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Molecular Mechanisms of Ovarian Cancer Development and Metastasis

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 55147

Special Issue Editors

Department of Obstetrics and Gynecology, School of Medicine, Shimane University, Shimane, Japan
Interests: Ovary; Endometriosis; Obstetrics; Gynecologic Oncology; Hysterectomy
Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan
Interests: Ovarian cancer; cervical cancer
Department of Gynecology, Masuda Red Cross Hospital, Shimane, Japan
Interests: gynecological oncology; ovarian cancer

Special Issue Information

Dear Colleagues,

Ovarian cancer is the most lethal gynecological malignancy in the world due to the lack of early detection tools and effective therapeutic intervention. Ovarian cancers are subdivided into five principal histotypes: high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous carcinoma. Recent research that elucidates the tumor biology and molecular pathways that mediate cancer progression and drug resistance has led to the development of various molecular targeted therapies involving monoclonal antibodies, small molecule receptor tyrosine kinase inhibitors and agents blocking downstream signaling pathways in ovarian cancer. Recent studies have identified that each histotype of ovarian cancer shows different molecular mechanisms of carcinogenesis. In light of this, there will be a Special Issue of the International Journal of Molecular Sciences, “Molecular Mechanisms of Ovarian Cancer Development and Metastasis” which will focus on how genomics, epigenomics and proteomics are altered in cancer progression. We invite you to contribute original articles that describe the carcinogenesis, tumor microenvironment, in vitro/vivo models, and targeted therapies that utilize clinical samples, cancer stem cells, next generation sequencing and exosomes in as many models and contexts as possible. Review articles describing recent topics including precision oncology using panel sequencing, tumor heterogeneity, cancer metabolism, or immunotherapy in ovarian cancer are also welcome.

Prof. Kentaro Nakayama
Dr. Kohei Nakamura
Dr. Seiya Sato
Dr. Hiroshi Katagiri
Guest Editors

Manuscript Submission Information

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Keywords

  • immunotherapy
  • tumor microenviroment
  • precision medicine
  • targeted therapies
  • exosomes
  • tumor heterogeneity
  • cancer metabolism

Published Papers (9 papers)

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Research

Jump to: Review

12 pages, 1551 KiB  
Article
Relationship between Microsatellite Instability, Immune Cells Infiltration, and Expression of Immune Checkpoint Molecules in Ovarian Carcinoma: Immunotherapeutic Strategies for the Future
by Hitomi Yamashita, Kentaro Nakayama, Masako Ishikawa, Tomoka Ishibashi, Kohei Nakamura, Kiyoka Sawada, Yuki Yoshimura, Nagisa Tatsumi, Sonomi Kurose, Toshiko Minamoto, Kouji Iida, Sultana Razia, Noriyoshi Ishikawa and Satoru Kyo
Int. J. Mol. Sci. 2019, 20(20), 5129; https://doi.org/10.3390/ijms20205129 - 16 Oct 2019
Cited by 20 | Viewed by 3154
Abstract
Ovarian cancer has the worst prognosis among gynecological cancers. Thus, new ovarian cancer treatment strategies are needed. Currently, immune checkpoint inhibitors such as anti-PD-1/PD-L1 antibody are attracting attention worldwide. The Food and Drug Administration approved the use of the PD-1 antibody pembrolizumab for [...] Read more.
Ovarian cancer has the worst prognosis among gynecological cancers. Thus, new ovarian cancer treatment strategies are needed. Currently, immune checkpoint inhibitors such as anti-PD-1/PD-L1 antibody are attracting attention worldwide. The Food and Drug Administration approved the use of the PD-1 antibody pembrolizumab for solid cancers with microsatellite instability (MSI)-H or mismatch repair (MMR) deficiency in 2017. However, few studies on ovarian carcinoma have evaluated the relationship among MSI status, lymphocyte infiltration into the tumor, and the expression of immune checkpoint molecules by histologic type. We evaluated the expression of MMR proteins, tumor-infiltrating lymphocytes (CD8+), and immune checkpoint molecules (PD-L1/PD-1) by immunohistochemistry in 136 ovarian cancer patients (76, 13, 23, and 24 cases were high-grade serous, mucinous, endometrioid, and clear cell carcinoma, respectively) to investigate the effectiveness of immune checkpoint inhibitors. Only six cases (4.4%) had loss of MMR protein expression. There was no significant relationship between MSI status and age (p = 0.496), FIGO stage (p = 0.357), initial treatment (primary debulking surgery [PDS] or neoadjuvant chemotherapy) (p = 0.419), residual tumor after PDS or interval debulking surgery (p = 0.202), and expression of CD8 (p = 0.126), PD-L1 (p = 0.432), and PD-1 (p = 0.653). These results suggest that only a small number of MSI cases in ovarian cancer can be effectively treated with immune checkpoint inhibitor monotherapy. Therefore, to improve the prognosis of ovarian carcinoma, a combination therapy of immune checkpoint inhibitors and other anticancer drugs is necessary. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis)
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14 pages, 3679 KiB  
Article
Correlation of the Aryl Hydrocarbon Receptor with FSHR in Ovarian Cancer Patients
by Eileen Deuster, Doris Mayr, Anna Hester, Thomas Kolben, Christine Zeder-Göß, Alexander Burges, Sven Mahner, Udo Jeschke, Fabian Trillsch and Bastian Czogalla
Int. J. Mol. Sci. 2019, 20(12), 2862; https://doi.org/10.3390/ijms20122862 - 12 Jun 2019
Cited by 18 | Viewed by 2837
Abstract
Expression of the aryl hydrocarbon receptor (AhR) has been described in various tumor entities from different organs. However, its role in ovarian cancer has not been thoroughly investigated. We aimed to elucidate the prognostic impact of AhR, its correlation with the follicle-stimulating hormone [...] Read more.
Expression of the aryl hydrocarbon receptor (AhR) has been described in various tumor entities from different organs. However, its role in ovarian cancer has not been thoroughly investigated. We aimed to elucidate the prognostic impact of AhR, its correlation with the follicle-stimulating hormone receptor (FSHR), and their functional role in ovarian cancer. By immunohistochemistry, AhR staining was analyzed in a subset of 156 samples of ovarian cancer patients. AhR staining was assessed in the nucleus and the cytoplasm using the semi-quantitative immunoreactive score (IRS), and the scores were grouped into high- and low-level expression. AhR expression was detected in all histological subtypes, with clear cell ovarian cancer displaying the highest staining intensity. Low cytoplasmic expression of AhR was associated with longer overall survival (median 183.46 vs. 85.07 months; p = 0.021). We found a positive correlation between AhR and FSHR (p = 0.005). Ovarian cancer patients with high cytoplasmic AhR and concurrent FSHR expression had the worst outcome (median 69.72 vs. 43.32 months; p = 0.043). Consequently, low cytoplasmic AhR expression seems to be associated with improved survival in ovarian cancer patients. Our data suggest that AhR and FSHR levels correlate with each other, and their concurrent expression was observed in ovarian cancer patients with the worst outcome. Further investigation of the interaction of both receptors and their functional role might better predict the impact of endocrine therapy in ovarian cancer. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis)
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16 pages, 4664 KiB  
Article
Gene Expression Indicates Altered Immune Modulation and Signaling Pathway Activation in Ovarian Cancer Patients Resistant to Topotecan
by Otília Menyhárt, János Tibor Fekete and Balázs Győrffy
Int. J. Mol. Sci. 2019, 20(11), 2750; https://doi.org/10.3390/ijms20112750 - 05 Jun 2019
Cited by 13 | Viewed by 2561
Abstract
Epithelial ovarian cancer (EOC) is one of the deadliest gynecological malignancies. Topotecan remains an essential tool in second-line therapy; even so, most patients develop resistance within a short period of time. We aimed to identify biomarkers of topotecan resistance by using gene expression [...] Read more.
Epithelial ovarian cancer (EOC) is one of the deadliest gynecological malignancies. Topotecan remains an essential tool in second-line therapy; even so, most patients develop resistance within a short period of time. We aimed to identify biomarkers of topotecan resistance by using gene expression signatures derived from patient specimens at surgery and available subsequent responses to therapy. Gene expression was collected for 1436 patients and 10,103 genes. Based on disease progression, patients were categorized as responders/nonresponders depending on their progression free survival (PFS) state at 9, 12, 15 and 18 months after surgery. For each gene, the median expression was compared between responders and nonresponders for two treatment regimens (chemotherapy including/excluding topotecan) with Mann–Whitney U test at each of the four different PFS cutoffs. Statistical significance was accepted in the case of p < 0.05 with a fold change (FC) ≥ 1.44. Four genes (EPB41L2, HLA-DQB1, LTF and SFRP1) were consistently overexpressed across multiple PFS cutoff times in initial tumor samples of patients with disease progression following topotecan treatment. A common theme linked to topotecan resistance was altered immune modulation. Genes associated with disease progression after systemic chemotherapy emphasize the role of the initial organization of the tumor microenvironment in therapy resistance. Our results uncover biomarkers with potential utility for patient stratification. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis)
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13 pages, 2413 KiB  
Article
Development of a Bioluminescent BRCA1-Deficient Xenograft Model of Disseminated, High-Grade Serous Ovarian Cancer
by Yen Ting Shen, Lucy Wang, James C. Evans, Christine Allen and Micheline Piquette-Miller
Int. J. Mol. Sci. 2019, 20(10), 2498; https://doi.org/10.3390/ijms20102498 - 21 May 2019
Cited by 2 | Viewed by 4328
Abstract
Successful translation of preclinical data relies on valid and comprehensive animal models. While high-grade serous ovarian cancer (HGSOC) is the most prevalent subtype, the most commonly used ovarian cancer cell lines are not representative of HGSOC. In addition, 50% of ovarian cancer patients [...] Read more.
Successful translation of preclinical data relies on valid and comprehensive animal models. While high-grade serous ovarian cancer (HGSOC) is the most prevalent subtype, the most commonly used ovarian cancer cell lines are not representative of HGSOC. In addition, 50% of ovarian cancer patients present with dysfunctional BRCA1/2, however currently there is a shortage of BRCA-deficient models. By utilizing the OVCAR8 cell line, which contains a hypermethylated BRCA1 promoter, the aim of the current study was to establish and characterize an animal model for BRCA-deficient HGSOC. Transfection of the luciferase gene to OVCAR8 cells enabled bioluminescent imaging for real-time, non-invasive monitoring of tumor growth. The resulting model was characterized by peritoneal metastasis and ascites formation at late stages of disease. Immunohistochemical staining revealed high-grade serous histology in all resected tumor nodules. Immunoblotting and qPCR analysis demonstrated BRCA1 deficiency was maintained in vivo. Moderate to strong correlations were observed between bioluminescent signal and tumor weight. Lastly, intraperitoneal administration of carboplatin significantly reduced tumor growth as measured by bioluminescence. The current model demonstrated BRCA1 deficiency and a high resemblance of the clinical features of HGSOC. This model may be well-suited for evaluation of therapeutic efficacy in BRCA-deficient HGSOC. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis)
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16 pages, 3023 KiB  
Article
Biological Insights into Chemotherapy Resistance in Ovarian Cancer
by Michelle A. Glasgow, Peter Argenta, Juan E. Abrahante, Mihir Shetty, Shobhana Talukdar, Paula A. Croonquist, Mahmoud A. Khalifa and Timothy K. Starr
Int. J. Mol. Sci. 2019, 20(9), 2131; https://doi.org/10.3390/ijms20092131 - 30 Apr 2019
Cited by 14 | Viewed by 4289
Abstract
The majority of patients with high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy; however, most will develop chemotherapy resistance. Gene signatures may change with the development of chemotherapy resistance in this population, which is important as it may lead to tailored therapies. [...] Read more.
The majority of patients with high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy; however, most will develop chemotherapy resistance. Gene signatures may change with the development of chemotherapy resistance in this population, which is important as it may lead to tailored therapies. The objective of this study was to compare tumor gene expression profiles in patients before and after treatment with neoadjuvant chemotherapy (NACT). Tumor samples were collected from six patients diagnosed with HGSOC before and after administration of NACT. RNA extraction and whole transcriptome sequencing was performed. Differential gene expression, hierarchical clustering, gene set enrichment analysis, and pathway analysis were examined in all of the samples. Tumor samples clustered based on exposure to chemotherapy as opposed to patient source. Pre-NACT samples were enriched for multiple pathways involving cell cycle growth. Post-NACT samples were enriched for drug transport and peroxisome pathways. Molecular subtypes based on the pre-NACT sample (differentiated, mesenchymal, proliferative and immunoreactive) changed in four patients after administration of NACT. Multiple changes in tumor gene expression profiles after exposure to NACT were identified from this pilot study and warrant further attention as they may indicate early changes in the development of chemotherapy resistance. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis)
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17 pages, 3623 KiB  
Article
miR-590-3p Targets Cyclin G2 and FOXO3 to Promote Ovarian Cancer Cell Proliferation, Invasion, and Spheroid Formation
by Mohamed Salem, Yanan Shan, Stefanie Bernaudo and Chun Peng
Int. J. Mol. Sci. 2019, 20(8), 1810; https://doi.org/10.3390/ijms20081810 - 12 Apr 2019
Cited by 44 | Viewed by 3586
Abstract
Ovarian cancer is the leading cause of death from gynecological cancers. MicroRNAs (miRNAs) are small, non-coding RNAs that interact with the 3′ untranslated region (3′ UTR) of target genes to repress their expression. We have previously reported that miR-590-3p promoted ovarian cancer growth [...] Read more.
Ovarian cancer is the leading cause of death from gynecological cancers. MicroRNAs (miRNAs) are small, non-coding RNAs that interact with the 3′ untranslated region (3′ UTR) of target genes to repress their expression. We have previously reported that miR-590-3p promoted ovarian cancer growth and metastasis, in part by targeting Forkhead box A (FOXA2). In this study, we further investigated the mechanisms by which miR-590-3p promotes ovarian cancer development. Using luciferase reporter assays, real-time PCR, and Western blot analyses, we demonstrated that miR-590-3p targets cyclin G2 (CCNG2) and Forkhead box class O3 (FOXO3) at their 3′ UTRs. Silencing of CCNG2 or FOXO3 mimicked, while the overexpression of CCNG2 or FOXO3 reversed, the stimulatory effect of miR-590-3p on cell proliferation and invasion. In hanging drop cultures, the overexpression of mir-590 or the transient transfection of miR-590-3p mimics induced the formation of compact spheroids. Transfection of the CCNG2 or FOXO3 plasmid into the mir-590 cells resulted in the partial disruption of the compact spheroid formation. Since we have shown that CCNG2 suppressed β-catenin signaling, we investigated if miR-590-3p regulated β-catenin activity. In the TOPFlash luciferase reporter assays, mir-590 increased β-catenin/TCF transcriptional activity and the nuclear accumulation of β-catenin. Silencing of β-catenin attenuated the effect of mir-590 on the compact spheroid formation. Taken together, these results suggest that miR-590-3p promotes ovarian cancer development, in part by directly targeting CCNG2 and FOXO3. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis)
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14 pages, 6198 KiB  
Article
Ex Vivo Expanded Human Vγ9Vδ2 T-Cells Can Suppress Epithelial Ovarian Cancer Cell Growth
by Tsui Lien Mao, Carol H. Miao, Yi Jen Liao, Ying Jen Chen, Chia Yu Yeh and Chao Lien Liu
Int. J. Mol. Sci. 2019, 20(5), 1139; https://doi.org/10.3390/ijms20051139 - 06 Mar 2019
Cited by 8 | Viewed by 3685
Abstract
γδ-T-cells have attracted attention because of their potent cytotoxicity towards tumors. Most γδ-T-cells become activated via a major histocompatibility complex (MHC)-independent pathway by the interaction of their receptor, Natural Killer Group 2 Member D (NKG2D) with the tumor-specific NKG2D ligands, including MHC class [...] Read more.
γδ-T-cells have attracted attention because of their potent cytotoxicity towards tumors. Most γδ-T-cells become activated via a major histocompatibility complex (MHC)-independent pathway by the interaction of their receptor, Natural Killer Group 2 Member D (NKG2D) with the tumor-specific NKG2D ligands, including MHC class I-related chain A/B (MICA/B) and UL16-binding proteins (ULBPs), to kill tumor cells. However, despite their potent antitumor effects, the treatment protocols specifically targeting ovarian tumors require further improvements. Ovarian cancer is one of the most lethal and challenging female malignancies worldwide because of delayed diagnoses and resistance to traditional chemotherapy. In this study, we successfully enriched and expanded γδ-T-cells up to ~78% from peripheral blood mononuclear cells (PBMCs) with mostly the Vγ9Vδ2-T-cell subtype in the circulation. We showed that expanded γδ-T-cells alone exerted significant cytotoxic activities towards specific epithelial-type OVCAR3 and HTB75 cells, whereas the combination of γδ-T cells and pamidronate (PAM), a kind of aminobisphosphonates (NBPs), showed significantly enhanced cytotoxic activities towards all types of ovarian cancer cells in vitro. Furthermore, in tumor xenografts of immunodeficient NSG mice, γδ-T-cells not only suppressed tumor growth but also completely eradicated preexisting tumors with an initial size of ~5 mm. Thus, we concluded that γδ-T-cells alone possess dramatic cytotoxic activities towards epithelial ovarian cancers both in vitro and in vivo. These results strongly support the potential of clinical immunotherapeutic application of γδ-T-cells to treat this serious female malignancy. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis)
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15 pages, 2752 KiB  
Article
Characterization of a Novel Third-Generation Anti-CD24-CAR against Ovarian Cancer
by Rüdiger Klapdor, Shuo Wang, Michael Morgan, Thilo Dörk, Ulrich Hacker, Peter Hillemanns, Hildegard Büning and Axel Schambach
Int. J. Mol. Sci. 2019, 20(3), 660; https://doi.org/10.3390/ijms20030660 - 03 Feb 2019
Cited by 68 | Viewed by 6867
Abstract
Novel therapeutic approaches against ovarian cancer (OC) are urgently needed because of its high rate of recurrence even after extensive surgery and multi-agent chemotherapy. We aimed to develop a novel anti-CD24 chimeric antigen receptor (CAR) as an immunotherapeutic approach against OC cells and [...] Read more.
Novel therapeutic approaches against ovarian cancer (OC) are urgently needed because of its high rate of recurrence even after extensive surgery and multi-agent chemotherapy. We aimed to develop a novel anti-CD24 chimeric antigen receptor (CAR) as an immunotherapeutic approach against OC cells and cancer stem cells (CSC). CSC represents a subpopulation of the tumor characterized by enhanced chemoresistance as well as the increased capability of self-renewal and metastasis. We designed a codon-optimized third-generation CAR containing the highly active single chain variable fragment (scFv) “SWA11” against CD24. We equipped the human NK-cell line NK-92 with the anti-CD24 CAR and an anti-CD19 control CAR using lentiviral transduction. Engineered NK-92 cells showed high cytotoxic activity against CD24-positive OC cell lines (SKOV3, OVCAR3). This effect was restricted to CD24-expressing cells as shown after lentiviral transduction of CD24-negative cell lines (A2780, HEK-293T) with CD24 transmembrane proteins. Additionally, NK-92 cells equipped with our novel anti-CD24 CAR were highly effective against patient-derived primary ovarian cancer cells. The activation of NK cells was shown by specific IFNγ secretion upon antigen stimulation. To further reduce possible off-target effects in vivo, we applied a dual-CAR approach using an anti-CD24-CD28-41BB fusion protein linked via a 2A sequence to an anti-mesothelin-CD3ζ-CAR. The dual-CAR was simultaneously active against CD24 and mesothelin expressing cells. Our novel anti-CD24-CAR showed a highly cytotoxic effect against OC cell lines and primary OC cells and will be evaluated in future in vivo trials as a promising immunotherapeutic approach against OC. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis)
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Review

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33 pages, 2777 KiB  
Review
High-Grade Serous Ovarian Cancer: Basic Sciences, Clinical and Therapeutic Standpoints
by Michael-Antony Lisio, Lili Fu, Alicia Goyeneche, Zu-hua Gao and Carlos Telleria
Int. J. Mol. Sci. 2019, 20(4), 952; https://doi.org/10.3390/ijms20040952 - 22 Feb 2019
Cited by 333 | Viewed by 23156
Abstract
Among a litany of malignancies affecting the female reproductive tract, that of the ovary is the most frequently fatal. Moreover, while the steady pace of scientific discovery has fuelled recent ameliorations in the outcomes of many other cancers, the rates of mortality for [...] Read more.
Among a litany of malignancies affecting the female reproductive tract, that of the ovary is the most frequently fatal. Moreover, while the steady pace of scientific discovery has fuelled recent ameliorations in the outcomes of many other cancers, the rates of mortality for ovarian cancer have been stagnant since around 1980. Yet despite the grim outlook, progress is being made towards better understanding the fundamental biology of this disease and how its biology in turn influences clinical behaviour. It has long been evident that ovarian cancer is not a unitary disease but rather a multiplicity of distinct malignancies that share a common anatomical site upon presentation. Of these, the high-grade serous subtype predominates in the clinical setting and is responsible for a disproportionate share of the fatalities from all forms of ovarian cancer. This review aims to provide a detailed overview of the clinical-pathological features of ovarian cancer with a particular focus on the high-grade serous subtype. Along with a description of the relevant clinical aspects of this disease, including novel trends in treatment strategies, this text will inform the reader of recent updates to the scientific literature regarding the origin, aetiology and molecular-genetic basis of high-grade serous ovarian cancer (HGSOC). Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis)
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