Aberrant Wnt signalling is implicated in numerous human cancers, and understanding the effects of modulation of pathway members may lead to the development of novel therapeutics. Expression of ...secreted frizzled related protein 4 (SFRP4), an extracellular modulator of the Wnt signalling pathway, is progressively lost in more aggressive ovarian cancer phenotypes. Here we show that recombinant SFRP4 (rSFRP4) treatment of a serous ovarian cancer cell line results in inhibition of β-catenin dependent Wnt signalling as measured by TOP/FOP Wnt reporter assay and decreased transcription of Wnt target genes, Axin2, CyclinD1 and Myc. In addition, rSFRP4 treatment significantly increased the ability of ovarian cancer cells to adhere to collagen and fibronectin, and decreased their ability to migrate across an inflicted wound. We conclude that these changes in cell behaviour may be mediated via mesenchymal to epithelial transition (MET), as rSFRP4 treatment also resulted in increased expression of the epithelial marker E-cadherin, and reduced expression of Vimentin and Twist. Combined, these results indicate that modulation of a single upstream gatekeeper of Wnt signalling can have effects on downstream Wnt signalling and ovarian cancer cell behaviour, as mediated through epithelial to mesenchymal plasticity (EMP). This raises the possibility that SFRP4 may be used both diagnostically and therapeutically in epithelial ovarian cancer.
Ovarian cancer, a challenging malignancy often diagnosed in advanced stages, has witnessed a transformative shift in treatment paradigms with the introduction of poly (ADP-ribose) polymerase (PARP) ...inhibitors. These agents that target DNA repair pathways through synthetic lethality have demonstrated remarkable efficacy across various ovarian cancer subtypes. Notably, olaparib, niraparib and rucaparib have emerged as pivotal players in this therapeutic revolution. This review explores the fundamental role of these three PARP inhibitors and gives an overview of the therapeutic landscape and the role of PARP inhibitors in the future including combination therapy.
The ability of circulating tumor cells (CTCs) to form clusters has been linked to increased metastatic potential. Yet biological features and vulnerabilities of CTC clusters remain largely unknown. ...Here, we profile the DNA methylation landscape of single CTCs and CTC clusters from breast cancer patients and mouse models on a genome-wide scale. We find that binding sites for stemness- and proliferation-associated transcription factors are specifically hypomethylated in CTC clusters, including binding sites for OCT4, NANOG, SOX2, and SIN3A, paralleling embryonic stem cell biology. Among 2,486 FDA-approved compounds, we identify Na+/K+ ATPase inhibitors that enable the dissociation of CTC clusters into single cells, leading to DNA methylation remodeling at critical sites and metastasis suppression. Thus, our results link CTC clustering to specific changes in DNA methylation that promote stemness and metastasis and point to cluster-targeting compounds to suppress the spread of cancer.
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•Binding sites for OCT4, SOX2, NANOG, and SIN3A are hypomethylated in CTC clusters•CTC cluster hypomethylation profile correlates with a poor prognosis in breast cancer•Treatment with FDA-approved Na+/K+-ATPase inhibitors dissociates CTC clusters•Dissociation reverts the methylation profile of CTC clusters and suppresses metastasis
A comparative analysis of the methylation landscape of single and clusters of circulating tumor cells reveals patterns of similarity to embryonic stem cells and identifies pharmacological agents that can target clustering, suppress stemness, and blunt metastatic spreading.
IntroductionRadical abdominal surgery is part of the standard treatment for women with advanced gynaecological carcinoma. The surgery often leads to intraoperative blood loss frequently exceeding ...1000 mL. Approximately 50% of women undergoing radical surgery require blood transfusions. Perioperative blood transfusions have been shown to increase the risk of postoperative complications, delayed wound healing, increased length of stay, increased postoperative morbidity and mortality. Previous studies have demonstrated an association between perioperative anaemia and surgical morbidity and mortality. By reducing transfusions and improving recovery from surgery, preoperative diagnostic and management of perioperative anaemia is a great opportunity to optimise postoperative patient outcome.Methods and analysisThis is a single-blind, monocentre, randomised trial with four parallel groups (three therapeutic groups and one control group without treatment according to current standards of care) conducted in women undergoing radical gynaecological surgery. The primary study objective is to determine the effect of perioperative treatment with either intravenous iron, tranexamic acid or with a combination of both medicines on the reduction of intraoperative and postoperative red blood cell transfusions in gynaecological carcinoma patients. A total of N=126 women with gynaecological carcinoma will be recruited at the University Hospital Basel, Department of Gynaecology. Blood parameters will be measured at the recruitment, prior to surgery, 2 days after surgery and on the 21st–28th day after surgery. Recruitment started in August 2021.Ethics and disseminationThe study will be performed according to the guidelines of the Declaration of Helsinki and is approved by the Ethics Committee for Northwest and Central Switzerland in Basel (EKNZ Protocol ID 2020-01194). The results of this study will be published and presented in various scientific forums.Trial registration numberNCT03792464.
The methods used to diagnose and classify ovarian cancer have changed over the past decade. We used hospital registry data to assess the incidence, treatment durations and hospital costs of ovarian ...cancer in Switzerland.
We carried out a retrospective analysis of a hospital registry covering all inpatient care episodes in Switzerland between 1998 and 2012. Ovarian cancer incidence was assessed by identifying patients with a first ovarian cancer diagnosis as the main reason for hospital stay after an event-free period. We assessed the duration and cost of ovarian cancer treatment sequences as well as the evolution of hospital patient volume over time.
The average age-adjusted incidence rate was 14.6 per 100,000 women per year between 2004 and 2012. This rate is substantially higher (+35.5%) than the corresponding rate published by the National Institute for Cancer Epidemiology and Registration (NICER). Hospital patient volume was low in most cases, with more than 40% of patients treated in hospitals with fewer than 20 cases per year. However, the share of patients treated in hospitals with more than 30 cases per year has increased substantially since 2009.
We found a substantial difference between the ovarian cancer incidence estimate based on hospital registry data and the corresponding estimate by NICER. The reasons for this substantial difference should be carefully explored. A case-wise comparison could determine whether the difference is due to over- or under-reporting in one of the two registries. The low ovarian cancer patient volume in many hospitals is in conflict with the numbers required for certified specialised cancer centres. The recent increase in patient volume in specialised cancer centres, however, might reflect a growing understanding of the needs and requirements of comprehensive cancer care.
Serous peritoneal and high‐grade serous ovarian/tubal cancers are treated identically with maximal cytoreductive surgery and platinum‐based chemotherapy. Here, we provide epidemiological, clinical, ...and molecular evidence that peritoneal cancer is more aggressive and shows a distinct molecular signature on gene and protein levels. Our data suggest alternative treatment decisions and to consider the tumor‐sampling site for diagnosis in the future.
In the era of personalized medicine, where transition from organ‐based to individualized genetic diagnosis takes place, the tailoring of treatment in cancer becomes increasingly important. This is particularly true for high‐grade, advanced FIGO stage serous adenocarcinomas of the ovary (OC), fallopian tube (TC), and peritoneum (PC), which are currently all treated identically. We analyzed three independent patient cohorts using histopathologically classified diagnosis and various molecular approaches (transcriptomics, immunohistochemistry, next‐generation sequencing, fluorescent and chromogenic in situ hybridization). Using multivariate Cox regression model, we found that PC is more aggressive compared with advanced‐stage OC independent of residual disease as shown by an earlier relapse‐free survival in two large cohorts (HR: 2.63, CI: 1.59–4.37, P < 0.001, and HR: 1.66, CI: 1.04–2.63, P < 0.033). In line with these findings, transcriptomic data revealed differentially expressed gene signatures identifying PC as high stromal response tumors. The third independent cohort (n = 4054) showed a distinction between these cancer types for markers suggested to be predictive for chemotherapy drug response. Our findings add additional evidence that ovarian and peritoneal cancers are epidemiologically and molecularly distinct diseases. Moreover, our data also suggest consideration of the tumor‐sampling site for future diagnosis and treatment decisions.
Epithelial ovarian cancer has the highest mortality rate among gynecological cancers. Altered glycosylation is associated with oncogenic transformation producing tumor‐associated carbohydrate ...antigens. We investigated the potential of natural occurring antiglycan antibodies in the diagnosis of ovarian cancer by using printed glycan array. Antiglycan antibodies bound to 203 chemically synthesized printed glycans were detected via biotin‐streptavidin fluorescence system in serum of women with normal operative findings (healthy controls; n = 24) and nonmucinous borderline or ovarian cancer of various FIGO stages (n = 33). Data were validated measuring blood group associated di‐, tri and tetrasaccharide antigens on known ABO blood groups. Antiglycan antibodies demonstrated high reproducibility (rc > 0.9). Cluster analysis identified repetitive patterns of specific core carbohydrate structures: 11 N‐linked glycans, 3 O‐linked glycans and 2 glycosphingolipids. Biomarker detection revealed 24 glycans including P1 (Galα1–4Galβ1–4GlcNAcβ; p < 0.001) significantly discriminating between (low‐) malignant tumors and healthy controls. Comparable sensitivity and specificity with tumor marker CA125 was achieved by a panel of multivariate selected and linear combined antiglycan antibody signals (79.2 and 84.8%, respectively). Our findings demonstrate the potential of glycan arrays in the development of a new generation of biomarkers for ovarian cancer.
Reverse Transcription - quantitative Polymerase Chain Reaction (RT-qPCR) is a standard technique in most laboratories. The selection of reference genes is essential for data normalization and the ...selection of suitable reference genes remains critical. Our aim was to 1) review the literature since implementation of the MIQE guidelines in order to identify the degree of acceptance; 2) compare various algorithms in their expression stability; 3) identify a set of suitable and most reliable reference genes for a variety of human cancer cell lines. A PubMed database review was performed and publications since 2009 were selected. Twelve putative reference genes were profiled in normal and various cancer cell lines (n = 25) using 2-step RT-qPCR. Investigated reference genes were ranked according to their expression stability by five algorithms (geNorm, Normfinder, BestKeeper, comparative ΔCt, and RefFinder). Our review revealed 37 publications, with two thirds patient samples and one third cell lines. qPCR efficiency was given in 68.4% of all publications, but only 28.9% of all studies provided RNA/cDNA amount and standard curves. GeNorm and Normfinder algorithms were used in 60.5% in combination. In our selection of 25 cancer cell lines, we identified HSPCB, RRN18S, and RPS13 as the most stable expressed reference genes. In the subset of ovarian cancer cell lines, the reference genes were PPIA, RPS13 and SDHA, clearly demonstrating the necessity to select genes depending on the research focus. Moreover, a cohort of at least three suitable reference genes needs to be established in advance to the experiments, according to the guidelines. For establishing a set of reference genes for gene normalization we recommend the use of ideally three reference genes selected by at least three stability algorithms. The unfortunate lack of compliance to the MIQE guidelines reflects that these need to be further established in the research community.
Antibody-drug conjugates (ADC) are emerging as powerful treatment strategies with outstanding target-specificity and high therapeutic activity in patients with cancer. Brentuximab vedotin represents ...a first-in-class ADC directed against CD30(+) malignancies. We hypothesized that its sustained clinical responses could be related to the stimulation of an anticancer immune response. In this study, we demonstrate that the dolastatin family of microtubule inhibitors, from which the cytotoxic component of brentuximab vedotin is derived, comprises potent inducers of phenotypic and functional dendritic cell (DC) maturation. In addition to the direct cytotoxic effect on tumor cells, dolastatins efficiently promoted antigen uptake and migration of tumor-resident DCs to the tumor-draining lymph nodes. Exposure of murine and human DCs to dolastatins significantly increased their capacity to prime T cells. Underlining the requirement of an intact host immune system for the full therapeutic benefit of dolastatins, the antitumor effect was far less pronounced in immunocompromised mice. We observed substantial therapeutic synergies when combining dolastatins with tumor antigen-specific vaccination or blockade of the PD-1-PD-L1 and CTLA-4 coinhibitory pathways. Ultimately, treatment with ADCs using dolastatins induces DC homing and activates cellular antitumor immune responses in patients. Our data reveal a novel mechanism of action for dolastatins and provide a strong rationale for clinical treatment regimens combining dolastatin-based therapies, such as brentuximab vedotin, with immune-based therapies.
Epithelial ovarian cancer is the fifth most common cause of cancer in women worldwide bearing the highest mortality rate among all gynecological cancers. Cell membrane glycans mediate various ...cellular processes such as cell signaling and become altered during carcinogenesis. The extent to which glycosylation changes are influenced by aberrant regulation of gene expression is nearly unknown for ovarian cancer and remains crucial in understanding the development and progression of this disease. To address this effect, we analyzed the membrane glycosylation of non-cancerous ovarian surface epithelial (HOSE 6.3 and HOSE 17.1) and serous ovarian cancer cell lines (SKOV 3, IGROV1, A2780, and OVCAR 3), the most common histotype among epithelial ovarian cancers. N-glycans were released from membrane glycoproteins by PNGase F and analyzed using nano-liquid chromatography on porous graphitized carbon and negative-ion electrospray ionization mass spectrometry (ESI-MS). Glycan structures were characterized based on their molecular masses and tandem MS fragmentation patterns. We identified characteristic glycan features that were unique to the ovarian cancer membrane proteins, namely the “bisecting N-acetyl-glucosamine” type N-glycans, increased levels of α 2–6 sialylated N-glycans and “N,N′-diacetyl-lactosamine” type N-glycans. These N-glycan changes were verified by examining gene transcript levels of the enzymes specific for their synthesis (MGAT3, ST6GAL1, and B4GALNT3) using qRT-PCR. We further evaluated the potential epigenetic influence on MGAT3 expression by treating the cell lines with 5-azacytidine, a DNA methylation inhibitor. For the first time, we provide evidence that MGAT3 expression may be epigenetically regulated by DNA hypomethylation, leading to the synthesis of the unique “bisecting GlcNAc” type N-glycans on the membrane proteins of ovarian cancer cells. Linking the observation of specific N-glycan substructures and their complex association with epigenetic programming of their associated synthetic enzymes in ovarian cancer could potentially be used for the development of novel anti-glycan drug targets and clinical diagnostic tools.
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