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Anti Proliferative and Apoptotic Activities of Müllerian Inhibiting Substance Combined with Calcitriol in Ovarian Cancer Cell Lines

Anti Proliferative and Apoptotic Activities of Müllerian Inhibiting Substance Combined with Calcitriol in Ovarian Cancer Cell Lines

MISRII is expressed in ovarian cancer cell lines Before evaluating the response of OCa cells to MIS, we first de- termined whether the cells expressed MISRII. Thus, expression of MISRII was examined in SKOV3, OVCAR3, and OVCA433 cell lines by western blot analysis, using a rabbit polyclonal an- tihuman MISRII antiserum. All cell lines showed specific stain- ing for MISRII, although expression in OVCAR3 was higher than in SKOV3 and OVCA433 (data not shown).

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miRNA expression profiling in formalin-fixed paraffin-embedded endometriosis and ovarian cancer samples

miRNA expression profiling in formalin-fixed paraffin-embedded endometriosis and ovarian cancer samples

In this study, we have demonstrated that miRNAs are aber- rantly expressed in endometriosis versus normal tissue and ovarian cancer versus normal tissue, and we were also able to identify a panel of miRNAs that are differentially expressed in ovarian cancer versus endometriosis tissue, the details of which can be observed in Figures 1 and S1. Thus, miRNAs can be used as prognostic and diagnostic markers, empha- sizing the functional differences that are able to regulate the key processes. The global miRNA expression pattern might undoubtedly discriminate endometriosis from normal tissue, ovarian cancer from normal tissue and also ovarian cancer from endometriosis tissue. The analysis has detected impor- tant number of miRNAs with an altered expression pattern being involved in malignant transformation. For qRT-PCR validated miRNAs, good sensitivity and specificity can be observed from ROC curves, in particular for ovarian cancer pathology. These panels of miRNAs can be taken into Table 3 IPA analysis based on altered miRNA pattern in the

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TGFBI promoter hypermethylation correlating with paclitaxel chemoresistance in ovarian cancer

TGFBI promoter hypermethylation correlating with paclitaxel chemoresistance in ovarian cancer

Human SKOV3, A2780 and OVCAR8 ovarian cancer cell lines were obtained from the bioengineering centre of The Affiliated Hospital of Medical College, Qingdao University, China. The chemoresistant cell lines (SKOV3/ DDP, SKOV3/TR, and A2780/TR) were purchased from the China Center for Type Culture Collection (Wuhan, China). These cells were maintained in DMEM with 10% fetal bovine serum and 100 U/ml penicillin/streptomycin at 37°C. SKOV3/TR and A2780/TR were cultured in RPMI-1640 medium containing 0.3 μ mol/L paclitaxel to maintain the drugresistant phenotype.

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Nuclear survivin expression is a positive prognostic factor in taxane-platinum-treated ovarian cancer patients

Nuclear survivin expression is a positive prognostic factor in taxane-platinum-treated ovarian cancer patients

chemotherapy was evaluated retrospectively according to the World Health Organisation response evaluation criteria [31]. The evaluation was based on data from medical records describing patient ’ s clinical condition and CA125 levels in 3-4 week intervals. Complete remission (CR) was defined as disappearance of all clini- cal and biochemical symptoms of ovarian cancer evalu- ated after completion of first-line chemotherapy and confirmed at four weeks. Within the CR group, we iden- tified a platinum-sensitive group (PS, disease-free survi- val longer than six months) and a highly platinum- sensitive group (HPS, disease-free survival longer than 24 months). Other tumours were described as platinum resistant [32].

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Original Article Dihydrofolate reductase as a predictor for poor response to platinum-based chemotherapy in epithelial ovarian cancer

Original Article Dihydrofolate reductase as a predictor for poor response to platinum-based chemotherapy in epithelial ovarian cancer

Previous studies supported that elevated expression of folate-dependent proteins was involved in chemotherapy resistance, such as thymidylate synthase [18], DHFR [19] and phosphoribosylglycinamide formyltransferase (GART) [20], which is crucial for cell replication. The platinum-based chemotherapy resistant cell lines also showed increased DNA replica- tion and repair activity [21]. The transformation of folate and 7, 8 dihydrofolate (DHF) into 5, 6, 7, 8 tetrahydrofolate (THF) is dependent on the catalytic activity of DHFR, which is an essential step in the synthesis of DNA nucleic acid bases [7]. In this study, we provided further evidence that folate-dependent proteins are involved in chemotherapy resistance and disease progres- sion of ovarian cancer. We identified that ele- vated mRNA levels of DHFR2, rather than DHFR1, was positively correlated with increased chemotherapy resistance. Furthermore, no sig- nificant correlation was observed between dis- ease progression and thymidylate synthase or GART mRNA levels (data not show). Further studies are still needed for the different func- tional role of DHFR variants, DHFR1 and 2, in disease progression of ovarian cancer, espe- cially in chemotherapy resistance.

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Meeting report from the 2018 12th Biennial Ovarian Cancer Research Symposium detection and prevention of ovarian cancer

Meeting report from the 2018 12th Biennial Ovarian Cancer Research Symposium detection and prevention of ovarian cancer

Dr Naoko Sasamoto (Brigham and Women’s Hospital) and colleagues presented their efforts on improving the efficiency and accuracy of using CA125 as a prediction method. They hypothesized that the distinct personal characteristics among individuals contrib- uted to the low specificity of CA125 as an ovarian cancer screening biomarker. Thus they proposed to identify personal characteristics that influence CA125 levels in order to create personalized thresh- olds for CA125, thereby improving its performance as an ovarian cancer screening biomarker. They conducted internal and external validation of two prediction models (linear and dichotomous) of circulating CA125 among post-menopausal women using 28 842 controls without ovarian cancer in four large population-based studies. Although both models appeared to provide some improve- ment to the CA125 method, a further fine-tuning of these models is required to increase the predictive ability of these models.

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Plasma levels of lysophosphatidic acid in ovarian cancer versus controls: a meta-analysis

Plasma levels of lysophosphatidic acid in ovarian cancer versus controls: a meta-analysis

Ovarian cancer (OC) is the deadliest among gynecological cancers, with 5-year survival rates ranging between 30-50 %. OC is not a single disease but is a collection of diverse tumors with distinct morphologies and genetic deficiencies. The pathogenesis of OC is not well charac- terized, but most OCs occurs spontaneously, with only 5-10 % of the cases linked to a genetic predisposition. According to the latest estimates, OC is the 7 th most common cancer worldwide, and the age-standardized incidence rates range from more than 11 per 100,000 women in central and eastern Europe to less than 5 per 100,000 in parts of Africa, and is the eighth most

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Ovarian cancer cell invasiveness is associated with discordant exosomal sequestration of Let 7 miRNA and miR 200

Ovarian cancer cell invasiveness is associated with discordant exosomal sequestration of Let 7 miRNA and miR 200

stability. Most importantly, exosomes are being secreted from living tumour cells and are distinct from apoptotic cell-derived microvesicles [8]. As exosomes contain cellu- lar protein and RNA molecules in cell type-specific man- ner, they may provide extensive information about the signature of the tumour [9]. Exosomes have been reported to express a diverse range of cell surface receptors, pro- teins (including, heat shock proteins, cytoskeletal proteins, adhesion molecules, membrane transport and fusion pro- teins) and miRNA with the potential to affect the acute and long-term function of the cells with which they inter- act. miRNA is a class of small (approximately 22 nt long), non-coding RNAs that negatively regulate gene expression by binding to the 3′ untranslated region of target mRNAs [10,11]. Once the miRNA is bound, the target messenger RNA (mRNA) is either cleaved for degradation or its translation is inhibited [12]. miRNAs are evolutionary conserved across species, reinforcing the vast influence of miRNAs on essential biological processes such as differen- tiation, proliferation, apoptosis [10,12,13]. Deregulation of these miRNAs will not only impact normal physiological processes but also implicated in diseases including cancer. Previous studies have established the significant difference in ovarian cancer miRNA profiles, reinforcing miRNA as a promising cancer biomarker, most studies, however, have examined the miRNA profile of tumour tissues. The collection of tissue samples is an invasive procedure and unsuitable for a diagnostic and screening tests. The utility of cell-free miRNA in biofluids has been investigated as a source of cancer biomarkers. Although this approach overcomes the issue of sample collection, the question remains on how miRNAs are released and avoid degrad- ation. Currently, limited data are available on the mechan- ism of free miRNA release. The origin of these miRNAs remains unclear and they may be released from apoptotic cells. If this is the case, free miRNAs may not be a useful indicator of tumours state and/or progression.

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Response to microtubule-interacting agents in primary epithelial ovarian cancer cells

Response to microtubule-interacting agents in primary epithelial ovarian cancer cells

is sufficient to arrest approximately 50% of the p53 −/− cells SKOV3, while a higher dosage of 50 nM is neces- sary to noticeably arrest cell cycle of the majority of the p53 + cells Hey. Interestingly, when cell cycle response to EpoB of the primary ovarian cancer cell line SS6 bearing mutation on p53 (Figure 2B) is compared to the re- sponse of the immortalized p53 −/− null cell line SKOV3 also carrying p53 mutations (Figure 3), an opposite effect can be observed. In fact, while SS6 primary cells are not affected by EpoB treatment, SKOV3 cell cycle is arrested by as low as 4 nM of the drug. Additionally, the primary cells SS4 and the immortalized cell line Hey, despite both carrying wild-type p53 sequences, show different sensitivity to EpoB, as SS4 cell cycle is arrested by lower concentrations compared to Hey cells. Altogether these data show that primary ovarian cancer cells freshly iso- lated from patients can be differently affected by chemo- therapeutic drugs compared to immortalized cell lines that are commonly used as in vitro models for human ovarian cancers. We therefore can speculate that pri- mary human ovarian cancer cell lines generated as we described may provide clinically relevant models more suitable for investigation of the in vitro biological char- acteristics of ovarian cancers, which in turn may lead to the discovery of new therapies for these tumors.

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A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.

A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.

(UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; MAY: National Institutes of Health (R01-CA122443, P30-CA15083, P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; MCC: Cancer Council Victoria, National Health and Medical Research Council of Australia (NHMRC) grants number 209057, 251533, 396414, and 504715; MDA: DOD Ovarian Cancer Research Program (W81XWH-07-0449); MEC: NIH (CA54281, CA164973, CA63464); MOF: Moffitt Cancer Center, Merck Pharmaceuticals, the state of Florida, Hillsborough County, and the city of Tampa; NCO: National Institutes of Health (R01-CA76016) and the Department of Defense (DAMD17-02-1-0666); NEC: National Institutes of Health R01-CA54419 and P50-CA105009 and Department of Defense W81XWH-10-1-02802; NHS: UM1 CA186107, P01 CA87969, R01 CA49449, R01- CA67262, UM1 CA176726; NJO: National Cancer Institute (NIH-K07 CA095666, R01-CA83918, NIH-K22- CA138563, P30-CA072720, and P30-CA008748) and the Cancer Institute of New Jersey; NOR: Helse Vest, The Norwegian Cancer Society, The Research Council of Norway; NTH: Radboud University Medical Centre; OPL: National Health and Medical Research Council (NHMRC) of Australia (APP1025142) and Brisbane Women's Club; ORE: OHSU Foundation; OVA: This work was supported by Canadian Institutes of Health Research grant (MOP-86727) and by NIH/NCI 1 R01CA160669-01A1; PLC: Intramural Research Program of the National Cancer Institute; POC: Pomeranian Medical University; POL: Intramural

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MiR-1207 overexpression promotes cancer stem cell–like traits in ovarian cancer by activating the Wnt/β-catenin signaling pathway

MiR-1207 overexpression promotes cancer stem cell–like traits in ovarian cancer by activating the Wnt/β-catenin signaling pathway

While little is known of miR-1207 in human cancers, a study by Chen L et al. suggested that miR- 1207 suppresses gastric cancer growth and invasion by targeting telomerase reverse transcriptase. In our study, we found that miR-1207 was significantly overexpressed in ovarian cancer. Furthermore, ectopic expression of miR- 1207 induced, whereas repression of endogenous miR- 1207 reduced ovarian CSC-like trait via directly targeting SFRP1, AXIN2, and ICAT, three essential negative regulators of Wnt/β-catenin signaling pathway. More importantly, the in vivo model revealed that expression of miR-1207 was in positive relation with the rate of tumor formation and in inverse correlation with prognosis of ovarian cancer patients. These findings reveal that miR-1207 might act as a bio-marker for predicting the prognosis and progression of patients with ovarian cancer.

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<p>Parity as a Prognostic Factor in Patients with Advanced-Stage Epithelial Ovarian Cancer</p>

<p>Parity as a Prognostic Factor in Patients with Advanced-Stage Epithelial Ovarian Cancer</p>

The study protocol was approved by the Ethics Committee for Research of Shiraz University of Medical Sciences (SUMS) (protocol number: 8910-01-01-93). The study protocol was conducted in compliance with the Declaration of Helsinki. All patients had given written informed consent to allow the collection of personal and clinical data retrospectively. The medical records of newly diagnosed patients with con fi rmed EOC at Motahari Clinic, a tertiary referral center for all women with ovarian cancer in the south of Iran, from January 1, 2001, to December 31, 2016, were retrospectively reviewed. The following cases were excluded from the study: non-analyzable patients, patients with non- epithelial ovarian cancer, with tumors with an unknown

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Clinical epidemiology of epithelial ovarian cancer in the UK

Clinical epidemiology of epithelial ovarian cancer in the UK

Abstract: Epithelial ovarian cancer is the fifth commonest cancer among women and the leading cause of gynecological cancer death in the UK. Most women present with advanced disease, mainly because the nonspecific nature of the symptoms lead to diagnostic delays. Recent data have shown a fall in ovarian cancer mortality rates in the UK, but rates are still higher when compared to other European countries or the USA. In addition, surgeons in the UK achieve on average lower optimal surgical cytoreduction rates in patients with advanced ovarian cancer. Despite a wealth of information on epidemiological risk factors, the pathogenesis of epithelial ovarian cancer remains largely unknown. This review presents the most recent data on inci- dence, mortality, and survival for epithelial ovarian cancer in the UK. Time trends, trends by age, international comparisons, and regional variation in incidence, survival, and mortality are presented within the context of a major reorganization of cancer services that took place in the UK over 10 years ago. Centralization of cancer services has meant that women with ovarian cancer receive treatment in specialist Cancer Centers.

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SHP2 overexpression enhances the invasion and metastasis of ovarian cancer in vitro and in vivo

SHP2 overexpression enhances the invasion and metastasis of ovarian cancer in vitro and in vivo

According to the results of the transwell assays, cell invasion and migration were markedly increased in ovarian cancer cells overexpressing SHP2 compared with control cells. In addition, SHP2 overexpression enhanced cell pro- liferation and promoted colony formation in the MTT and colony formation assays, indicating that SHP2 stimulates the growth of ovarian cancer cells. We evaluated the effect of SHP2 overexpression on tumorigenesis using a nude mouse xenograft tumor model to further confirm the impact of SHP2 on ovarian cancer cell growth and found that SHP2 overex- pression promoted tumor growth in nude mice. In conclusion, SHP2 overexpression inhibits apoptosis and promotes the proliferation, invasion, in vivo tumorigenicity, and metastasis of ovarian cancer; moreover, SHP2 expression is associated with ovarian tumor differentiation. In addition, the effects of SHP2 overexpression on ovarian cancer are mediated by the activation of the PI3K/AKT signaling pathway. On the basis of our results, SHP2 might be involved in the development of ovarian cancer, and these findings might facilitate the development of novel strategies for the treatment of drug- resistant ovarian cancer and provide novel insights into the role of SHP2 in cancer.

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Preclinical activity of melflufen (J1) in ovarian cancer

Preclinical activity of melflufen (J1) in ovarian cancer

Ovarian cancer carries a significant mortality. Since symptoms tend to be minimal, the disease is often diagnosed when peritoneal metastases are already present. The standard of care in advanced ovarian cancer consists of platinum-based chemotherapy combined with cytoreductive surgery. Unfortunately, even after optimal cytoreduction and adjuvant chemotherapy, most patients with stage III disease will develop a recurrence. Intraperitoneal administration of chemotherapy is an alternative treatment for patients with localized disease. The pharmacological and physiochemical properties of melflufen, a peptidase potentiated alkylator, raised the hypothesis that this drug could be useful in ovarian cancer and particularily against peritoneal carcinomatosis. In this study the preclinical effects of melflufen were investigated in different ovarian cancer models. Melflufen was active against ovarian cancer cell lines, primary cultures of patient-derived ovarian cancer cells, and inhibited the growth of subcutaneous A2780 ovarian cancer xenografts alone and when combined with gemcitabine or liposomal doxorubicin when administered intravenously. In addition, an intra- and subperitoneal xenograft model showed activity of intraperitoneal administered melflufen for peritoneal carcinomatosis, with minimal side effects and modest systemic exposure. In conclusion, results from this study support further investigations of melflufen for the treatment of peritoneal carcinomatosis from ovarian cancer, both for intravenous and intraperitoneal administration.

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Original Article MicroRNA-153 regulated AKT1 expression and suppressed cell proliferation of epithelial ovarian cancer cells

Original Article MicroRNA-153 regulated AKT1 expression and suppressed cell proliferation of epithelial ovarian cancer cells

In order to investigate the role of miR-153 in ovarian cancer, the expression levels of miR- 153 were first determined in 20 pairs of human ovarian cancer tissues and adjacent normal tis- sues using Real-time quantitative PCR. The results of RT-PCR shown that miR-153 levels was decreased in the 18 patients (18/20, 90.0%) (Figure 1A). The results also indicated that the expression levels of miR-153 were sig- nificantly lower in the EOC tissues than in the adjacent normal tissues (Figure 1B). Furth- ermore, we detected the expression levels of miR-153 in human normal epithelial ovarian cell line HOSEpiC and human ovarian carcino- ma cell lines. We found the expression level of miR-153 was significantly lower in the EOC cells than that in HOSEpiC cells (Figure 1C). In fur- ther experiments, the A2780 cell line was selected for the research object because the level of miR-153 in this cell line is the lowest. These findings indicate that the expression of miR-153 is down-regulated in EOC tissues and cell lines.

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Association between the ERCC1 polymorphism and platinum-based chemotherapy effectiveness in ovarian cancer: a meta-analysis

Association between the ERCC1 polymorphism and platinum-based chemotherapy effectiveness in ovarian cancer: a meta-analysis

Statistical analyses were conducted with Stata 13.0 (College Station, TX). Hardy-Weinberg Equilibrium (HWE) was performed in controls by asymptotic Pearson’s Chi-square test for each polymorphism in each study. The association between polymorphism and platinum-based chemotherapy effectiveness in ovarian cancer was estimated with odds ratios (OR) and corre- sponding 95% confidence intervals (CIs). Between stud- ies heterogeneity was tested using Q test and I2 test, and the heterogeneity was considered significant if P-value was less than 0.05. Fixed-effects model was adopted when P-value was more than 0.05; otherwise random- effects model was used [12]. The publication bias was evaluated using Begg’s test, Egger’s test and Harbord’s test [13–15]. P < 0.05 was considered statistically significant.

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Development and evaluation of an ELISA method for the measurement of kallikrein related peptidase 5 (KLK5) in human serum

Development and evaluation of an ELISA method for the measurement of kallikrein related peptidase 5 (KLK5) in human serum

KLK5 has been shown to be differentially expressed at the mRNA and the protein levels in many endocrine- related malignancies, including ovarian, breast, and tes- ticular cancer, and that it has the potential to be a new cancer biomarker [13-16]. The KLK5’s presence in bio- logical fluids, such as in the serum of patients with ovar- ian cancer, has already been measured [17]. High levels were also detected in ascites fluid from metastatic ovar- ian cancer patients and in ovarian cancer tissue extracts. 67% of patients with ovarian cancer had elevated KLK5 levels in serum [16]. KLK5 is significantly elevated in ovarian cancer tissues compared with low-malignant- potential (LMP) tumors. High KLK5 tumor tissue levels are associated with advanced stage of the disease and significantly shorter progression-free survival and overall survival. The present study focus on evaluating the KLK5 as new serum biomarker in ovarian cancer, which may serve as a screening tool, may allow assessment of prog- nosis in patients with ovarian cancer and may be as a potential new target for therapy [13,18].

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Ubiquitin E3 ligase MARCH7 promotes ovarian tumor growth

Ubiquitin E3 ligase MARCH7 promotes ovarian tumor growth

MARCH7 was crucial for the progress of ovarian cancer. Elevation of β-catenin in the cytosol and the nucleus can occur independently through various pathways [25, 26]. Furthermore, β-catenin is a central factor in canonical Wnt signaling [27]. We found that ectopic expression of MARCH7 in ovarian cancer A2780 cells increased the expression of β-catenin in the cytoplasm and promote its translocation to the nucleus. Downregulation of MARCH7 in ovarian cancer SKOV3 cells decreased the expression of β-catenin in the cytoplasm and repressed its translocation to the nucleus. These results confirmed that MARCH7 promoted β-catenin translocation to the nucleus in ovarian cancer cells. Once within the nucleus, β-catenin regulates expression of genes involved in the activation of the Wnt/β-catenin signaling pathway, including sp5, lef1 and c-myc. We had shown that MARCH7 upregulated β-catenin, therefore, to test whether MARCH7 may also be implicated in regulating the Wnt/β-catenin pathway, we investigated its regulatory effect on TopFlash reporter activity, sp5, lef1 and c-myc. Our results showed that MARCH7 mediated TopFlash reporter activity and expression of sp5, lef1, and c-myc mRNA. Based on these findings, we concluded that MARCH7 participated in Wnt/ β-catenin signaling in human ovarian cancer cells.

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First in man application of a novel therapeutic cancer vaccine formulation with the capacity to induce multi functional T cell responses in ovarian, breast and prostate cancer patients

First in man application of a novel therapeutic cancer vaccine formulation with the capacity to induce multi functional T cell responses in ovarian, breast and prostate cancer patients

Our novel cancer vaccine DPX-0907 contains a polynucleotide-based adjuvant and a universal T helper peptide, along with seven HLA-A2 restricted peptides derived from tumor-associated antigens. These antigens are involved in multiple, critical cancer pathways such as tissue invasion and metastasis (P5; Integrin β8 subunit precursor, P14; Junction plakoglobin and P15; EDDR1), evading apoptotic cell death (P3; BAP31) and providing the ability to resist anti-growth signals (P7; Abl binding protein C3) [5-9], with resultant specific immune responses expected to reduce the chance for progression of tumor escape variants [9,10]. These peptides were among 16 described using mass spectrometry analysis of HLA-A2-bound peptides from HLA-A2 + ovarian cancer cell lines [5]. We have previously described and tested this vaccine candidate in preclinical models [5,11]. The vaccine-incorporated peptides are presented by MHC class I on the cell surface of breast, ovarian and prostate cancer cells, but not on normal cells [6]. Their inclusion in DPX-0907 yields an immunogenic vaccine in HLA- A2 transgenic mice that promotes the activation of both Type 1 T cell responses, while minimizing the induction of regulatory mechanisms [11].

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