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Molecular Mechanisms of Ovarian Cancer Development and Metastasis 3.0
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Molecular Mechanisms of Ovarian Cancer Development and Metastasis 3.0

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 November 2021) | Viewed by 13512

Special Issue Editor

Prof. Dr. Kentaro Nakayama

E-Mail Website
Guest Editor
Department of Obstetrics and Gynecology, School of Medicine, Shimane University, Shimane 693-8501, Japan
Interests: ovarian cancer; precision oncology; panel sequencing; targeted therapies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our 2020 Special Issue “Molecular Mechanisms of Ovarian Cancer Development and Metastasis 2.0” and our 2019 Special Issue “Molecular Mechanisms of Ovarian Cancer Development and Metastasis”.

Ovarian cancer is the most lethal gynecological malignancy in the world due to the lack of early detection tools and effective therapeutic interventions. 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 3.0”, which will focus on how genomics, epigenomics, and proteomics are altered in cancer progression. We invite you to contribute original articles on the carcinogenesis; tumor microenvironment; in vitro/vivo models; organoid models; and targeted therapies that utilize clinical samples, cancer stem cells, next-generation sequencing, circular RNA, and exosomes in as many models and contexts as possible. In addition, recent increased longevity has caused the aging of not only ovarian but many other cancer patients. Along with the invention of new chemo drugs, patients’ tolerability should be taken into consideration, particularly that of older patients. Malnutrition and sarcopenia are frequently observed among seniors and have been recognized as modifiable prognostic factors. It has been recognized that nutritional care and rehabilitation can be an effective supportive therapy for cancer patients. Review articles describing recent topics, including precision oncology using panel sequencing, tumor heterogeneity, cancer metabolism, immunotherapy, and attractive supportive therapy in ovarian cancer, are also welcome.

Prof. Dr. Kentaro Nakayama
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • cancer organoid
  • circular RNA
  • exosomes
  • clinical sequencing
  • cancer metabolism
  • immunotherapy
  • personalized medicine
  • molecular target therapy

Published Papers (6 papers)

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Research

15 pages, 2681 KiB  
Article
Exosome Secretion and Epithelial-Mesenchymal Transition in Ovarian Cancer Are Regulated by Phospholipase D
by Hadil Onallah, Sheethal Thomas Mannully, Ben Davidson and Reuven Reich
Int. J. Mol. Sci. 2022, 23(21), 13286; https://doi.org/10.3390/ijms232113286 - 31 Oct 2022
Cited by 2 | Viewed by 1566
Abstract
Phospholipase D (PLD) isoenzymes participate in a variety of cellular functions that are mostly attributed to phosphatidic acid (PA) synthesis. Dysregulation of PLD regulates tumor progression and metastasis, yet little is known about the underlying mechanism. We previously reported on the expression and [...] Read more.
Phospholipase D (PLD) isoenzymes participate in a variety of cellular functions that are mostly attributed to phosphatidic acid (PA) synthesis. Dysregulation of PLD regulates tumor progression and metastasis, yet little is known about the underlying mechanism. We previously reported on the expression and clinical role of the PLD isoenzymes PLD1 and PLD2 in tubo-ovarian high-grade serous carcinoma (HGSC). In the present study, we investigated the biological function of PLD1 and PLD2 using the OVCAR-3 and OVCAR-8 HGSC cell lines. KO cell lines for both PLDs were generated using CRISPR/CAS9 technology and assayed for exosome secretion, spheroid formation, migration, invasion and expression of molecules involved in epithelial-mesenchymal transition (EMT) and intracellular signaling. Significant differences between PLD1 and PLD2 KO cells and controls were observed for all the above parameters, supporting an important role for PLD in regulating migration, invasion, metastasis and EMT. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis 3.0)
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14 pages, 3245 KiB  
Communication
NGF/TRKA Promotes ADAM17-Dependent Cleavage of P75 in Ovarian Cells: Elucidating a Pro-Tumoral Mechanism
by Maritza P. Garrido, Christopher Vallejos, Silvanna Girardi, Fernando Gabler, Alberto Selman, Fernanda López, Margarita Vega and Carmen Romero
Int. J. Mol. Sci. 2022, 23(4), 2124; https://doi.org/10.3390/ijms23042124 - 15 Feb 2022
Cited by 4 | Viewed by 2005
Abstract
Nerve growth factor (NGF) and its high-affinity receptor TRKA are overexpressed in epithelial ovarian cancer (EOC) displaying a crucial role in the disease progression. Otherwise, NGF interacts with its low-affinity receptor P75, activating pro-apoptotic pathways. In neurons, P75 could be cleaved by metalloproteinases [...] Read more.
Nerve growth factor (NGF) and its high-affinity receptor TRKA are overexpressed in epithelial ovarian cancer (EOC) displaying a crucial role in the disease progression. Otherwise, NGF interacts with its low-affinity receptor P75, activating pro-apoptotic pathways. In neurons, P75 could be cleaved by metalloproteinases (α and γ-secretases), leading to a decrease in P75 signaling. Therefore, this study aimed to evaluate whether the shedding of P75 occurs in EOC cells and whether NGF/TRKA could promote the cleavage of the P75 receptor. The immunodetection of the α-secretase, ADAM17, TRKA, P75, and P75 fragments was assessed by immunohisto/cytochemistry and Western blot in biopsies and ovarian cell lines. The TRKA and secretases’ inhibition was performed using specific inhibitors. The results show that P75 immunodetection decreased during EOC progression and was negatively correlated with the presence of TRKA in EOC biopsies. NGF/TRKA increases ADAM17 levels and the fragments of P75 in ovarian cells. This effect is abolished when cells are previously treated with ADAM17, γ-secretase, and TRKA inhibitors. These results indicate that NGF/TRKA promotes the shedding of P75, involving the activation of secretases such as ADAM17. Since ADAM17 has been proposed as a screening marker for early detection of EOC, our results contribute to understanding better the role of ADAM17 and NGF/TRKA in EOC pathogenesis, which includes the NGF/TRKA-mediated cleavage of P75. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis 3.0)
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18 pages, 7062 KiB  
Article
Ovarian Cancer Cells in Ascites Form Aggregates That Display a Hybrid Epithelial-Mesenchymal Phenotype and Allows Survival and Proliferation of Metastasizing Cells
by Sonia Capellero, Jessica Erriquez, Chiara Battistini, Roberta Porporato, Giulia Scotto, Fulvio Borella, Maria F. Di Renzo, Giorgio Valabrega and Martina Olivero
Int. J. Mol. Sci. 2022, 23(2), 833; https://doi.org/10.3390/ijms23020833 - 13 Jan 2022
Cited by 13 | Viewed by 2902
Abstract
Peritoneal metastases are the leading cause of morbidity and mortality in ovarian cancer. Cancer cells float in peritoneal fluid, named ascites, together with a definitely higher number of non neo-neoplastic cells, as single cells or multicellular aggregates. The aim of this work is [...] Read more.
Peritoneal metastases are the leading cause of morbidity and mortality in ovarian cancer. Cancer cells float in peritoneal fluid, named ascites, together with a definitely higher number of non neo-neoplastic cells, as single cells or multicellular aggregates. The aim of this work is to uncover the features that make these aggregates the metastasizing units. Immunofluorescence revealed that aggregates are made almost exclusively of ovarian cancer cells expressing the specific nuclear PAX8 protein. The same cells expressed epithelial and mesenchymal markers, such as EPCAM and αSMA, respectively. Expression of fibronectin further supported a hybrid epithelia-mesenchymal phenotype, that is maintained when aggregates are cultivated and proliferate. Hematopoietic cells as well as macrophages are negligible in the aggregates, while abundant in the ascitic fluid confirming their prominent role in establishing an eco-system necessary for the survival of ovarian cancer cells. Using ovarian cancer cell lines, we show that cells forming 3D structures neo-expressed thoroughly fibronectin and αSMA. Functional assays showed that αSMA and fibronectin are necessary for the compaction and survival of 3D structures. Altogether these data show that metastasizing units display a hybrid phenotype that allows maintenance of the 3D structures and the plasticity necessary for implant and seeding into peritoneal lining. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis 3.0)
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15 pages, 1680 KiB  
Article
Identification of a Novel Oncogenic Fusion Gene SPON1-TRIM29 in Clinical Ovarian Cancer That Promotes Cell and Tumor Growth and Enhances Chemoresistance in A2780 Cells
by Saya Nagasawa, Kazuhiro Ikeda, Daisuke Shintani, Chiujung Yang, Satoru Takeda, Kosei Hasegawa, Kuniko Horie and Satoshi Inoue
Int. J. Mol. Sci. 2022, 23(2), 689; https://doi.org/10.3390/ijms23020689 - 08 Jan 2022
Cited by 3 | Viewed by 2117
Abstract
Gene structure alterations, such as chromosomal rearrangements that develop fusion genes, often contribute to tumorigenesis. It has been shown that the fusion genes identified in public RNA-sequencing datasets are mainly derived from intrachromosomal rearrangements. In this study, we explored fusion transcripts in clinical [...] Read more.
Gene structure alterations, such as chromosomal rearrangements that develop fusion genes, often contribute to tumorigenesis. It has been shown that the fusion genes identified in public RNA-sequencing datasets are mainly derived from intrachromosomal rearrangements. In this study, we explored fusion transcripts in clinical ovarian cancer specimens based on our RNA-sequencing data. We successfully identified an in-frame fusion transcript SPON1-TRIM29 in chromosome 11 from a recurrent tumor specimen of high-grade serous carcinoma (HGSC), which was not detected in the corresponding primary carcinoma, and validated the expression of the identical fusion transcript in another tumor from a distinct HGSC patient. Ovarian cancer A2780 cells stably expressing SPON1-TRIM29 exhibited an increase in cell growth, whereas a decrease in apoptosis was observed, even in the presence of anticancer drugs. The siRNA-mediated silencing of SPON1-TRIM29 fusion transcript substantially impaired the enhanced growth of A2780 cells expressing the chimeric gene treated with anticancer drugs. Moreover, a subcutaneous xenograft model using athymic mice indicated that SPON1-TRIM29-expressing A2780 cells rapidly generated tumors in vivo compared to control cells, whose growth was significantly repressed by the fusion-specific siRNA administration. Overall, the SPON1-TRIM29 fusion gene could be involved in carcinogenesis and chemotherapy resistance in ovarian cancer, and offers potential use as a diagnostic and therapeutic target for the disease with the fusion transcript. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis 3.0)
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13 pages, 1976 KiB  
Article
Long Intergenic Noncoding RNA OIN1 Promotes Ovarian Cancer Growth by Modulating Apoptosis-Related Gene Expression
by Toshihiko Takeiwa, Yuichi Mitobe, Kazuhiro Ikeda, Kosei Hasegawa, Kuniko Horie and Satoshi Inoue
Int. J. Mol. Sci. 2021, 22(20), 11242; https://doi.org/10.3390/ijms222011242 - 18 Oct 2021
Cited by 6 | Viewed by 2308
Abstract
Patients with advanced ovarian cancer usually exhibit high mortality rates, thus more efficient therapeutic strategies are expected to be developed. Recent transcriptomic studies revealed that long intergenic noncoding RNAs (lincRNAs) can be a new class of molecular targets for cancer management, because lincRNAs [...] Read more.
Patients with advanced ovarian cancer usually exhibit high mortality rates, thus more efficient therapeutic strategies are expected to be developed. Recent transcriptomic studies revealed that long intergenic noncoding RNAs (lincRNAs) can be a new class of molecular targets for cancer management, because lincRNAs likely exert tissue-specific activities compared with protein-coding genes or other noncoding RNAs. We here show that an unannotated lincRNA originated from chromosome 10q21 and designated as ovarian cancer long intergenic noncoding RNA 1 (OIN1), is often overexpressed in ovarian cancer tissues compared with normal ovaries as analyzed by RNA sequencing. OIN1 silencing by specific siRNAs significantly exerted proliferation inhibition and enhanced apoptosis in ovarian cancer cells. Notably, RNA sequencing showed that OIN1 expression was negatively correlated with the expression of apoptosis-related genes ras association domain family member 5 (RASSF5) and adenosine A1 receptor (ADORA1), which were upregulated by OIN1 knockdown in ovarian cancer cells. OIN1-specifc siRNA injection was effective to suppress in vivo tumor growth of ovarian cancer cells inoculated in immunodeficient mice. Taken together, OIN1 could function as a tumor-promoting lincRNA in ovarian cancer through modulating apoptosis and will be a potential molecular target for ovarian cancer management. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis 3.0)
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15 pages, 4938 KiB  
Article
Trace Amine-Associated Receptor 1 (TAAR1) Is a Positive Prognosticator for Epithelial Ovarian Cancer
by Tilman L. R. Vogelsang, Aurelia Vattai, Elisa Schmoeckel, Till Kaltofen, Anca Chelariu-Raicu, Mingjun Zheng, Sven Mahner, Doris Mayr, Udo Jeschke and Fabian Trillsch
Int. J. Mol. Sci. 2021, 22(16), 8479; https://doi.org/10.3390/ijms22168479 - 06 Aug 2021
Cited by 7 | Viewed by 1873
Abstract
Trace amine-associated receptor 1 (TAAR1) is a Gαs- protein coupled receptor that plays an important role in the regulation of the immune system and neurotransmission in the CNS. In ovarian cancer cell lines, stimulation of TAAR1 via 3-iodothyronamine (T1AM) [...] Read more.
Trace amine-associated receptor 1 (TAAR1) is a Gαs- protein coupled receptor that plays an important role in the regulation of the immune system and neurotransmission in the CNS. In ovarian cancer cell lines, stimulation of TAAR1 via 3-iodothyronamine (T1AM) reduces cell viability and induces cell death and DNA damage. Aim of this study was to evaluate the prognostic value of TAAR1 on overall survival of ovarian carcinoma patients and the correlation of TAAR1 expression with clinical parameters. Ovarian cancer tissue of n = 156 patients who were diagnosed with epithelial ovarian cancer (serous, n = 110 (high-grade, n = 80; low-grade, n = 24; unknown, n = 6); clear cell, n = 12; endometrioid, n = 21; mucinous, n = 13), and who underwent surgery at the Department of Obstetrics and Gynecology, University Hospital of the Ludwig-Maximilians University Munich, Germany between 1990 and 2002, were analyzed. The tissue was stained immunohistochemically with anti-TAAR1 and evaluated with the semiquantitative immunoreactive score (IRS). TAAR1 expression was correlated with grading, FIGO and TNM-classification, and analyzed via the Spearman’s rank correlation coefficient. Further statistical analysis was obtained using nonparametric Kruskal-Wallis rank-sum test and Mann-Whitney-U-test. This study shows that high TAAR1 expression is a positive prognosticator for overall survival in ovarian cancer patients and is significantly enhanced in low-grade serous carcinomas compared to high-grade serous carcinomas. The influence of TAAR1 as a positive prognosticator on overall survival indicates a potential prognostic relevance of signal transduction of thyroid hormone derivatives in epithelial ovarian cancer. Further studies are required to evaluate TAAR1 and its role in the development of ovarian cancer. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis 3.0)
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