlate with chemoresistance and indicate poor prognosis of serous epithelial ovarian cancer.

AIM: This study aimed to explore whether the dysregulation of lnc-small nucleolar RNA host gene 1 (SNHG1) and miR-216b-5p correlated with chemoresistance and indicated poor prognosis of serous epithelial ovarian cancer (EOC). METHODS AND RESULTS: The expression of lnc-SNHG1 was upregulated, while miR-216b-5p showed low expression in patients with chemoresistant EOC compared with patients with chemosensitive EOC. The multivariate Cox regression analysis showed that the expression of miR-216b-5p and FIGO stage were independent prognostic factors for the overall survival (OS) of patients with serous EOC. Kaplan-Meier curves revealed a significant association of the increased expression level of lnc-SNHG1 with shorter OS and disease-free survival (DFS). Patients with a low expression level of miR-216b-5p also had shorter OS and DFS. The biological functions were tested using CCK-8 assay, colony formation assay, wound healing assay, and cell apoptosis. The knockdown of SNHG1 and the overexpression of miR-216b-5p stimulated paclitaxel sensitivity in A2780/Taxol cells through inhibiting cell growth and migration and promoting apoptosis. The inhibition of miR-216b-5p could rescue the effect of lnc-SNHG1 inhibition on the sensitivity of A2780/Taxol cells to paclitaxel. Luciferase reporter assay, RNA Binding Protein Immunoprecipitation Assay (RIP), and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) indicated that lnc-SNHG1 acted as a sponge of miR-216b-5p in A2780/Taxol cells. CONCLUSIONS: This study showed that the overexpression of lnc-SNHG1 and decreased expression level of miR-216b-5p correlated with the chemoresistance of patients with serous EOC and indicated shorter OS and DFS. Lnc-SNHG1 functioned as a ceRNA with miR-216b-5p, which was critical in modulating the paclitaxel sensitivity of ovarian cancer cells.

DEAD-Box Helicase 4 (Ddx4)+ Stem Cells Sustain Tumor Progression in Non-Serous Ovarian Cancers.

DEAD-Box Helicase 4 (Ddx4)+ ovarian stem cells are able to differentiate into several cell types under appropriate stimuli. Ddx4 expression has been correlated with poor prognosis of serous ovarian cancer (OC), while the potential role of Ddx4+ cells in non-serous epithelial OC (NS-EOC) is almost unexplored. The aim of this study was to demonstrate the presence of Ddx4+ cells in NS-EOC and investigate the effect of follicle-stimulating hormone (FSH) on this population. Increased Ddx4 expression was demonstrated in samples from patients with advanced NS-EOC, compared to those with early-stage disease. Under FSH stimulation, OC-derived Ddx4+ cells differentiated into mesenchymal-like (ML) cells, able to deregulate genes involved in cell migration, invasiveness, stemness and chemoresistance in A2780 OC cells. This effect was primarily induced by ML-cells deriving from advanced NS-EOC, suggesting that a tumor-conditioned germ cell niche inhabits its microenvironment and is able to modulate, in a paracrine manner, tumor cell behavior through transcriptome modulation.

Expression profiles of PRKG1, SDF2L1 and PPP1R12A are predictive and prognostic factors for therapy response and survival in high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGS-EOCs) is generally sensitive to front-line platinum (Pt)-based chemotherapy although most patients at an advanced stage relapse with progressive resistant disease. Clinical or molecular data to identify primary resistant cases at diagnosis are not yet available. HGS-EOC biopsies from 105 Pt-sensitive (Pt-s) and 89 Pt-resistant (Pt-r) patients were retrospectively selected from two independent tumor tissue collections. Pathway analysis was done integrating miRNA and mRNA expression profiles. Signatures were further validated in silico on a cohort of 838 HGS-EOC cases from a published dataset. In all, 131 mRNAs and 5 miRNAs belonging to different functionally related molecular pathways distinguish Pt-s from Pt-r cases. Then, 17 out of 23 selected elements were validated by orthogonal approaches (SI signature). As resistance to Pt is associated with a short progression-free survival (PFS) and overall survival (OS), the prognostic role of the SI signature was assessed, and 14 genes associated with PFS and OS, in multivariate analyses (SII signature). The prognostic value of the SII signature was validated in a third extensive cohort. The expression profiles of SDF2L1, PPP1R12A and PRKG1 genes (SIII signature) served as independent prognostic biomarkers of Pt-response and survival. The study identified a prognostic molecular signature based on the combined expression profile of three genes which had never been associated with the clinical outcome of HGS-EOC. This may lead to early identification, at the time of diagnosis, of patients who would not greatly benefit from standard chemotherapy and are thus eligible for novel investigational approaches.

Prognostic Significance of Lymph Node Ratio in Ovarian Cancer.

Lymphadenectomy is critical in the clinical prognosis of ovarian cancer patients. Therefore, we assessed whether lymph node ratio (LNR) has predictive value on overall survival (OS) of patients with serous epithelial ovarian cancer (SEOC). A total of 7,815 eligible SEOC patients were identified from the Surveillance, Epidemiology, and End Results (SEER) database, who underwent surgical resection between 1973 and 2013. We used the time-dependent receiver operating characteristic (ROC) curve and the area under curve to determine the optimal cut-off value of LNR. The predictive role of LNR was analyzed by Cox proportional hazards regression model. The effects of LNR and positive lymph nodes (PLN) on OS were evaluated by comparing the time-dependent ROC curves. The time-dependent ROC curves showed that the optimal LNR cut-off value was 42.0% for nodal-positive SEOC. As shown in Kaplan-Meier survival curves, survival was significantly poorer for all patients with LNR≥42.0% (log-rank test: P<0.0001), regardless of the stage. In the multivariate Cox analysis, LNR≥42.0% remained a significant and independent predictor of mortality risk for all patients [hazards ratio: 1.526, 95% confidence interval: 1.415-1.647; P<0.0001], compared with those LNR<42.0%. These results suggest that LNR, rather than the number of PLN or stage, could be regarded as a promising predictor of mortality risk, particularly in stage-III SEOC patients.

Galectin-3 and ß-catenin are associated with a poor prognosis in serous epithelial ovarian cancer.

PURPOSE: This study was designed to explore the expression levels of Galectin-3 (Gal-3) and ß-catenin in serous epithelial ovarian cancer (SEOC), the linkage between their expressions, and the clinicopathological features of SEOC patients. PATIENTS AND METHODS: Seventy-four SEOC patients' specimens were detected for Gal-3 and ß-Catenin expressions using immunohistochemistry, and the association between ß-catenin or Gal-3 protein expressions and clinicopathological features, treatment effects, and prognosis were analyzed using SPSS 19.0. Western blot was used to analyze protein expressions of Wnt/ß-catenin pathway in ovarian cancer cell lines. RESULTS: There was a statistically significant positive correlation between Gal-3 and ß-catenin expressions in SEOC (r=0.304 and P=0.001). Gal-3 expression was related to the grade (P=0.037), clinical stage (P=0.034), platinum resistance (P=0.030), and recurrence (P=0.001) in SEOC. There was a significant correlation between ß-catenin with recurrence in SEOC (P=0.035). Platinum resistance (P=0.003) and Gal-3 expression (P<0.001) were independent risk factors for poorer overall survival (OS). OS of the strongly positive Gal-3 group was significantly lower than that of the negative and weakly positive groups (log-rank test, P=0.001). OS of the positive ß-catenin group was lower than that of the negative ß-catenin group (log-rank test, P=0.034). Downregulating Gal-3 expression attenuated the protein expressions of Wnt/ß-catenin pathway in ovarian cancer cell lines. CONCLUSION: Gal-3 might activate Wnt/ß-catenin signaling pathway in SEOC. Hence, Gal-3 may serve as a prognostic factor for SEOC. Targeting Gal-3 may be a promising new treatment approach for SEOC.

Prognostic implication of the metastatic lesion-to-ovarian cancer standardised uptake value ratio in advanced serous epithelial ovarian cancer.

OBJECTIVES: To evaluate the prognostic value of metabolic activity of metastatic lesions measured by 18F-flurodeoxyglucose (18F-FDG) uptake on preoperative positron emission tomography/computed tomography (PET/CT) in patients with advanced serous epithelial ovarian cancer (EOC). METHODS: Clinico-pathological variables and PET/CT parameters such as the maximum standardised uptake value of the ovarian cancer (SUVovary), metastatic lesions (SUVmeta), and the metastatic lesion-to-ovarian cancer standardised uptake value ratio (SUVmeta/SUVovary) were assessed in International Federation of Gynaecology and Obstetrics (FIGO) stage III, IV patients. RESULTS: Clinico-pathological data were retrospectively reviewed for 94 eligible patients. The median progression-free survival (PFS) was 18.5 months (range, 6-90 months), and 57 (60.6%) patients experienced recurrence. Older age [P = 0.017, hazard ratio (HR) 1.036, 95% CI 1.006-1.066], residual disease after surgery (P = 0.024, HR 1.907, 95% CI 1.087-3.346), and high SUVmeta/SUVovary (P = 0.019, HR 2.321, 95% CI 1.148-4.692) were independent risk factors of recurrence. Patients with high SUVmeta/SUVovary showed a significantly worse PFS than those with low SUVmeta/SUVovary (P = 0.007, log-rank test). CONCLUSIONS: Preoperative SUVmeta/SUVovary was significantly associated with recurrence and has an incremental prognostic value for PFS in patients with advanced serous EOC. KEY POINTS: • The prognostic value of the metabolic activity of metastatic lesions was investigated. • SUVmeta/SUVovary was significantly associated with recurrence of serous EOC. • Preoperative SUVmeta/SUVovary can be a predicator of serous EOC recurrence.

Cumulative defects in DNA repair pathways drive the PARP inhibitor response in high-grade serous epithelial ovarian cancer cell lines.

PARP inhibitors (PARPi), such as Olaparib, have shown promising results in high-grade serous (HGS) epithelial ovarian cancer (EOC) treatment. PARPi sensitivity has been mainly associated with homologous recombination (HR) deficiency, but clinical trials have shown that predicting actual patient response is complex. Here, we investigated gene expression microarray, HR functionality and Olaparib sensitivity of 18 different HGS EOC cell lines and demonstrate that PARPi sensitivity is not only associated with HR defects. Gene target validation show that down regulation of genes in the nucleotide excision repair (NER) and mismatch repair (MMR) pathways (ERCC8 and MLH1, respectively) increases PARPi response. The highest sensitivity was observed when genes in both the HR and either NER or MMR pathways were concomitantly down regulated. Using clinical samples, patients with these concurrent down regulations could be identified. Based on these results, a novel model to predict PARPi sensitivity is herein proposed. This model implies that the extreme responders identified in clinical trials have deficiencies in HR and either NER or MMR.

Size matters: Survival benefit conferred by intratumoral T cells is dependent on surgical outcome, treatment sequence and T cell differentiation.

Outcome of cytoreductive surgery, treatment sequence and the differentiation status of T cells are key factors to take into account when studying the prognostic value of tumor-infiltrating lymphocytes (TIL) in high grade serous ovarian cancer.

Expression of tumor antigens on primary ovarian cancer cells compared to established ovarian cancer cell lines.

In order to select a suitable combination of cancer cell lines as an appropriate source of antigens for dendritic cell-based immunotherapy of ovarian cancer, we analyzed the expression level of 21 tumor associated antigens (BIRC5, CA125, CEA, DDX43, EPCAM, FOLR1, Her-2/neu, MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A10, MAGE-A12, MUC-1, NY-ESO-1, PRAME, p53, TPBG, TRT, WT1) in 4 established ovarian cancer cell lines and in primary tumor cells isolated from the high-grade serous epithelial ovarian cancer tissue. More than 90% of tumor samples expressed very high levels of CA125, FOLR1, EPCAM and MUC-1 and elevated levels of Her-2/neu, similarly to OVCAR-3 cell line. The combination of OV-90 and OVCAR-3 cell lines showed the highest overlap with patients' samples in the TAA expression profile.

Molecular Mechanism Linking BRCA1 Dysfunction to High Grade Serous Epithelial Ovarian Cancers with Peritoneal Permeability and Ascites.

Ovarian cancer constitutes the second most common gynecological cancer with a five-year survival rate of 40%. Among the various histotypes associated with hereditary ovarian cancer, high-grade serous epithelial ovarian carcinoma (HGSEOC) is the most predominant and women with inherited mutations in BRCA1 have a lifetime risk of 40-60%. HGSEOC is a challenge for clinical oncologists, due to late presentation of patient, diagnosis and high rate of relapse. Ovarian tumors have a wide range of clinical presentations including development of ascites as a result of deregulated endothelial function thereby causing increased vascular permeability of peritoneal vessels. The molecular mechanisms remain elusive. Studies have shown that fallopian tube cancers develop in women with BRCA1 gene mutations more often than previously suspected. Recent studies suggest that many primary peritoneal cancers and some high-grade serous epithelial ovarian carcinomas actually start in the fallopian tubes. In this article we have addressed the molecular pathway of a recently identified potential biomarker Ubc9 whose deregulated expression due to BRCA1 dysfunction can result in HGSEOC with peritoneal permeability and formation of ascites. We also discuss the role of downstream targets Caveolin-1 and Vascular Endothelial Growth Factor (VEGF) in the pathogenesis of ascites in ovarian carcinomas. Finally we hypothesize a signaling axis between Ubc9 over expression, loss of Caveolin-1 and induction of VEGF in BRCA1 mutant HGSEOC cells. We suggest that Ubc9-mediated stimulation of VEGF as a novel mechanism underlying ovarian cancer aggressiveness and ascites formation. Agents that target Ubc9 and VEGF signaling may represent a novel therapeutic strategy to impede peritoneal growth and spread of HGSEOC.

Sox2 gene amplification significantly impacts overall survival in serous epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer. Recently, the existence of ovarian cancer stem cells has been reported. Sox2, Nanog and Oct4 are key markers of "stemness". The objective of this study was to determine whether Sox2, Nanog, and Oct4 are associated with EOC and poor outcome. The expression of these markers was assessed by immunofluorescence staining and real-time RT-PCR in human EOC cell lines MDAH-2774 and SKOV-3, while the cancer genome atlas (TCGA) dataset was analyzed for associations with survival. Sox2, Nanog and Oct4 (POU5F1) were all detected by immunofluorescence staining and these results were confirmed by real-time RT-PCR. The TCGA dataset revealed a 26%, 9%, and 6% amplification of Sox2, Nanog and POU5F1, respectively. Additionally, K-M survival analyses showed a significant median overall survival difference (41 versus 48.3 months, P = .01) for Sox2 amplification, but not for Nanog (44.1 versus 36.2 months, P > .05) and POU5F1 (43.5 versus 45.0 months, P > .05). Our results suggest that Sox2 gene amplification significantly influences overall survival.

Culture models to define key mediators of cancer matrix remodeling.

High grade serous epithelial ovarian cancer (HG-SOC) is one of the most devastating gynecological cancers affecting women worldwide, with a poor survival rate despite clinical treatment advances. HG-SOC commonly metastasizes within the peritoneal cavity, primarily to the mesothelial cells of the omentum, which regulate an extracellular matrix rich in collagens type I, III, and IV along with laminin, vitronectin, and fibronectin. Cancer cells depend on their ability to penetrate and invade secondary tissue sites to spread, however a detailed understanding of the molecular mechanisms underlying these processes remain largely unknown. Given the high metastatic potential of HG-SOC and the associated poor clinical outcome, it is extremely important to identify the pathways and the components of which that are responsible for the progression of this disease. In vitro methods of recapitulating human disease processes are the critical first step in such investigations. In this context, establishment of an in vitro "tumor-like" micro-environment, such as 3D culture, to study early disease and metastasis of human HG-SOC is an important and highly insightful method. In recent years, many such methods have been established to investigate the adhesion and invasion of human ovarian cancer cell lines. The aim of this review is to summarize recent developments in ovarian cancer culture systems and their use to investigate clinically relevant findings concerning the key players in driving human HG-SOC.

Recent technological advances in using mouse models to study ovarian cancer.

Serous epithelial ovarian cancer (SEOC) is the most lethal gynecological cancer in the United States with disease recurrence being the major cause of morbidity and mortality. Despite recent advances in our understanding of the molecular mechanisms responsible for the development of SEOC, the survival rate for women with this disease has remained relatively unchanged in the last two decades. Preclinical mouse models of ovarian cancer, including xenograft, syngeneic, and genetically engineered mice, have been developed to provide a mechanism for studying the development and progression of SEOC. Such models strive to increase our understanding of the etiology and dissemination of ovarian cancer in order to overcome barriers to early detection and resistance to standard chemotherapy. Although there is not a single model that is most suitable for studying ovarian cancer, improvements have led to current models that more closely mimic human disease in their genotype and phenotype. Other advances in the field, such as live animal imaging techniques, allow effective monitoring of the microenvironment and therapeutic efficacy. New and improved preclinical mouse models, combined with technological advances to study such models, will undoubtedly render success of future human clinical trials for patients with SEOC.