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Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies
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Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 64283

Special Issue Editors

Dr. Andrew Stephens

E-Mail Website
Guest Editor
Centre for Cancer Research, Hudson Institute of Medical Research, Victoria VIC 3168, Australia
School of Translational Sciences, Monash University, Victoria VIC 3800, Australia
Interests: Ovarian cancer; diagnostics; therapeutics; cancer immunity; precision medicine; theranostics; translational medicine; biobanking
Dr. Maree Bilandzic

E-Mail Website
Guest Editor
Centre for Cancer Research, Hudson Institute of Medical Research, Victoria VIC 3168, Australia
School of Translational Sciences, Monash University, Victoria VIC 3800, Australia
Interests: metastasis; leader cells; invasion; precision medicine

Special Issue Information

Dear Colleagues,

Ovarian cancer remains one of the most lethal of gynaecological malignancies, characterised in most patients by recurrent, persistent disease and the rapid acquisition of chemo-resistance. Substantial molecular heterogeneity and co-existing phenotypes at diagnosis further complicate treatment choices and efficacy. New, “game-changing” therapies, applied successfully for the treatment of other solid tumour types, have proven largely ineffective against ovarian cancers. There is a clear and urgent need for improved diagnostic, prognostic and therapeutic tools, with clear translational potential, to assist in clinical management and reduce mortality from this disease.

Early diagnosis—ideally of pre-cancerous lesions, and particularly in asymptomatic women—remains a major challenge in ovarian cancer management. Equally as important, prognostic and predictive approaches are required to detect recurrence and enhance therapeutic management for patients in whom primary care is likely to fail. Combined with approaches to identify new druggable targets and therapeutic strategies—whether synergistic or stand-alone—research is poised to exert a substantial and positive impact over clinical ovarian cancer management.

This Special Issue will focus on emerging technologies with the potential to improve the diagnosis, prognostic evaluation and therapeutic management ovarian cancers.

Dr. Andrew Stephens
Dr. Maree Bilandzic
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • diagnostic
  • prognostic
  • theranostic
  • therapy
  • metastasis
  • biomarker
  • regression
  • chemoresistance
  • invasion

Published Papers (17 papers)

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Research

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20 pages, 1662 KiB  
Article
Combining TNFR2-Expressing Tregs and IL-6 as Superior Diagnostic Biomarkers for High-Grade Serous Ovarian Cancer Masses
by Nirmala Chandralega Kampan, Apriliana Ellya Ratna Kartikasari, Cyril Deceneux, Mutsa Tatenda Madondo, Orla M. McNally, Katie Louise Flanagan, Norhaslinda A. Aziz, Andrew N. Stephens, John Reynolds, Michael A. Quinn and Magdalena Plebanski
Cancers 2023, 15(3), 667; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15030667 - 21 Jan 2023
Cited by 5 | Viewed by 2348
Abstract
We hypothesised that the inclusion of immunosuppressive and inflammatory biomarkers in HGSOC patients would improve the sensitivity and specificity of the preoperative marker prediction of malignancy in patients with ovarian masses. We tested a panel of 29 soluble immune factors by multiplex bead [...] Read more.
We hypothesised that the inclusion of immunosuppressive and inflammatory biomarkers in HGSOC patients would improve the sensitivity and specificity of the preoperative marker prediction of malignancy in patients with ovarian masses. We tested a panel of 29 soluble immune factors by multiplex bead immunoassay and 16 phenotypic T cell markers by flow cytometry in pre-treatment blood samples from 66 patients undergoing surgery for suspected ovarian cancer or ovarian cancer risk reduction. The potential diagnostic utility of all parameters was explored using Volcano plots, principal component analysis (PCA) and receiver operator characteristic (ROC) analysis. We also assessed the effect of culturing PBMCs from 20 healthy donors in the presence of malignant ascites fluid. The combination of TNFR2+ Tregs and IL-6 in the pre-treatment blood of patients with advanced HGSOC effectively discriminated patients with benign or malignant ovarian masses. In vitro culturing of the PBMCs of healthy donors in malignant ascites promoted an increase in TNFR2-expressing Tregs, which were decreased following blockade with IL-6 or STAT3 activity. Pre-treatment serum IL-6 and peripheral blood TNFR2+ Tregs may be potential clinical biomarkers that can discriminate patients with malignant compared to benign ovarian cancer masses, and the relationship between IL-6 and TNFR2+ Treg is likely to be mediated via the STAT3 signalling pathway. Full article
(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)
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24 pages, 7649 KiB  
Article
Chemoresistant Cancer Cell Lines Are Characterized by Migratory, Amino Acid Metabolism, Protein Catabolism and IFN1 Signalling Perturbations
by Mitchell Acland, Noor A. Lokman, Clifford Young, Dovile Anderson, Mark Condina, Chris Desire, Tannith M. Noye, Wanqi Wang, Carmela Ricciardelli, Darren J. Creek, Martin K. Oehler, Peter Hoffmann and Manuela Klingler-Hoffmann
Cancers 2022, 14(11), 2763; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14112763 - 02 Jun 2022
Cited by 4 | Viewed by 2509
Abstract
Chemoresistance remains the major barrier to effective ovarian cancer treatment. The molecular features and associated biological functions of this phenotype remain poorly understood. We developed carboplatin-resistant cell line models using OVCAR5 and CaOV3 cell lines with the aim of identifying chemoresistance-specific molecular features. [...] Read more.
Chemoresistance remains the major barrier to effective ovarian cancer treatment. The molecular features and associated biological functions of this phenotype remain poorly understood. We developed carboplatin-resistant cell line models using OVCAR5 and CaOV3 cell lines with the aim of identifying chemoresistance-specific molecular features. Chemotaxis and CAM invasion assays revealed enhanced migratory and invasive potential in OVCAR5-resistant, compared to parental cell lines. Mass spectrometry analysis was used to analyse the metabolome and proteome of these cell lines, and was able to separate these populations based on their molecular features. It revealed signalling and metabolic perturbations in the chemoresistant cell lines. A comparison with the proteome of patient-derived primary ovarian cancer cells grown in culture showed a shared dysregulation of cytokine and type 1 interferon signalling, potentially revealing a common molecular feature of chemoresistance. A comprehensive analysis of a larger patient cohort, including advanced in vitro and in vivo models, promises to assist with better understanding the molecular mechanisms of chemoresistance and the associated enhancement of migration and invasion. Full article
(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)
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16 pages, 1702 KiB  
Article
Next Generation Plasma Proteomics Identifies High-Precision Biomarker Candidates for Ovarian Cancer
by Ulf Gyllensten, Julia Hedlund-Lindberg, Johanna Svensson, Johanna Manninen, Torbjörn Öst, Jon Ramsell, Matilda Åslin, Emma Ivansson, Marta Lomnytska, Maria Lycke, Tomas Axelsson, Ulrika Liljedahl, Jessica Nordlund, Per-Henrik Edqvist, Tobias Sjöblom, Mathias Uhlén, Karin Stålberg, Karin Sundfeldt, Mikael Åberg and Stefan Enroth
Cancers 2022, 14(7), 1757; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14071757 - 30 Mar 2022
Cited by 11 | Viewed by 5362
Abstract
Background: Ovarian cancer is the eighth most common cancer among women and has a 5-year survival of only 30–50%. The survival is close to 90% for patients in stage I but only 20% for patients in stage IV. The presently available biomarkers have [...] Read more.
Background: Ovarian cancer is the eighth most common cancer among women and has a 5-year survival of only 30–50%. The survival is close to 90% for patients in stage I but only 20% for patients in stage IV. The presently available biomarkers have insufficient sensitivity and specificity for early detection and there is an urgent need to identify novel biomarkers. Methods: We employed the Explore PEA technology for high-precision analysis of 1463 plasma proteins and conducted a discovery and replication study using two clinical cohorts of previously untreated patients with benign or malignant ovarian tumours (N = 111 and N = 37). Results: The discovery analysis identified 32 proteins that had significantly higher levels in malignant cases as compared to benign diagnoses, and for 28 of these, the association was replicated in the second cohort. Multivariate modelling identified three highly accurate models based on 4 to 7 proteins each for separating benign tumours from early-stage and/or late-stage ovarian cancers, all with AUCs above 0.96 in the replication cohort. We also developed a model for separating the early-stage from the late-stage achieving an AUC of 0.81 in the replication cohort. These models were based on eleven proteins in total (ALPP, CXCL8, DPY30, IL6, IL12, KRT19, PAEP, TSPAN1, SIGLEC5, VTCN1, and WFDC2), notably without MUCIN-16. The majority of the associated proteins have been connected to ovarian cancer but not identified as potential biomarkers. Conclusions: The results show the ability of using high-precision proteomics for the identification of novel plasma protein biomarker candidates for the early detection of ovarian cancer. Full article
(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)
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17 pages, 2399 KiB  
Article
Real-World Data on Detection of Germline and Somatic Pathogenic/Likely Pathogenic Variants in BRCA1/2 and Other Susceptibility Genes in Ovarian Cancer Patients Using Next Generation Sequencing
by Vida Stegel, Ana Blatnik, Erik Škof, Vita Šetrajčič Dragoš, Mateja Krajc, Brigita Gregorič, Petra Škerl, Ksenija Strojnik, Gašper Klančar, Marta Banjac, Janez Žgajnar, Maja Ravnik and Srdjan Novaković
Cancers 2022, 14(6), 1434; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061434 - 10 Mar 2022
Cited by 5 | Viewed by 2343
Abstract
Detection of germline and somatic pathogenic/likely pathogenic variants (PV/LPV) in BRCA genes is at the moment a prerequisite for use of PARP inhibitors in different treatment settings of different tumors. The aim of our study was to determine the most appropriate testing workflow [...] Read more.
Detection of germline and somatic pathogenic/likely pathogenic variants (PV/LPV) in BRCA genes is at the moment a prerequisite for use of PARP inhibitors in different treatment settings of different tumors. The aim of our study was to determine the most appropriate testing workflow in epithelial ovarian cancer (EOC) patients using germline and tumor genotyping of BRCA and other hereditary breast and/or ovarian cancer (HBOC) susceptibility genes. Consecutive patients with advanced non-mucinous EOC, who responded to platinum-based chemotherapy, were included in the study. DNA extracted from blood and FFPE tumor tissue were genotyped using NGS panels TruSightCancer/Hereditary and TruSight Tumor 170. Among 170 EOC patients, 21.8% had BRCA germline or somatic PV/LPV, and additionally 6.4% had PV/LPV in other HBOC genes. Sensitivity of tumor genotyping for detection of germline PV/LPV was 96.2% for BRCA genes and 93.3% for HBOC genes. With germline genotyping-only strategy, 58.8% of HBOC PV/LPV and 68.4% of BRCA PV/LPV were detected. By tumor genotyping-only strategy, 96.1% of HBOC PV/LPV and 97.4% of BRCA PV/LPV were detected. Genotyping of tumor first, followed by germline genotyping seems to be a reasonable approach for detection of PV/LPV in breast and/or ovarian cancer susceptibility genes in non-mucinous EOC patients. Full article
(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)
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15 pages, 6572 KiB  
Article
AKR1B1 as a Prognostic Biomarker of High-Grade Serous Ovarian Cancer
by Marko Hojnik, Nataša Kenda Šuster, Špela Smrkolj, Damjan Sisinger, Snježana Frković Grazio, Ivan Verdenik and Tea Lanišnik Rižner
Cancers 2022, 14(3), 809; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030809 - 05 Feb 2022
Cited by 10 | Viewed by 2464
Abstract
Although aldo-keto reductases (AKRs) have been widely studied in cancer, no study to date has examined the roles of AKR family 1 members B1 (AKR1B1) and B10 (AKR1B10) in a large group of ovarian cancer patients. AKR1B1 and AKR1B10 play a significant role [...] Read more.
Although aldo-keto reductases (AKRs) have been widely studied in cancer, no study to date has examined the roles of AKR family 1 members B1 (AKR1B1) and B10 (AKR1B10) in a large group of ovarian cancer patients. AKR1B1 and AKR1B10 play a significant role in inflammation and the metabolism of different chemotherapeutics as well as cell differentiation, proliferation, and apoptosis. Due to these functions, we examined the potential of AKR1B1 and AKR1B10 as tissue biomarkers. We assessed the immunohistochemical levels of AKR1B1 and AKR1B10 in tissue paraffin sections from 99 patients with high-grade serous ovarian cancer (HGSC) and compared these levels with clinicopathological characteristics, survival, and response to chemotherapy. A higher immunohistochemical AKR1B1 expression correlated with a better overall and disease-free survival of HGSC patients whereas AKR1B10 expression did not show any significant differences. A multivariant Cox analysis demonstrated that a high AKR1B1 expression was an important prognostic factor for both overall and disease-free survival. However, AKR1B1 and AKR1B10 were not associated with different responses to chemotherapy. Our data suggest that AKR1B1 is involved in the pathogenesis of HGSC and is a potential prognostic biomarker for this cancer. Full article
(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)
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14 pages, 1914 KiB  
Article
Loss of MAGEC3 Expression Is Associated with Prognosis in Advanced Ovarian Cancers
by James Ellegate, Jr., Michalis Mastri, Emily Isenhart, John J. Krolewski, Gurkamal Chatta, Eric Kauffman, Melissa Moffitt and Kevin H. Eng
Cancers 2022, 14(3), 731; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030731 - 30 Jan 2022
Cited by 2 | Viewed by 3254
Abstract
Rare variants in MAGEC3 are associated with BRCA negative, early-onset ovarian cancers. Given this association, we evaluated the impact of MAGEC3 protein expression on prognosis and transcription. We quantified normal and tumor protein expression of MAGEC3 via immunohistochemistry in n = 394 advanced [...] Read more.
Rare variants in MAGEC3 are associated with BRCA negative, early-onset ovarian cancers. Given this association, we evaluated the impact of MAGEC3 protein expression on prognosis and transcription. We quantified normal and tumor protein expression of MAGEC3 via immunohistochemistry in n = 394 advanced ovarian cancers, assessed the correlation of these values with clinicopathologic and immunological features and modeled survival using univariate and multivariate models. To extend these results, we quantified MAGEC3 protein expression in n = 180 cancers and used matching RNA sequencing data to determine MAGEC3-associated differentially expressed genes and to build an RNA-based model of MAGEC3 protein levels. This model was tested in a third independent cohort of patients from TCGA’s OV dataset (n = 282). MAGEC3 protein was sporadically lost in ovarian cancers, with half of the cases falling below the 9.5th percentile of normal tissue expression. Cases with MAGEC3 loss demonstrated better progression-free survival [HR = 0.71, p = 0.004], and analyses performed on predicted protein scores were consistent [HR = 0.57 p = 0.002]. MAGEC3 protein was correlated with CD8 protein expression [Pearson’s r = 0.176, p = 0.011], NY-ESO-1 seropositivity, and mRNA expression of tumor antigens at Xq28. Results of gene set enrichment analysis showed that genes associated with MAGEC3 protein expression cluster around G2/M checkpoint (NES = 3.20, FDR < 0.001) and DNA repair (NES = 2.28, FDR < 0.001) hallmark pathways. These results show that MAGEC3 is a prognostic biomarker in ovarian cancer. Full article
(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)
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13 pages, 1231 KiB  
Article
Clinicopathological Determinants of Recurrence Risk and Survival in Mucinous Ovarian Carcinoma
by Robert L. Hollis, Lorna J. Stillie, Samantha Hopkins, Clare Bartos, Michael Churchman, Tzyvia Rye, Fiona Nussey, Scott Fegan, Rachel Nirsimloo, Gareth J. Inman, C. Simon Herrington and Charlie Gourley
Cancers 2021, 13(22), 5839; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225839 - 21 Nov 2021
Cited by 8 | Viewed by 1987
Abstract
Mucinous ovarian carcinoma (MOC) is a unique form of ovarian cancer. MOC typically presents at early stage but demonstrates intrinsic chemoresistance; treatment of advanced-stage and relapsed disease is therefore challenging. We harness a large retrospective MOC cohort to identify factors associated with recurrence [...] Read more.
Mucinous ovarian carcinoma (MOC) is a unique form of ovarian cancer. MOC typically presents at early stage but demonstrates intrinsic chemoresistance; treatment of advanced-stage and relapsed disease is therefore challenging. We harness a large retrospective MOC cohort to identify factors associated with recurrence risk and survival. A total of 151 MOC patients were included. The 5 year disease-specific survival (DSS) was 84.5%. Risk of subsequent recurrence after a disease-free period of 2 and 5 years was low (8.3% and 5.6% over the next 10 years). The majority of cases were FIGO stage I (35.6% IA, 43.0% IC). Multivariable analysis identified stage and pathological grade as independently associated with DSS (p < 0.001 and p < 0.001). Grade 1 stage I patients represented the majority of cases (53.0%) and demonstrated exceptional survival (10 year DSS 95.3%); survival was comparable between grade I stage IA and stage IC patients, and between grade I stage IC patients who did and did not receive adjuvant chemotherapy. At 5 years following diagnosis, the proportion of grade 1, 2 and 3 patients remaining disease free was 89.5%, 74.9% and 41.7%; the corresponding proportions for FIGO stage I, II and III/IV patients were 91.1%, 76.7% and 19.8%. Median post-relapse survival was 5.0 months. Most MOC patients present with low-grade early-stage disease and are at low risk of recurrence. New treatment options are urgently needed to improve survival following relapse, which is associated with extremely poor prognosis. Full article
(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)
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16 pages, 2391 KiB  
Article
ADAM17—A Potential Blood-Based Biomarker for Detection of Early-Stage Ovarian Cancer
by Christoph Rogmans, Jan Dominik Kuhlmann, Gerrit Hugendieck, Theresa Link, Norbert Arnold, Jörg Paul Weimer, Inken Flörkemeier, Anna-Christina Rambow, Wolfgang Lieb, Nicolai Maass, Dirk O. Bauerschlag and Nina Hedemann
Cancers 2021, 13(21), 5563; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215563 - 06 Nov 2021
Cited by 11 | Viewed by 2748
Abstract
Ovarian cancer has the highest mortality rate among gynecological tumors. This is based on late diagnosis and the lack of early symptoms. To improve early detection, it is essential to find reliable biomarkers. The metalloprotease ADAM17 could be a potential marker, as it [...] Read more.
Ovarian cancer has the highest mortality rate among gynecological tumors. This is based on late diagnosis and the lack of early symptoms. To improve early detection, it is essential to find reliable biomarkers. The metalloprotease ADAM17 could be a potential marker, as it is highly expressed in many solid tumors, including ovarian and breast cancer. The aim of this work is to evaluate the relevance of ADAM17 as a potential diagnostic blood-based biomarker in ovarian cancer. Ovarian cancer cell lines IGROV-1 and A2780, as well as primary patient-derived tumor cells obtained from tumor tissue and ascitic fluid, were cultured to analyze ADAM17 abundance in the culture supernatant. In a translational approach, a cohort of 117 well-characterized ovarian cancer patients was assembled and ADAM17 levels in serum and corresponding ascitic fluid were determined at primary diagnosis. ADAM17 was quantified by enzyme-linked immunosorbent assay (ELISA). In the present study, ADAM17 was detected in the culture supernatant of ovarian cancer cell lines and primary cells. In addition, ADAM17 was found in serum and ascites of ovarian cancer patients. ADAM17 level was significantly increased in ovarian cancer patients compared to an age-matched control group (p < 0.0001). Importantly early FIGO I/II stages, which would not have been detected by CA-125, were associated with higher ADAM17 concentrations (p = 0.007). This is the first study proposing ADAM17 as a serum tumor marker in the setting of a gynecological tumor disease. Usage of ADAM17 in combination with CA-125 and other markers could help detect early stages of ovarian cancer. Full article
(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)
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16 pages, 4525 KiB  
Article
Survival Is Related to Estrogen Signal Transduction Pathway Activity in Postmenopausal Women Diagnosed with High-Grade Serous Ovarian Carcinoma
by Laura van Lieshout, Phyllis van der Ploeg, Yvonne Wesseling-Rozendaal, Anja van de Stolpe, Steven Bosch, Marjolein Lentjes-Beer, Meggy Ottenheijm, Annelen Meriaan, Caroline Vos, Joanne de Hullu, Leon Massuger, Ruud Bekkers and Jurgen Piek
Cancers 2021, 13(20), 5101; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205101 - 12 Oct 2021
Cited by 4 | Viewed by 1679
Abstract
High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, has a high mortality rate. Although there are some factors associated with survival, such as stage of disease, there are remarkable differences in survival among women diagnosed with advanced stage disease. [...] Read more.
High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, has a high mortality rate. Although there are some factors associated with survival, such as stage of disease, there are remarkable differences in survival among women diagnosed with advanced stage disease. In this study, we investigate possible relations between survival and signal transduction pathway (STP) activity. We assessed the functional activity of the androgen receptor (AR), estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor beta (TGF-β) and canonical wingless-type MMTV integration site (Wnt) pathway in 85 primary tumor samples of patients with FIGO stage IIIC to IVB HGSC and disease-free survival (DFS) below 12 (n = 52) or over 24 months (n = 33). There were no significant differences in median pathway activity between patients with a short and long DFS. In univariate Cox proportional hazards analysis, ER pathway activity was related to a favorable DFS and overall survival (OS) in postmenopausal women (p = 0.033 and p = 0.041, respectively), but not in premenopausal women. We divided the postmenopausal group into subgroups based on ER pathway activity quartiles. Survival analysis revealed that postmenopausal women in the lowest ER quartile had a shorter DFS and OS (log-rank p = 0.006 and p < 0.001, respectively). Furthermore, we were able to form subgroups of patients based on an inverse relation between ER and PI3K pathway activity. In conclusion, in postmenopausal patients with advanced stage HGSC, a poorer survival outcome was associated with low functional ER pathway activity. Full article
(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)
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13 pages, 2353 KiB  
Article
Targeting CA-125 Transcription by Development of a Conditionally Replicative Adenovirus for Ovarian Cancer Treatment
by Er Yue, Guangchao Yang, Yuanfei Yao, Guangyu Wang, Atish Mohanty, Fang Fan, Ling Zhao, Yanqiao Zhang, Tamara Mirzapoiazova, Tonya C. Walser, Lorna Rodriguez-Rodriguez, Yuman Fong, Ravi Salgia and Edward Wenge Wang
Cancers 2021, 13(17), 4265; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13174265 - 24 Aug 2021
Cited by 7 | Viewed by 2549
Abstract
CA-125, encoded by the MUC16 gene, is highly expressed in most ovarian cancer cells and thus serves as a tumor marker for monitoring disease progression or treatment response in ovarian cancer patients. However, targeting MUC16/CA-125 for ovarian cancer treatment has not been [...] Read more.
CA-125, encoded by the MUC16 gene, is highly expressed in most ovarian cancer cells and thus serves as a tumor marker for monitoring disease progression or treatment response in ovarian cancer patients. However, targeting MUC16/CA-125 for ovarian cancer treatment has not been successful to date. In the current study, we performed multiple steps of high-fidelity PCR and obtained a 5 kb DNA fragment upstream of the human MUC16 gene. Reporter assays indicate that this DNA fragment possesses transactivation activity in CA-125-high cancer cells, but not in CA-125-low cancer cells, indicating that the DNA fragment contains the transactivation region that controls specific expression of the MUC16 gene in ovarian cancer cells. We further refined the promoter and found a 1040 bp fragment with similar transcriptional activity and specificity. We used this refined MUC16 promoter to replace the E1A promoter in the adenovirus type 5 genome DNA, where E1A is an essential gene for adenovirus replication. We then generated a conditionally replicative oncolytic adenovirus (CRAd) that replicates in and lyses CA-125-high cancer cells, but not CA-125-low or -negative cancer cells. In vivo studies showed that intraperitoneal virus injection prolonged the survival of NSG mice inoculated intraperitoneally (ip) with selected ovarian cancer cell lines. Furthermore, the CRAd replicates in and lyses primary ovarian cancer cells, but not normal cells, collected from ovarian cancer patients. Collectively, these data indicate that targeting MUC16 transactivation utilizing CRAd is a feasible approach for ovarian cancer treatment that warrants further investigation. Full article
(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)
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16 pages, 1969 KiB  
Article
Mapping Epitopes Recognised by Autoantibodies Shows Potential for the Diagnosis of High-Grade Serous Ovarian Cancer and Monitoring Response to Therapy for This Malignancy
by Rhiane Moody, Kirsty Wilson, Nirmala Chandralega Kampan, Orla M. McNally, Thomas W. Jobling, Anthony Jaworowski, Andrew N. Stephens and Magdalena Plebanski
Cancers 2021, 13(16), 4201; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164201 - 20 Aug 2021
Cited by 2 | Viewed by 2055
Abstract
Autoantibodies recognising phosphorylated heat shock factor 1 (HSF1-PO4) protein are suggested as potential new diagnostic biomarkers for early-stage high-grade serous ovarian cancer (HGSOC). We predicted in silico B-cell epitopes in human and murine HSF1. Three epitope regions were synthesised as peptides. Circulating immunoglobulin [...] Read more.
Autoantibodies recognising phosphorylated heat shock factor 1 (HSF1-PO4) protein are suggested as potential new diagnostic biomarkers for early-stage high-grade serous ovarian cancer (HGSOC). We predicted in silico B-cell epitopes in human and murine HSF1. Three epitope regions were synthesised as peptides. Circulating immunoglobulin A (cIgA) against the predicted peptide epitopes or HSF1-PO4 was measured using ELISA, across two small human clinical trials of HGSOC patients at diagnosis. To determine whether chemotherapy would promote changes in reactivity to either HSF1-PO4 or the HSF-1 peptide epitopes, IgA responses were further assessed in a sample of patients after a full cycle of chemotherapy. Anti-HSF1-PO4 responses correlated with antibody responses to the three selected epitope regions, regardless of phosphorylation, with substantial cross-recognition of the corresponding human and murine peptide epitope variants. Assessing reactivity to individual peptide epitopes, compared to HSF1-PO4, improved assay sensitivity. IgA responses to HSF1-PO4 further increased significantly post treatment, indicating that HSF1-PO4 is a target for immunity in response to chemotherapy. Although performed in a small cohort, these results offer potential insights into the interplay between autoimmunity and ovarian cancer and offer new peptide biomarkers for early-stage HGSOC diagnosis, to monitor responses to chemotherapy, and widely for pre-clinical HGSOC research. Full article
(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)
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19 pages, 5391 KiB  
Article
The Small-Molecule Inhibitor MRIA9 Reveals Novel Insights into the Cell Cycle Roles of SIK2 in Ovarian Cancer Cells
by Monika Raab, Marcel Rak, Roberta Tesch, Khayal Gasimli, Sven Becker, Stefan Knapp, Klaus Strebhardt and Mourad Sanhaji
Cancers 2021, 13(15), 3658; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13153658 - 21 Jul 2021
Cited by 13 | Viewed by 2895
Abstract
The activity of the Salt inducible kinase 2 (SIK2), a member of the AMP-activated protein kinase (AMPK)-related kinase family, has been linked to several biological processes that maintain cellular and energetic homeostasis. SIK2 is overexpressed in several cancers, including ovarian cancer, where it [...] Read more.
The activity of the Salt inducible kinase 2 (SIK2), a member of the AMP-activated protein kinase (AMPK)-related kinase family, has been linked to several biological processes that maintain cellular and energetic homeostasis. SIK2 is overexpressed in several cancers, including ovarian cancer, where it promotes the proliferation of metastases. Furthermore, as a centrosome kinase, SIK2 has been shown to regulate the G2/M transition, and its depletion sensitizes ovarian cancer to paclitaxel-based chemotherapy. Here, we report the consequences of SIK2 inhibition on mitosis and synergies with paclitaxel in ovarian cancer using a novel and selective inhibitor, MRIA9. We show that MRIA9-induced inhibition of SIK2 blocks the centrosome disjunction, impairs the centrosome alignment, and causes spindle mispositioning during mitosis. Furthermore, the inhibition of SIK2 using MRIA9 increases chromosomal instability, revealing the role of SIK2 in maintaining genomic stability. Finally, MRIA9 treatment enhances the sensitivity to paclitaxel in 3D-spheroids derived from ovarian cancer cell lines and ovarian cancer patients. Our study suggests selective targeting of SIK2 in ovarian cancer as a therapeutic strategy for overcoming paclitaxel resistance. Full article
(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)
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Review

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14 pages, 600 KiB  
Review
The “Sweet Spot” of Targeting Tumor Metabolism in Ovarian Cancers
by Katelyn Tondo-Steele and Karen McLean
Cancers 2022, 14(19), 4696; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194696 - 27 Sep 2022
Cited by 7 | Viewed by 2097
Abstract
The objective of this review is to explore the metabolomic environment of epithelial ovarian cancer that contributes to chemoresistance and to use this knowledge to identify possible targets for therapeutic intervention. The Warburg effect describes increased glucose uptake and lactate production in cancer [...] Read more.
The objective of this review is to explore the metabolomic environment of epithelial ovarian cancer that contributes to chemoresistance and to use this knowledge to identify possible targets for therapeutic intervention. The Warburg effect describes increased glucose uptake and lactate production in cancer cells. In ovarian cancer, we require a better understanding of how cancer cells reprogram their glycogen metabolism to overcome their nutrient deficient environment and become chemoresistant. Glucose metabolism in ovarian cancer cells has been proposed to be influenced by altered fatty acid metabolism, oxidative phosphorylation, and acidification of the tumor microenvironment. We investigate several markers of altered metabolism in ovarian cancer including hypoxia-induced factor 1, VEGF, leptin, insulin-like growth factors, and glucose transporters. We also discuss the signaling pathways involved with these biomarkers including PI3K/AKT/mTOR, JAK/STAT and OXPHOS. This review outlines potential metabolic targets to overcome chemoresistance in ovarian cancer. Continued research of the metabolic changes in ovarian cancer is needed to identify and target these alterations to improve treatment approaches. Full article
(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)
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46 pages, 4407 KiB  
Review
Current and Emerging Methods for Ovarian Cancer Screening and Diagnostics: A Comprehensive Review
by Juliane M. Liberto, Sheng-Yin Chen, Ie-Ming Shih, Tza-Huei Wang, Tian-Li Wang and Thomas R. Pisanic II
Cancers 2022, 14(12), 2885; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14122885 - 11 Jun 2022
Cited by 21 | Viewed by 6189
Abstract
With a 5-year survival rate of less than 50%, ovarian high-grade serous carcinoma (HGSC) is one of the most highly aggressive gynecological malignancies affecting women today. The high mortality rate of HGSC is largely attributable to delays in diagnosis, as most patients remain [...] Read more.
With a 5-year survival rate of less than 50%, ovarian high-grade serous carcinoma (HGSC) is one of the most highly aggressive gynecological malignancies affecting women today. The high mortality rate of HGSC is largely attributable to delays in diagnosis, as most patients remain undiagnosed until the late stages of -disease. There are currently no recommended screening tests for ovarian cancer and there thus remains an urgent need for new diagnostic methods, particularly those that can detect the disease at early stages when clinical intervention remains effective. While diagnostics for ovarian cancer share many of the same technical hurdles as for other cancer types, the low prevalence of the disease in the general population, coupled with a notable lack of sensitive and specific biomarkers, have made the development of a clinically useful screening strategy particularly challenging. Here, we present a detailed review of the overall landscape of ovarian cancer diagnostics, with emphasis on emerging methods that employ novel protein, genetic, epigenetic and imaging-based biomarkers and/or advanced diagnostic technologies for the noninvasive detection of HGSC, particularly in women at high risk due to germline mutations such as BRCA1/2. Lastly, we discuss the translational potential of these approaches for achieving a clinically implementable solution for screening and diagnostics of early-stage ovarian cancer as a means of ultimately improving patient outcomes in both the general and high-risk populations. Full article
(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)
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17 pages, 667 KiB  
Review
The Protein Landscape of Mucinous Ovarian Cancer: Towards a Theranostic
by Arkan Youssef, Mohammad B. Haskali and Kylie L. Gorringe
Cancers 2021, 13(22), 5596; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225596 - 09 Nov 2021
Cited by 5 | Viewed by 2585
Abstract
MOC is a rare histotype of epithelial ovarian cancer, and current management options are inadequate for the treatment of late stage or recurrent disease. A shift towards personalised medicines in ovarian cancer is being observed, with trials targeting specific molecular pathways, however, MOC [...] Read more.
MOC is a rare histotype of epithelial ovarian cancer, and current management options are inadequate for the treatment of late stage or recurrent disease. A shift towards personalised medicines in ovarian cancer is being observed, with trials targeting specific molecular pathways, however, MOC lags due to its rarity. Theranostics is a rapidly evolving category of personalised medicine, encompassing both a diagnostic and therapeutic approach by recognising targets that are expressed highly in tumour tissue in order to deliver a therapeutic payload. The present review evaluates the protein landscape of MOC in recent immunohistochemical- and proteomic-based research, aiming to identify potential candidates for theranostic application. Fourteen proteins were selected based on cell membrane localisation: HER2, EGFR, FOLR1, RAC1, GPR158, CEACAM6, MUC16, PD-L1, NHE1, CEACAM5, MUC1, ACE2, GP2, and PTPRH. Optimal proteins to target using theranostic agents must exhibit high membrane expression on cancerous tissue with low expression on healthy tissue to afford improved disease outcomes with minimal off-target effects and toxicities. We provide guidelines to consider in the selection of a theranostic target for MOC and suggest future directions in evaluating the results of this review. Full article
(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)
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47 pages, 2273 KiB  
Review
Malignant Ascites in Ovarian Cancer: Cellular, Acellular, and Biophysical Determinants of Molecular Characteristics and Therapy Response
by Brittany P. Rickard, Christina Conrad, Aaron J. Sorrin, Mustafa Kemal Ruhi, Jocelyn C. Reader, Stephanie A. Huang, Walfre Franco, Giuliano Scarcelli, William J. Polacheck, Dana M. Roque, Marcela G. del Carmen, Huang-Chiao Huang, Utkan Demirci and Imran Rizvi
Cancers 2021, 13(17), 4318; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13174318 - 26 Aug 2021
Cited by 48 | Viewed by 14124
Abstract
Ascites refers to the abnormal accumulation of fluid in the peritoneum resulting from an underlying pathology, such as metastatic cancer. Among all cancers, advanced-stage epithelial ovarian cancer is most frequently associated with the production of malignant ascites and is the leading cause of [...] Read more.
Ascites refers to the abnormal accumulation of fluid in the peritoneum resulting from an underlying pathology, such as metastatic cancer. Among all cancers, advanced-stage epithelial ovarian cancer is most frequently associated with the production of malignant ascites and is the leading cause of death from gynecologic malignancies. Despite decades of evidence showing that the accumulation of peritoneal fluid portends the poorest outcomes for cancer patients, the role of malignant ascites in promoting metastasis and therapy resistance remains poorly understood. This review summarizes the current understanding of malignant ascites, with a focus on ovarian cancer. The first section provides an overview of heterogeneity in ovarian cancer and the pathophysiology of malignant ascites. Next, analytical methods used to characterize the cellular and acellular components of malignant ascites, as well the role of these components in modulating cell biology, are discussed. The review then provides a perspective on the pressures and forces that tumors are subjected to in the presence of malignant ascites and the impact of physical stress on therapy resistance. Treatment options for malignant ascites, including surgical, pharmacological and photochemical interventions are then discussed to highlight challenges and opportunities at the interface of drug discovery, device development and physical sciences in oncology. Full article
(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)
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26 pages, 2077 KiB  
Review
Engineered EV-Mimetic Nanoparticles as Therapeutic Delivery Vehicles for High-Grade Serous Ovarian Cancer
by Amal A. Al-Dossary, Essam A. Tawfik, Adaugo C. Isichei, Xin Sun, Jiahe Li, Abdullah A. Alshehri, Munther Alomari, Fahad A. Almughem, Ahmad M. Aldossary, Hussein Sabit and Abdulaziz M. Almalik
Cancers 2021, 13(12), 3075; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13123075 - 20 Jun 2021
Cited by 12 | Viewed by 4822
Abstract
High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy among women. Several obstacles impede the early diagnosis and effective treatment options for ovarian cancer (OC) patients, which most importantly include the development of platinum-drug-resistant strains. Currently, extensive efforts are being put [...] Read more.
High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy among women. Several obstacles impede the early diagnosis and effective treatment options for ovarian cancer (OC) patients, which most importantly include the development of platinum-drug-resistant strains. Currently, extensive efforts are being put into the development of strategies capable of effectively circumventing the physical and biological barriers present in the peritoneal cavity of metastatic OC patients, representing a late stage of gastrointestinal and gynecological cancer with an extremely poor prognosis. Naturally occurring extracellular vesicles (EVs) have been shown to play a pivotal role in progression of OC and are now being harnessed as a delivery vehicle for cancer chemotherapeutics. However, there are limitations to their clinical application due to current challenges in their preparation techniques. Intriguingly, there is a recent drive towards the use of engineered synthetic EVs for the delivery of chemotherapeutics and RNA interference therapy (RNAi), as they show the promise of overcoming the obstacles in the treatment of OC patients. This review discusses the therapeutic application of EVs in OC and elucidates the potential use of engineered EV-mimetic nanoparticles as a delivery vehicle for RNAi therapy and other chemotherapeutics, which would potentially improve clinical outcomes of OC patients. Full article
(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)
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