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Recent Advances in Molecular Biology and Treatment Strategies for Refractory...
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Recent Advances in Molecular Biology and Treatment Strategies for Refractory Ovarian Cancer

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

Deadline for manuscript submissions: closed (30 January 2022) | Viewed by 24280

Special Issue Editors

Dr. Toru Sugiyama

E-Mail Website
Guest Editor
Department of Obstetrics and Gynecology, St. Mary's Hospital, Kurume, Japan
Interests: gynecological cancer; ovarian cancer; endometrial cancer; cervical cancer
Prof. Dr. Hiroaki Itamochi

E-Mail Website
Guest Editor
Department of Clinical Oncology, Iwate Medical University, Yahaba, Japan
Interests: gynecological cancer; ovarian cancer; endometrial cancer; cervical cancer; molecular biology; molecular genetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

The incidence of ovarian cancer in 2018 was projected to be 295,414 new cases with 184,799 deaths worldwide. These figures represent 3.4% and 4.4% of all female cancers and all cancer deaths in women, respectively. Despite the emergence of targeted therapies such as bevacizumab and PARP inhibitors, cytoreductive surgery followed by chemotherapy (platinum + taxane) is currently the mainstay of treatment for epithelial ovarian cancer (EOC). Although this treatment initially yields a high response rate (>80%), recurrences are inevitable, and oftentimes patients develop resistance to platinum and taxane.

Resistance to chemotherapy remains a challenge when treating patients with EOC. The recent identification of biological characteristics of EOC has shown that the serous type appears to be more sensitive to chemotherapy than other histological subtypes. Patients with clear cell carcinoma or mucinous carcinoma of the ovary have shown a significantly worse prognosis that is thought to reflect the resistance of these tumors to conventional chemotherapy. Therefore, effective and novel treatment strategies (e.g., incorporating molecular targeted agents) are required to improve outcomes for patients with advanced EOC.

The study of EOC at a molecular level could reveal potential biomarkers of disease diagnosis and progression, as well as possible therapeutic targets in areas such as angiogenesis and homologous recombination deficiencies. Recently, high-throughput sequencing of DNA has been successfully applied to several cancers, enabling the discovery of cancer genes and network-attacking mutations that can possibly translate into advances in cancer diagnosis and treatment. This Special Issue will highlight the identification of prognostic and predictive markers for EOC and the molecular mechanisms of the most promising targeted agents under clinical evaluation.

Dr. Toru Sugiyama
Prof. Hiroaki Itamochi
Guest Editors

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 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. 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

  • molecular biology
  • ovarian cancer
  • clear cell carcinoma
  • mucinous carcinoma
  • targeted agent

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Published Papers (7 papers)

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Research

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14 pages, 2171 KiB  
Article
Lipid Droplet Accumulation Independently Predicts Poor Clinical Prognosis in High-Grade Serous Ovarian Carcinoma
by Naoyuki Iwahashi, Midori Ikezaki, Masakazu Fujimoto, Yoshihiro Komohara, Yukio Fujiwara, Madoka Yamamoto, Mika Mizoguchi, Kentaro Matsubara, Yudai Watanabe, Ibu Matsuzaki, Shin-ichi Murata, Yoshito Ihara, Kazuhiko Ino and Kazuchika Nishitsuji
Cancers 2021, 13(20), 5251; https://doi.org/10.3390/cancers13205251 - 19 Oct 2021
Cited by 9 | Viewed by 2790
Abstract
High-grade serous ovarian carcinoma (HGSOC) is an epithelial cancer that accounts for most ovarian cancer deaths. Metabolic abnormalities such as extensive aerobic glycolysis and aberrant lipid metabolism are well-known characteristics of cancer cells. Indeed, accumulation of lipid droplets (LDs) in certain types of [...] Read more.
High-grade serous ovarian carcinoma (HGSOC) is an epithelial cancer that accounts for most ovarian cancer deaths. Metabolic abnormalities such as extensive aerobic glycolysis and aberrant lipid metabolism are well-known characteristics of cancer cells. Indeed, accumulation of lipid droplets (LDs) in certain types of malignant tumors has been known for more than 50 years. Here, we investigated the correlation between LD accumulation and clinical prognosis. In 96 HGSOC patients, we found that high expression of the LD marker adipophilin was associated with poor progression-free and overall survival (p = 0.0022 and p = 0.014, respectively). OVCAR-3 ovarian carcinoma cells accumulated LDs in a glucose-dependent manner, which suggested the involvement of aerobic glycolysis and subsequently enhanced lipogenesis, with a result being LD accumulation. The acyl-CoA: cholesterol acyltransferase 1 inhibitor K604 and the hydroxymethylglutaryl-CoA reductase inhibitor pitavastatin blocked LD accumulation in OVCAR-3 cells and reduced phosphorylation of the survival-related kinases Akt and ERK1/2, both of which have been implicated in malignancy. Our cell-based assays thus suggested that enhanced aerobic glycolysis resulted in LD accumulation and activation of survival-related kinases. Overall, our results support the idea that cancers with lipogenic phenotypes are associated with poor clinical prognosis, and we suggest that adipophilin may serve as an independent indicator of a poor prognosis in HGSOC. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Biology and Treatment Strategies for Refractory Ovarian Cancer)
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10 pages, 846 KiB  
Article
A Novel Predictive Tool for Discriminating Endometriosis Associated Ovarian Cancer from Ovarian Endometrioma: The R2 Predictive Index
by Naoki Kawahara, Ryuta Miyake, Shoichiro Yamanaka and Hiroshi Kobayashi
Cancers 2021, 13(15), 3829; https://doi.org/10.3390/cancers13153829 - 29 Jul 2021
Cited by 12 | Viewed by 2210
Abstract
Background: Magnetic resonance (MR) relaxometry provides a noninvasive tool to discriminate between ovarian endometrioma (OE) and endometriosis-associated ovarian cancer (EAOC), with a sensitivity and specificity of 86% and 94%, respectively. MRI models that can measure R2 values are limited, and the R2 values [...] Read more.
Background: Magnetic resonance (MR) relaxometry provides a noninvasive tool to discriminate between ovarian endometrioma (OE) and endometriosis-associated ovarian cancer (EAOC), with a sensitivity and specificity of 86% and 94%, respectively. MRI models that can measure R2 values are limited, and the R2 values differ between MRI models. This study aims to extract the factors contributing to the R2 value, and to make a formula for estimating the R2 values, and to assess whether the R2 predictive index calculated by the formula could discriminate EAOC from OE. Methods: This retrospective study was conducted at our institution from November 2012 to February 2019. A total of 247 patients were included in this study. Patients with benign ovarian tumors mainly received laparoscopic surgery, and the patients suspected of having malignant tumors underwent laparotomy. Information from a chart review of the patients’ medical records was collected. Results: In the investigative cohort, among potential factors correlated with the R2 value, multiple regression analyses revealed that tumor diameter and CEA could predict the R2 value. In the validation cohort, multivariate analysis confirmed that age, CRP, and the R2 predictive index were the independent factors. Conclusions: The R2 predictive index is useful and valuable to the detection of the malignant transformation of endometrioma. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Biology and Treatment Strategies for Refractory Ovarian Cancer)
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Review

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18 pages, 1389 KiB  
Review
The Role of Mesothelin Expression in Serous Ovarian Carcinoma: Impacts on Diagnosis, Prognosis, and Therapeutic Targets
by Giovanna Giordano, Elena Ferioli and Alessandro Tafuni
Cancers 2022, 14(9), 2283; https://doi.org/10.3390/cancers14092283 - 3 May 2022
Cited by 10 | Viewed by 3252
Abstract
Mesothelin (MSLN) is a protein expressed in the mesothelial cell lining of the pleura, peritoneum, and pericardium; its biological functions in normal cells are still unknown. Experimental studies using knockout mice have suggested that this molecule does not play an important role in [...] Read more.
Mesothelin (MSLN) is a protein expressed in the mesothelial cell lining of the pleura, peritoneum, and pericardium; its biological functions in normal cells are still unknown. Experimental studies using knockout mice have suggested that this molecule does not play an important role in development and reproduction. In contrast, it has been observed that this molecule is produced in abnormal amounts in several malignant neoplasms, such as mesotheliomas and pancreatic adenocarcinomas. Many molecular studies have also demonstrated that mesothelin is overexpressed in HSOCs. Here, we discuss the current knowledge of mesothelin and focus on its role in clinical and pathological diagnoses, as well as its impact on the prognosis of HSOC. Moreover, regarding the binding of MSLN to the ovarian cancer antigen CA125, which has been demonstrated in many studies, we also report on signal transduction pathways that may play an important role in the spread and neoplastic progression of this lethal neoplasm. Given that mesothelin is overexpressed in many solid tumours and has antigenic properties, this molecule could be considered an antigenic target for the treatment of many malignancies. Consequently, we also review the literature to report on mesothelin-targeting therapies for HSOC that have been recently investigated in many clinical studies. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Biology and Treatment Strategies for Refractory Ovarian Cancer)
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20 pages, 807 KiB  
Review
Therapeutic Strategies Focused on Cancer-Associated Hypercoagulation for Ovarian Clear Cell Carcinoma
by Ryo Tamura, Kosuke Yoshihara and Takayuki Enomoto
Cancers 2022, 14(9), 2125; https://doi.org/10.3390/cancers14092125 - 24 Apr 2022
Cited by 12 | Viewed by 3631
Abstract
Ovarian clear cell carcinoma (OCCC) is associated with chemotherapy resistance and poor prognosis, especially in advanced cases. Although comprehensive genomic analyses have clarified the significance of genomic alterations such as ARID1A and PIK3CA mutations in OCCC, therapeutic strategies based on genomic alterations have [...] Read more.
Ovarian clear cell carcinoma (OCCC) is associated with chemotherapy resistance and poor prognosis, especially in advanced cases. Although comprehensive genomic analyses have clarified the significance of genomic alterations such as ARID1A and PIK3CA mutations in OCCC, therapeutic strategies based on genomic alterations have not been confirmed. On the other hand, OCCC is clinically characterized by a high incidence of thromboembolism. Moreover, OCCC specifically shows high expression of tissue factor and interleukin-6, which play a critical role in cancer-associated hypercoagulation and may be induced by OCCC-specific genetic alterations or the endometriosis-related tumor microenvironment. In this review, we focused on the association between cancer-associated hypercoagulation and molecular biology in OCCC. Moreover, we reviewed the effectiveness of candidate drugs targeting hypercoagulation, such as tissue factor- or interleukin-6-targeting drugs, anti-inflammatory drugs, anti-hypoxia signaling drugs, anticoagulants, and combined immunotherapy with these drugs for OCCC. This review is expected to contribute to novel basic research and clinical trials for the prevention, early detection, and treatment of OCCC focused on hypercoagulation. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Biology and Treatment Strategies for Refractory Ovarian Cancer)
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26 pages, 820 KiB  
Review
Comparing the Secretomes of Chemorefractory and Chemoresistant Ovarian Cancer Cell Populations
by Amy H. Lee, Carolina Mejia Peña and Michelle R. Dawson
Cancers 2022, 14(6), 1418; https://doi.org/10.3390/cancers14061418 - 10 Mar 2022
Cited by 7 | Viewed by 5180
Abstract
High-grade serous ovarian cancer (HGSOC) constitutes the majority of all ovarian cancer cases and has staggering rates of both refractory and recurrent disease. While most patients respond to the initial treatment with paclitaxel and platinum-based drugs, up to 25% do not, and of [...] Read more.
High-grade serous ovarian cancer (HGSOC) constitutes the majority of all ovarian cancer cases and has staggering rates of both refractory and recurrent disease. While most patients respond to the initial treatment with paclitaxel and platinum-based drugs, up to 25% do not, and of the remaining that do, 75% experience disease recurrence within the subsequent two years. Intrinsic resistance in refractory cases is driven by environmental stressors like tumor hypoxia which alter the tumor microenvironment to promote cancer progression and resistance to anticancer drugs. Recurrent disease describes the acquisition of chemoresistance whereby cancer cells survive the initial exposure to chemotherapy and develop adaptations to enhance their chances of surviving subsequent treatments. Of the environmental stressors cancer cells endure, exposure to hypoxia has been identified as a potent trigger and priming agent for the development of chemoresistance. Both in the presence of the stress of hypoxia or the therapeutic stress of chemotherapy, cancer cells manage to cope and develop adaptations which prime populations to survive in future stress. One adaptation is the modification in the secretome. Chemoresistance is associated with translational reprogramming for increased protein synthesis, ribosome biogenesis, and vesicle trafficking. This leads to increased production of soluble proteins and extracellular vesicles (EVs) involved in autocrine and paracrine signaling processes. Numerous studies have demonstrated that these factors are largely altered between the secretomes of chemosensitive and chemoresistant patients. Such factors include cytokines, growth factors, EVs, and EV-encapsulated microRNAs (miRNAs), which serve to induce invasive molecular, biophysical, and chemoresistant phenotypes in neighboring normal and cancer cells. This review examines the modifications in the secretome of distinct chemoresistant ovarian cancer cell populations and specific secreted factors, which may serve as candidate biomarkers for aggressive and chemoresistant cancers. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Biology and Treatment Strategies for Refractory Ovarian Cancer)
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13 pages, 311 KiB  
Review
Novel Therapeutic Strategies for Refractory Ovarian Cancers: Clear Cell and Mucinous Carcinomas
by Tadahiro Shoji, Shunsuke Tatsuki, Marina Abe, Hidetoshi Tomabechi, Eriko Takatori, Yoshitaka Kaido, Takayuki Nagasawa, Masahiro Kagabu, Tsukasa Baba and Hiroaki Itamochi
Cancers 2021, 13(23), 6120; https://doi.org/10.3390/cancers13236120 - 4 Dec 2021
Cited by 6 | Viewed by 3260
Abstract
Ovarian cancer has the worst prognosis among gynecological cancers. In particular, clear cell and mucinous carcinomas are less sensitive to chemotherapy. The establishment of new therapies is necessary to improve the treatment outcomes for these carcinomas. In previous clinical studies, chemotherapy with cytotoxic [...] Read more.
Ovarian cancer has the worst prognosis among gynecological cancers. In particular, clear cell and mucinous carcinomas are less sensitive to chemotherapy. The establishment of new therapies is necessary to improve the treatment outcomes for these carcinomas. In previous clinical studies, chemotherapy with cytotoxic anticancer drugs has failed to demonstrate better treatment outcomes than paclitaxel + carboplatin therapy. In recent years, attention has been focused on treatment with molecular target drugs and immune checkpoint inhibitors that target newly identified biomarkers. The issues that need to be addressed include the most appropriate combination of therapies, identifying patients who may benefit from each therapy, and how results should be incorporated into the standard of care for ovarian clear cell and mucinous carcinomas. In this article, we have reviewed the most promising therapies for ovarian clear cell and mucinous carcinomas, which are regarded as intractable, with an emphasis on therapies currently being investigated in clinical studies. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Biology and Treatment Strategies for Refractory Ovarian Cancer)

Other

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21 pages, 543 KiB  
Systematic Review
New Achievements from Molecular Biology and Treatment Options for Refractory/Relapsed Ovarian Cancer—A Systematic Review
by Cornelia Bachmann
Cancers 2023, 15(22), 5356; https://doi.org/10.3390/cancers15225356 - 10 Nov 2023
Cited by 5 | Viewed by 2730
Abstract
Ovarian cancer (OC) has a high rate of mortality and is the fifth most common cause of death in females all over the world. The etiology is still unclear. Numerous factors such as smoking, obesity, and unhealthy diet may affect the risk of [...] Read more.
Ovarian cancer (OC) has a high rate of mortality and is the fifth most common cause of death in females all over the world. The etiology is still unclear. Numerous factors such as smoking, obesity, and unhealthy diet may affect the risk of OC. Having a family history of breast and OC is one of the main risks for developing OC. Mutations of BRCA1/2 are associated with OC risk as well. The histopathological classification of OC reveals the four most common types: serous, clear cell, endometrioid, and mucinous; these are epithelial OC types, and other types are rare. Furthermore, OC can be subdivided into types I and II. Type I tumors are most probably caused by atypical proliferative tumors. Type II tumors include high-grade carcinoma of the serous type, carcinosarcoma, and carcinoma, which are not differentiated and generally originate from tubal intraepithelial carcinoma of the serous type. Typically, type I tumors are present in early stages, usually with good prognosis. Type II tumors are classified as high-grade tumors and are most often diagnosed at advanced FIGO stages with poor prognosis. High-grade serous OC accounts for 90% of serous OC. Tumor heterogeneity aggravates OC treatment. The standard care for primary epithelial ovarian cancer (EOC) is cytoreductive surgery followed by platinum-based chemotherapy. Neoadjuvant chemotherapy can be used in certain cases followed by cytoreductive surgery. The main prognostic factor is complete tumor resection. However, about 70% of patients relapse. Resistance to chemotherapeutic agents remains a major challenge in EOC treatment, in which many different factors are involved. In recent years, the examination of molecular parameters and their prognostic impact has become increasingly relevant in EOC, and furthermore, the use of immunotherapy has expanded the therapeutic range. As the clinical need is greatest for relapsed patients, this systematic review will focus on recent advances in molecular biology with prognostic and predictive markers and treatment options for recurrent/refractory OC. Inclusion criteria for the review: potential prospective or predictive biomarkers in preclinical or clinical use in relapsed and refractory OC, prognostic impact, clinical and preclinical trials, and immunotherapy. Exclusion criteria for the review: primary OC, no full text or abstract available, not the topic mentioned above, and text not available in English. Risk of bias: the included studies were evaluated descriptively for the topics mentioned above, and data were not compared with each other. The objective is to highlight the molecular mechanisms of the most promising targeted agents under clinical investigation to demonstrate their potential relevance in recurrent/refractory OC. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Biology and Treatment Strategies for Refractory Ovarian Cancer)
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