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17 pages, 5080 KiB

Open AccessArticle

Honeycomb-like Structured Film, a Novel Therapeutic Device, Suppresses Tumor Growth in an In Vivo Ovarian Cancer Model

by Tsuyoshi Ohta, Masaru Tanaka, Seitaro Taki, Hiroyuki Nakagawa and Satoru Nagase

Cancers 2023, 15(1), 237; https://doi.org/10.3390/cancers15010237 - 30 Dec 2022

Viewed by 1736

Abstract

Ovarian cancer cell dissemination can lead to the mortality of patients with advanced ovarian cancer. Complete surgery for no gross residual disease contributes to a more favorable prognosis than that of patients with residual disease. HCFs have highly regular porous structures and their [...] Read more.

Ovarian cancer cell dissemination can lead to the mortality of patients with advanced ovarian cancer. Complete surgery for no gross residual disease contributes to a more favorable prognosis than that of patients with residual disease. HCFs have highly regular porous structures and their 3D porous structures act as scaffolds for cell adhesion. HCFs are fabricated from biodegradable polymers and have been widely used in tissue engineering. This study aimed to show that HCFs suppress tumor growth in an in vivo ovarian cancer model. The HCF pore sizes had a significant influence on tumor growth inhibition, and HCFs induced morphological changes that rounded out ovarian cancer cells. Furthermore, we identified gene ontology (GO) terms and clusters of genes downregulated by HCFs. qPCR analysis demonstrated that a honeycomb structure downregulated the expression of CXCL2, FOXC1, MMP14, and SNAI2, which are involved in cell proliferation, migration, invasion, angiogenesis, focal adhesion, extracellular matrix (ECM), and epithelial–mesenchymal transition (EMT). Collectively, HCFs induced abnormal focal adhesion and cell morphological changes, subsequently inhibiting the differentiation, proliferation and motility of ovarian cancer cells. Our data suggest that HCFs could be a novel device for inhibiting residual tumor growth after surgery, and could reduce surgical invasiveness and improve the prognosis for patients with advanced ovarian cancer. Full article

(This article belongs to the Special Issue New Insights of Ovarian Cancer Treatment)

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24 pages, 4385 KiB

Open AccessArticle

Upregulation of Succinate Dehydrogenase (SDHA) Contributes to Enhanced Bioenergetics of Ovarian Cancer Cells and Higher Sensitivity to Anti-Metabolic Agent Shikonin

by Lin Wang, Magdalena Cybula, Maria Rostworowska, Luyao Wang, Patryk Mucha, Magdalena Bulicz and Magdalena Bieniasz

Cancers 2022, 14(20), 5097; https://doi.org/10.3390/cancers14205097 - 18 Oct 2022

Cited by 4 | Viewed by 2530

Abstract

We discovered that the overexpression of mitochondrial enzyme succinate dehydrogenase (SDHA) is particularly prevalent in ovarian carcinoma and promotes highly metabolically active phenotype. Succinate dehydrogenase deficiency has been previously studied in some rare disorders. However, the role of SDHA upregulation and its impact [...] Read more.

We discovered that the overexpression of mitochondrial enzyme succinate dehydrogenase (SDHA) is particularly prevalent in ovarian carcinoma and promotes highly metabolically active phenotype. Succinate dehydrogenase deficiency has been previously studied in some rare disorders. However, the role of SDHA upregulation and its impact on ovarian cancer metabolism has never been investigated, emphasizing the need for further research. We investigated the functional consequences of SDHA overexpression in ovarian cancer. Using proteomics approaches and biological assays, we interrogated protein content of metabolic pathways, cell proliferation, anchorage-independent growth, mitochondrial respiration, glycolytic function, and ATP production rates in those cells. Lastly, we performed a drug screening to identify agents specifically targeting the SDHA overexpressing tumor cells. We showed that SDHA overexpressing cells are characterized by enhanced energy metabolism, relying on both glycolysis and oxidative phosphorylation to meet their energy needs. In addition, SDHA-high phenotype was associated with cell vulnerability to glucose and glutamine deprivation, which led to a substantial reduction of ATP yield. We also identified an anti-metabolic compound shikonin with a potent efficacy against SDHA overexpressing ovarian cancer cells. Our data underline the unappreciated role of SDHA in reprogramming of ovarian cancer metabolism, which represents a new opportunity for therapeutic intervention. Full article

(This article belongs to the Special Issue New Insights of Ovarian Cancer Treatment)

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11 pages, 1373 KiB

Open AccessArticle

Primary Treatment Results in Patients with Ovarian, Fallopian or Peritoneal Cancer—Results of a Clinical Cancer Registry Database Analysis in Germany

by Robert Armbrust, Peter Ledwon, Anne Von Rüsten, Constanze Schneider and Jalid Sehouli

Cancers 2022, 14(19), 4638; https://doi.org/10.3390/cancers14194638 - 24 Sep 2022

Cited by 2 | Viewed by 1308

Abstract

Background: The current therapy of ovarian cancer is based on the so-called “Three-Pillar-Model”, consisting of surgery, chemotherapy and maintenance therapy. This study represents the first major analysis of a federal cancer database of OC patients from the states Berlin/Brandenburg in Germany. The primary [...] Read more.

Background: The current therapy of ovarian cancer is based on the so-called “Three-Pillar-Model”, consisting of surgery, chemotherapy and maintenance therapy. This study represents the first major analysis of a federal cancer database of OC patients from the states Berlin/Brandenburg in Germany. The primary objective was to evaluate the prevailing established quality indicators surgical outcome, adjuvant chemotherapy and integrity of surgical staging in early stages. Methods: Data from the Clinical Cancer Registry for Brandenburg and Berlin of the years 2009–2019 were analyzed. Objectives were defined by a working group of selected physicians. Descriptive statistics were performed, as well as survival analysis. Results: A total of 2771 primary OC cases were included. Results regarding histological subtype met the suspected allocation with predominantly high-grade serous OC in advanced stage. The rate of complete surgical staging in FIGO stages I–IIA was 57%, and the rate of macroscopic complete resection in >FIGO III was 53%. Five-year survival rate varied from 79% (FIGO I) to 40% (FIGO III). Rate of adjuvant chemotherapy was above 50%. Conclusion: The results elucidate quality measurements and treatment results and show good treatment outcomes in patients with primary diagnosis. However, they also indicate deficits and can help to establish new quality indicators to further improve the treatment. Full article

(This article belongs to the Special Issue New Insights of Ovarian Cancer Treatment)

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17 pages, 5723 KiB

Open AccessArticle

Low Expression of RGS2 Promotes Poor Prognosis in High-Grade Serous Ovarian Cancer

by Jana Ihlow, Nanna Monjé, Inga Hoffmann, Philip Bischoff, Bruno Valentin Sinn, Wolfgang Daniel Schmitt, Catarina Alisa Kunze, Sylvia Darb-Esfahani, Hagen Kulbe, Elena Ioana Braicu, Jalid Sehouli, Carsten Denkert, David Horst and Eliane Tabea Taube

Cancers 2022, 14(19), 4620; https://doi.org/10.3390/cancers14194620 - 23 Sep 2022

Cited by 2 | Viewed by 1699

Abstract

RGS2 regulates G-protein signaling by accelerating hydrolysis of GTP and has been identified as a potentially druggable target in carcinomas. Since the prognosis of patients with high-grade serous ovarian carcinoma (HGSOC) remains utterly poor, new therapeutic options are urgently needed. Previous in vitro [...] Read more.

RGS2 regulates G-protein signaling by accelerating hydrolysis of GTP and has been identified as a potentially druggable target in carcinomas. Since the prognosis of patients with high-grade serous ovarian carcinoma (HGSOC) remains utterly poor, new therapeutic options are urgently needed. Previous in vitro studies have linked RGS2 suppression to chemoresistance in HGSOC, but in situ data are still missing. In this study, we characterized the expression of RGS2 and its relation to prognosis in HGSOC on the protein level by immunohistochemistry in 519 patients treated at Charité, on the mRNA level in 299 cases from TCGA and on the single-cell level in 19 cases from publicly available datasets. We found that RGS2 is barely detectable on the mRNA level in both bulk tissue (median 8.2. normalized mRNA reads) and single-cell data (median 0 normalized counts), but variably present on the protein level (median 34.5% positive tumor cells, moderate/strong expression in approximately 50% of samples). Interestingly, low expression of RGS2 had a negative impact on overall survival (p = 0.037) and progression-free survival (p = 0.058) on the protein level in lower FIGO stages and in the absence of residual tumor burden. A similar trend was detected on the mRNA level. Our results indicated a significant prognostic impact of RGS2 protein suppression in HGSOC. Due to diverging expression patterns of RGS2 on mRNA and protein levels, posttranslational modification of RGS2 is likely. Our findings warrant further research to unravel the functional role of RGS2 in HGSOC, especially in the light of new drug discovery. Full article

(This article belongs to the Special Issue New Insights of Ovarian Cancer Treatment)

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14 pages, 1126 KiB

Open AccessArticle

Real-World Data on Newly Diagnosed BRCA-Mutated High-Grade Epithelial Ovarian Cancers: The French National Multicenter ESME Database

by Marta Bini, Stanislas Quesada, Pierre Meeus, Manuel Rodrigues, Eric Leblanc, Anne Floquet, Patricia Pautier, Frédéric Marchal, Magali Provansal, Loïc Campion, Sylvain Causeret, Sophie Gourgou, Isabelle Ray-Coquard, Jean-Marc Classe, Christophe Pomel, Thibault De La Motte Rouge, Emmanuel Barranger, Aude Marie Savoye, Cécile Guillemet, Laurence Gladieff, Martin Demarchi, Roman Rouzier, C Courtinard, Clémence Romeo and Florence Joly Show full author list Hide full author list

Cancers 2022, 14(16), 4040; https://doi.org/10.3390/cancers14164040 - 21 Aug 2022

Viewed by 1888

Abstract

Background: In spite of the frequency and clinical impact of BRCA1/2 alterations in high-grade epithelial ovarian cancer (HGEOC), real-world information based on robust data warehouse has been scarce to date. Methods: Consecutive patients with BRCA-mutated HGEOC treated between 2011 and 2016 within [...] Read more.

Background: In spite of the frequency and clinical impact of BRCA1/2 alterations in high-grade epithelial ovarian cancer (HGEOC), real-world information based on robust data warehouse has been scarce to date. Methods: Consecutive patients with BRCA-mutated HGEOC treated between 2011 and 2016 within French comprehensive cancer centers from the Unicancer network were extracted from the ESME database. The main objective of the study was the assessment of clinicopathological and treatments parameters. Results: Out of the 8021 patients included in the ESME database, 266 patients matching the selection criteria were included. BRCA1 mutation was found in 191 (71.8%) patients, while 75 (28.2%) had a BRCA2 mutation only; 95.5% of patients received a cytoreductive surgery. All patients received a taxane/platinum-based chemotherapy (median = six cycles). Complete and partial response were obtained in 53.3% and 20.4% of the cases, respectively. Maintenance therapy was administered in 55.3% of the cases, bevacizumab being the most common agent. After a median follow up of 51.7 months, a median progression-free survival of 28.6 months (95% confidence interval (CI) [26.5; 32.7]) and an estimated 5-year median overall survival of 69.2% (95% CI [61.6; 70.3]) were reported. Notably, BRCA1- and BRCA2-mutated cases exhibited a trend towards different median progression-free survivals, with 28.0 (95% CI [24.4; 32.3]) and 33.3 months (95% CI [26.7; 46.1]), respectively (p-value = 0.053). Furthermore, five-year OS for BRCA1-mutated patients was 64.5% (95% CI [59.7; 69.2]), while it was 82.5% (95% CI [76.6; 88.5]) for BRCA2-mutated ones (p-value = 0.029). Conclusions: This study reports the largest French multicenter cohort of BRCA-mutated HGEOCs based on robust data from the ESME, exhibiting relevant real-world data regarding this specific population. Full article

(This article belongs to the Special Issue New Insights of Ovarian Cancer Treatment)

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Review

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19 pages, 1025 KiB

Open AccessReview

c-MYC-Driven Polyamine Metabolism in Ovarian Cancer: From Pathogenesis to Early Detection and Therapy

by Yihui Chen, Ricardo A. León-Letelier, Ali Hussein Abdel Sater, Jody Vykoukal, Jennifer B. Dennison, Samir Hanash and Johannes F. Fahrmann

Cancers 2023, 15(3), 623; https://doi.org/10.3390/cancers15030623 - 19 Jan 2023

Cited by 2 | Viewed by 2413

Abstract

c-MYC and its paralogues MYCN and MYCL are among the most frequently amplified and/or overexpressed oncoproteins in ovarian cancer. c-MYC plays a key role in promoting ovarian cancer initiation and progression. The polyamine pathway is a bona fide target of c-MYC signaling, and [...] Read more.

c-MYC and its paralogues MYCN and MYCL are among the most frequently amplified and/or overexpressed oncoproteins in ovarian cancer. c-MYC plays a key role in promoting ovarian cancer initiation and progression. The polyamine pathway is a bona fide target of c-MYC signaling, and polyamine metabolism is strongly intertwined with ovarian malignancy. Targeting of the polyamine pathway via small molecule inhibitors has garnered considerable attention as a therapeutic strategy for ovarian cancer. Herein, we discuss the involvement of c-MYC signaling and that of its paralogues in promoting ovarian cancer tumorigenesis. We highlight the potential of targeting c-MYC-driven polyamine metabolism for the treatment of ovarian cancers and the utility of polyamine signatures in biofluids for early detection applications. Full article

(This article belongs to the Special Issue New Insights of Ovarian Cancer Treatment)

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16 pages, 2580 KiB

Open AccessReview

The Potential of Novel Lipid Agents for the Treatment of Chemotherapy-Resistant Human Epithelial Ovarian Cancer

by Mark W. Nachtigal, Alon D. Altman, Rajat Arora, Frank Schweizer and Gilbert Arthur

Cancers 2022, 14(14), 3318; https://doi.org/10.3390/cancers14143318 - 07 Jul 2022

Cited by 1 | Viewed by 2318

Abstract

Recurrent epithelial ovarian cancer (EOC) coincident with chemotherapy resistance remains the main contributor to patient mortality. There is an ongoing investigation to enhance patient progression-free and overall survival with novel chemotherapeutic delivery, such as the utilization of antiangiogenic medications, PARP inhibitors, or immune [...] Read more.

Recurrent epithelial ovarian cancer (EOC) coincident with chemotherapy resistance remains the main contributor to patient mortality. There is an ongoing investigation to enhance patient progression-free and overall survival with novel chemotherapeutic delivery, such as the utilization of antiangiogenic medications, PARP inhibitors, or immune modulators. Our preclinical studies highlight a novel tool to combat chemotherapy-resistant human EOC. Glycosylated antitumor ether lipids (GAELs) are synthetic glycerolipids capable of killing established human epithelial cell lines from a wide variety of human cancers, including EOC cell lines representative of different EOC histotypes. Importantly, GAELs kill high-grade serous ovarian cancer (HGSOC) cells isolated from the ascites of chemotherapy-sensitive and chemotherapy-resistant patients grown as monolayers of spheroid cultures. In addition, GAELs were well tolerated by experimental animals (mice) and were capable of reducing tumor burden and blocking ascites formation in an OVCAR-3 xenograft model. Overall, GAELs show great promise as adjuvant therapy for EOC patients with or without chemotherapy resistance. Full article

(This article belongs to the Special Issue New Insights of Ovarian Cancer Treatment)

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13 pages, 680 KiB

Open AccessReview

Can Schlafen 11 Help to Stratify Ovarian Cancer Patients Treated with DNA-Damaging Agents?

by Marketa Bednarikova, Jitka Hausnerova, Lucie Ehrlichova, Kvetoslava Matulova, Eliska Gazarkova, Lubos Minar and Vit Weinberger

Cancers 2022, 14(10), 2353; https://doi.org/10.3390/cancers14102353 - 10 May 2022

Viewed by 1848

Abstract

Platinum-based chemotherapy has been the cornerstone of systemic treatment in ovarian cancer. Since no validated molecular predictive markers have been identified yet, the response to platinum-based chemotherapy has been evaluated clinically, based on platinum-free interval. The new promising marker Schlafen 11 seems to [...] Read more.

Platinum-based chemotherapy has been the cornerstone of systemic treatment in ovarian cancer. Since no validated molecular predictive markers have been identified yet, the response to platinum-based chemotherapy has been evaluated clinically, based on platinum-free interval. The new promising marker Schlafen 11 seems to correlate with sensitivity or resistance to DNA-damaging agents, including platinum compounds or PARP inhibitors in various types of cancer. We provide background information about the function of Schlafen 11, its evaluation in tumor tissue, and its prevalence in ovarian cancer. We discuss the current evidence of the correlation of Schlafen 11 expression in ovarian cancer with treatment outcomes and the potential use of Schlafen 11 as the key predictive and prognostic marker that could help to better stratify ovarian cancer patients treated with platinum-based chemotherapy or PARP inhibitors. We also provide perspectives on future directions in the research on this promising marker. Full article

(This article belongs to the Special Issue New Insights of Ovarian Cancer Treatment)

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