Special Issue "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: 30 June 2022.

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 2400 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 (9 papers)

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Research

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Article
Clinicopathological Determinants of Recurrence Risk and Survival in Mucinous Ovarian Carcinoma
Cancers 2021, 13(22), 5839; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225839 - 21 Nov 2021
Viewed by 340
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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Article
ADAM17—A Potential Blood-Based Biomarker for Detection of Early-Stage Ovarian Cancer
Cancers 2021, 13(21), 5563; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215563 - 06 Nov 2021
Viewed by 634
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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Article
Survival Is Related to Estrogen Signal Transduction Pathway Activity in Postmenopausal Women Diagnosed with High-Grade Serous Ovarian Carcinoma
Cancers 2021, 13(20), 5101; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205101 - 12 Oct 2021
Viewed by 440
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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Article
Targeting CA-125 Transcription by Development of a Conditionally Replicative Adenovirus for Ovarian Cancer Treatment
Cancers 2021, 13(17), 4265; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13174265 - 24 Aug 2021
Viewed by 598
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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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
Cancers 2021, 13(16), 4201; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164201 - 20 Aug 2021
Viewed by 637
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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Article
The Small-Molecule Inhibitor MRIA9 Reveals Novel Insights into the Cell Cycle Roles of SIK2 in Ovarian Cancer Cells
Cancers 2021, 13(15), 3658; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13153658 - 21 Jul 2021
Viewed by 798
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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Review
The Protein Landscape of Mucinous Ovarian Cancer: Towards a Theranostic
Cancers 2021, 13(22), 5596; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225596 - 09 Nov 2021
Viewed by 497
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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Review
Malignant Ascites in Ovarian Cancer: Cellular, Acellular, and Biophysical Determinants of Molecular Characteristics and Therapy Response
Cancers 2021, 13(17), 4318; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13174318 - 26 Aug 2021
Cited by 3 | Viewed by 1164
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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Review
Engineered EV-Mimetic Nanoparticles as Therapeutic Delivery Vehicles for High-Grade Serous Ovarian Cancer
Cancers 2021, 13(12), 3075; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13123075 - 20 Jun 2021
Viewed by 1886
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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