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Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies 2.0

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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 (31 May 2021) | Viewed by 26085

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Special Issue Editors

Dr. Carmela Ricciardelli

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Guest Editor

Discipline Obstetrics and Gynaecology, Group Leader Reproductive Cancer Research, Robinson Research Institute, Adelaide Medical School, The University of Adelaide, Adelaide, Australia
Interests: ovarian cancer; tumour microenvironment; extracellular matrix; metastasis
Special Issues, Collections and Topics in MDPI journals

Dr. Hiroaki Kajiyama

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Guest Editor

Nagoya University, Nagoya, Japan
Interests: immunotherapy of ovarian cancer; medical applications of plasma

Prof. Martin Oehler

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Guest Editor

Royal Adelaide Hospital, Adelaide, Australia
Interests: Gynaecological Oncology

Special Issue Information

Dear Colleagues,

This Special Issue calls for a joint collaborative effort to illustrate how the understanding of the molecular mechanisms of gynecological cancers may lead to potential targeted therapies.

Considerable progress has been made in deciphering the molecular mechanisms for gynecologic cancers in the past decade. Integrated genomic analyses of large cohorts of ovarian cancer and uterine cancer, through The Cancer Genome Atlas (TCGA) effort, have generated a large amount of data regarding early mutation events and dysregulated pathways in carcinogenesis. Various clinical trials, based on specific molecular features, are being developed or in early phase clinical studies. Targeting cancer metabolism, tumor microenvironment, and immunotherapy are also in the horizon.

We encourage and invite researchers with related experiences in ovarian cancer, uterine cancer, cervical cancer, or other rare gynecological cancers to contribute original research articles or review articles.

Dr. Hiroaki Kajiyama
Dr. Carmela Ricciardelli
Prof. Martin Oehler
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 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

ovarian cancer
uterine cancer
cervical cancer
tyrosine kinases
growth factor receptors
DNA repair
cell cycle
cancer metabolism
resistance to targeted therapies
immunotherapies

Published Papers (7 papers)

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Research

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13 pages, 2150 KiB

Open AccessArticle

Identification of Novel lncRNAs in Ovarian Cancer and Their Impact on Overall Survival

by Nicholas Cardillo, Douglas Russo, Andreea Newtson, Henry Reyes, Yasmin Lyons, Eric Devor, David Bender, Michael J. Goodheart and Jesus Gonzalez-Bosquet

Int. J. Mol. Sci. 2021, 22(3), 1079; https://doi.org/10.3390/ijms22031079 - 22 Jan 2021

Cited by 9 | Viewed by 2076

Abstract

Long non-coding RNA’s (lncRNA) are RNA sequences that do not encode proteins and are greater than 200 nucleotides in length. They regulate complex cellular mechanisms and have been associated with prognosis in various types of cancer. We aimed to identify lncRNA sequences that are associated with high grade serous ovarian cancer (HGSC) and assess their impact on overall survival. RNA was extracted from 112 HGSC patients and 12 normal fallopian tube samples from our Biobank tissue repository. RNA was sequenced and the Ultrafast and Comprehensive lncRNA detection and quantification pipeline (UClncR) was used for the identification of lncRNA sequences. Univariate logistic and multivariate lasso regression analyses identified lncRNA that was associated with HGSC. Univariate and multivariate Cox proportional hazard ratios were used to evaluate independent predictors of survival. 1943 of 16,325 investigated lncRNA’s were differentially expressed in HGSC as compared to controls (p < 0.001). Nine of these demonstrated association with cancer after multivariate lasso regression. Our multivariate analysis of survival identified four lncRNA’s associated with survival in HGSC. Three out of these four were found to be independently significant after accounting for all clinical covariates. Lastly, seven lncRNAs were independently associated with initial response to chemotherapy; four portended a worse response, while three were associated with improved response. More research is needed, but there is potential for these lncRNAs to be used as biomarkers of HGSC or predictors of treatment outcome in the future. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies 2.0)

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21 pages, 7684 KiB

Open AccessArticle

Reduced Gonadotrophin Receptor Expression Is Associated with a More Aggressive Ovarian Cancer Phenotype

by Janelle Cheung, Noor A. Lokman, Riya D. Abraham, Anne M. Macpherson, Eunice Lee, Frank Grutzner, Nicolae Ghinea, Martin K. Oehler and Carmela Ricciardelli

Int. J. Mol. Sci. 2021, 22(1), 71; https://doi.org/10.3390/ijms22010071 - 23 Dec 2020

Cited by 12 | Viewed by 2889

Abstract

Follicle-stimulating hormone (FSH) and luteinising hormone (LH) play important roles in regulating cell growth and proliferation in the ovary. However, few studies have explored the expression of FSH and LH receptors (FSHR and LHCGR) in ovarian cancer, and their functional roles in cancer progression remain inconclusive. This study investigated the potential impact of both mRNA (FSHR, LHCGR) and protein (FSHR, LHCGR) expression on ovarian cancer progression using publicly available online databases, qRT-PCR (high grade serous ovarian cancers, HGSOC, n = 29 and benign ovarian tumors, n = 17) and immunohistochemistry (HGSOC, n = 144). In addition, we investigated the effect of FSHR and LHCGR siRNA knockdown on the pro-metastatic behavior of serous ovarian cancer cells in vitro. High FSHR or high LHCGR expression in patients with all subtypes of high-grade ovarian cancer was significantly associated with longer progression-free survival (PFS) and overall survival (OS). High FSHR protein expression was associated with increased PFS (p = 0.050) and OS (p = 0.025). HGSOC patients with both high FSHR and high LHCGR protein levels had the best survival outcome, whilst both low FSHR and low LHCGR expression was associated with poorest survival (p = 0.019). Knockdown of FSHR significantly increased the invasion of serous ovarian cancer cells (OVCAR3 and COV362) in vitro. LHCGR knockdown also promoted invasion of COV362 cells. This study highlights that lower FSHR and LHCGR expression is associated with a more aggressive epithelial ovarian cancer phenotype and promotes pro-metastatic behaviour. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies 2.0)

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14 pages, 4760 KiB

Open AccessArticle

Microphthalmia-Associated Transcription Factor-Dependent Melanoma Cell Adhesion Molecule Activation Promotes Peritoneal Metastasis of Ovarian Cancer

by Kazuhisa Kitami, Masato Yoshihara, Yoshihiro Koya, Mai Sugiyama, Shohei Iyoshi, Kaname Uno, Kazumasa Mogi, Sho Tano, Hiroki Fujimoto, Akihiro Nawa, Fumitaka Kikkawa and Hiroaki Kajiyama

Int. J. Mol. Sci. 2020, 21(24), 9776; https://doi.org/10.3390/ijms21249776 - 21 Dec 2020

Cited by 4 | Viewed by 2333

Abstract

Ovarian cancer (OvCa) is one of the leading causes of death due to its high metastasis rate to the peritoneum. Recurrent peritoneal tumors also develop despite the use of conventional platinum-based chemotherapies. Therefore, it is still important to explore the factors associated with peritoneal metastasis, as these predict the prognosis of patients with OvCa. In this study, we investigated the function of microphthalmia-associated transcription factor (MITF), which contributes to the development of melanoma, in epithelial ovarian cancer (OvCa). High MITF expression was significantly associated with a poor prognosis in OvCa. Notably, MITF contributed to the motility and invasion of OvCa cells, and specifically with their peri-mesothelial migration. In addition, MITF-positive cells expressed the melanoma cell adhesion molecule (MCAM/CD146), which was initially identified as a marker of melanoma progression and metastasis, and MCAM expression was regulated by MITF. MCAM was also identified as a significant prognostic factor for poor progression-free survival in patients with OvCa. Collectively, our results suggest that MITF is a novel therapeutic target that potentially promotes peritoneal metastasis of OvCa. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies 2.0)

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15 pages, 1490 KiB

Open AccessArticle

LDOC1 as Negative Prognostic Marker for Vulvar Cancer Patients

by Giulia Wanka, Elisa Schmoeckel, Doris Mayr, Sophie Fuerst, Christina Kuhn, Sven Mahner, Julia Knabl, Maria Margarete Karsten, Christian Dannecker, Helene H. Heidegger, Aurelia Vattai, Udo Jeschke and Julia Jueckstock

Int. J. Mol. Sci. 2020, 21(23), 9287; https://doi.org/10.3390/ijms21239287 - 05 Dec 2020

Cited by 6 | Viewed by 2246

Abstract

So far, studies about targeted therapies and predictive biomarkers for vulva carcinomas are rare. The leucine zipper downregulated in cancer 1 gene (LDOC1) has been identified in various carcinomas as a tumor-relevant protein influencing patients’ survival and prognosis. Due to the lack of information about LDOC1 and its exact functionality, this study focuses on the expression of LDOC1 in vulvar carcinoma cells and its surrounding immune cells as well as its correlation to clinicopathological characteristics and prognosis. Additionally, a possible regulation of LDOC1 in vulvar cancer cell lines via the NF-κB signaling pathway was analyzed. Vulvar carcinoma sections of 157 patients were immunohistochemically stained and examined regarding LDOC1 expression by using the immunoreactive score (IRS). To characterize LDOC1-positively stained immune cell subpopulations, immunofluorescence double staining was performed. The effect of the NF-κB inhibitor C-DIM 12 (3,3′-[(4-chlorophenyl)methylene]bis[1 H-indole]) on vulvar cancer cell lines A431 and SW 954 was measured according to MTT and BrdU assays. Baseline expression levels of LDOC1 in the vulvar cancer cell lines A431 and SW 954 was analyzed by real-time PCR. LDOC1 was expressed by about 90% of the cancer cells in the cytoplasm and about half of the cells in the nucleus. Cytoplasmatic expression of LDOC1 was associated with decreased ten-year overall survival of the patient, whereas nuclear staining showed a negative association with disease-free survival. Infiltrating immune cells were mainly macrophages followed by regulatory T cells. Incubation with C-DIM 12 decreased the cell viability and proliferation of vulvar cancer cell line A431, but not of cell line SW 954. LDOC1 expression on mRNA level was twice as high in the cell line A431 compared to the cell line SW 954. Overexpression of LDOC1 was associated with unfavorable overall and disease-free survival. Tumor growth could be inhibited by C-DIM 12 in vitro if the expressed LDOC1 level was high enough. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies 2.0)

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14 pages, 15672 KiB

Open AccessArticle

Hypoxia Regulates DPP4 Expression, Proteolytic Inactivation, and Shedding from Ovarian Cancer Cells

by Laura R. Moffitt, Maree Bilandzic, Amy L. Wilson, Yiqian Chen, Mark D. Gorrell, Martin K. Oehler, Magdalena Plebanski and Andrew N. Stephens

Int. J. Mol. Sci. 2020, 21(21), 8110; https://doi.org/10.3390/ijms21218110 - 30 Oct 2020

Cited by 11 | Viewed by 2269

Abstract

The treatment of ovarian cancer has not significantly changed in decades and it remains one of the most lethal malignancies in women. The serine protease dipeptidyl peptidase 4 (DPP4) plays key roles in metabolism and immunity, and its expression has been associated with either pro- or anti-tumour effects in multiple tumour types. In this study, we provide the first evidence that DPP4 expression and enzyme activity are uncoupled under hypoxic conditions in ovarian cancer cells. Whilst we identified strong up-regulation of DPP4 mRNA expression under hypoxic growth, the specific activity of secreted DPP4 was paradoxically decreased. Further investigation revealed matrix metalloproteinases (MMP)-dependent inactivation and proteolytic shedding of DPP4 from the cell surface, mediated by at least MMP10 and MMP13. This is the first report of uncoupled DPP4 expression and activity in ovarian cancer cells, and suggests a previously unrecognized, cell- and tissue-type-dependent mechanism for the regulation of DPP4 in solid tumours. Further studies are necessary to identify the functional consequences of DPP4 processing and its potential prognostic or therapeutic value. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies 2.0)

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Review

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16 pages, 1048 KiB

Open AccessReview

Molecular Features and Clinical Management of Hereditary Gynecological Cancers

by Arisa Ueki and Akira Hirasawa

Int. J. Mol. Sci. 2020, 21(24), 9504; https://doi.org/10.3390/ijms21249504 - 14 Dec 2020

Cited by 13 | Viewed by 3368

Abstract

Hereditary gynecological cancers are caused by several inherited genes. Tumors that arise in the female reproductive system, such as ovaries and the uterus, overlap with hereditary cancers. Several hereditary cancer-related genes are important because they might lead to therapeutic targets. Treatment of hereditary cancers should be updated in line with the advent of various new methods of evaluation. Next-generation sequencing has led to rapid, economical genetic analyses that have prompted a concomitant and significant paradigm shift with respect to hereditary cancers. Molecular tumor profiling is an epochal method for determining therapeutic targets. Clinical treatment strategies are now being designed based on biomarkers based on tumor profiling. Furthermore, the National Comprehensive Cancer Network (NCCN) guidelines significantly changed the genetic testing process in 2020 to initially consider multi-gene panel (MGP) evaluation. Here, we reviewed the molecular features and clinical management of hereditary gynecological malignancies, such as hereditary breast and ovarian cancer (HBOC), and Lynch, Li–Fraumeni, Cowden, and Peutz–Jeghers syndromes. We also reviewed cancer-susceptible genes revealed by MGP tests. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies 2.0)

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24 pages, 1185 KiB

Open AccessReview

Recycling the Purpose of Old Drugs to Treat Ovarian Cancer

by Mariana Nunes, Miguel Henriques Abreu, Carla Bartosch and Sara Ricardo

Int. J. Mol. Sci. 2020, 21(20), 7768; https://doi.org/10.3390/ijms21207768 - 20 Oct 2020

Cited by 17 | Viewed by 10110

Abstract

The main challenge in ovarian cancer treatment is the management of recurrences. Facing this scenario, therapy selection is based on multiple factors to define the best treatment sequence. Target therapies, such as bevacizumab and polymerase (PARP) inhibitors, improved patient survival. However, despite their achievements, ovarian cancer survival remains poor; these therapeutic options are highly costly and can be associated with potential side effects. Recently, it has been shown that the combination of repurposed, conventional, chemotherapeutic drugs could be an alternative, presenting good patient outcomes with few side effects and low costs for healthcare institutions. The main aim of this review is to strengthen the importance of repurposed drugs as therapeutic alternatives, and to propose an in vitro model to assess the therapeutic value. Herein, we compiled the current knowledge on the most promising non-oncological drugs for ovarian cancer treatment, focusing on statins, metformin, bisphosphonates, ivermectin, itraconazole, and ritonavir. We discuss the primary drug use, anticancer mechanisms, and applicability in ovarian cancer. Finally, we propose the use of these therapies to perform drug efficacy tests in ovarian cancer ex vivo cultures. This personalized testing approach could be crucial to validate the existing evidences supporting the use of repurposed drugs for ovarian cancer treatment. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies 2.0)

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