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Molecular Mechanisms of Ovarian Cancer Development and Metastasis 2.0
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Molecular Mechanisms of Ovarian Cancer Development and Metastasis 2.0

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 (31 December 2020) | Viewed by 21759

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 previous 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 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 2.0”, 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. 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 when it comes to 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. 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.

Published Papers (6 papers)

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Research

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24 pages, 30045 KiB  
Article
Impact of Selected Signaling Proteins on SNAIL 1 and SNAIL 2 Expression in Ovarian Cancer Cell Lines in Relation to Cells’ Cisplatin Resistance and EMT Markers Level
by Michal Kielbik, Izabela Szulc-Kielbik and Magdalena Klink
Int. J. Mol. Sci. 2021, 22(2), 980; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020980 - 19 Jan 2021
Cited by 12 | Viewed by 3206
Abstract
It has been increasingly recognized that SNAIL1 and SNAIL2, as major EMT-inducers, might also be involved in drug resistance of cancer cells. We sought to determine a relation between SNAIL1/2, E-cadherin and N-cadherin expression, as well as ovarian cancer cells’ resistance to cisplatin [...] Read more.
It has been increasingly recognized that SNAIL1 and SNAIL2, as major EMT-inducers, might also be involved in drug resistance of cancer cells. We sought to determine a relation between SNAIL1/2, E-cadherin and N-cadherin expression, as well as ovarian cancer cells’ resistance to cisplatin and EMT markers’ level. Thus, four ovarian cancer cell lines, were used: A2780, A2780cis, SK-OV-3 and OVCAR-3. We assessed the impact of ERK1/2, AKT and STAT3 proteins (chosen by the profiling activity of over 40 signaling proteins) on SNAIL1/2 expression, along with E-cadherin and N-cadherin levels. We showed that expression of SNAIL1 and N-cadherin are the highest in cisplatin-resistant A2780cis and SK-OV-3 cells, while high SNAIL2 and E-cadherin levels were observed in cisplatin-sensitive A2780 cells. The highest E-cadherin level was noticed in OVCAR-3 cells. SNAIL1/2 expression was dependent on ERK1/2 activity in cisplatin-resistant and potentially invasive SK-OV-3 and OVCAR-3 cells. STAT-3 regulates expression of SNAIL1/2 and leads to the so-called “cadherin switch” in cancer cells, independently of their chemoresistance. In conclusion, SNAIL1, but not SNAIL2, seems to be involved in ovarian cancer cells’ cisplatin resistance. STAT3 is a universal factor determining the expression of SNAIL1/2 in ovarian cancer cells regardless of their chemoresitance or invasive capabilities. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis 2.0)
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13 pages, 2063 KiB  
Article
Sitagliptin Modulates the Response of Ovarian Cancer Cells to Chemotherapeutic Agents
by Agnieszka Kosowska, Wojciech Garczorz, Agnieszka Kłych-Ratuszny, Mohammad Reza F. Aghdam, Małgorzata Kimsa-Furdzik, Klaudia Simka-Lampa and Tomasz Francuz
Int. J. Mol. Sci. 2020, 21(23), 8976; https://doi.org/10.3390/ijms21238976 - 26 Nov 2020
Cited by 11 | Viewed by 2151
Abstract
The strong association between diabetes mellitus type 2 and cancer is observed. The incidence of both diseases is increasing globally due to the interaction between them. Recent studies suggest that there is also an association between cancer incidence and anti-diabetic medications. An inhibitor [...] Read more.
The strong association between diabetes mellitus type 2 and cancer is observed. The incidence of both diseases is increasing globally due to the interaction between them. Recent studies suggest that there is also an association between cancer incidence and anti-diabetic medications. An inhibitor of dipeptidyl-peptidase 4 (DPP-4), sitagliptin, is used in diabetes treatment. We examined the influence of sitagliptin alone or in combination with a cytostatic drug (paclitaxel) on the development of epithelial ovarian cancer cells and the process of metastasis. We examined migration, invasiveness, apoptosis, and metalloproteinases (MMPs) and their inhibitors’ (TIMPs) production in two human ovarian cancer cell lines. Sitagliptin induced apoptosis by caspase 3/7 activation in paclitaxel-treated SKOV-3 and OVCAR-3 cells. Sitagliptin maintained paclitaxel influence on ERK and Akt signaling pathways. Sitagliptin additionally reduced migration and invasiveness of SKOV-3 cells. There were distinct differences of metalloproteinases production in sitagliptin-stimulated ovarian cancer cells in both cell lines, despite their identical histological classification. Only the SKOV-3 cell line expressed MMPs and TIMPs. SKOV-3 cells co-treated with sitagliptin and paclitaxel decreased concentrations of MMP-1, MMP-2, MMP-7, MMP-10, TIMP-1, TIMP-2. The obtained data showed that sitagliptin used with paclitaxel may be considered as a possibility of pharmacological modulation of intracellular transmission pathways to improve the response to chemotherapy. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis 2.0)
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21 pages, 8900 KiB  
Article
NGF/TRKA Decrease miR-145-5p Levels in Epithelial Ovarian Cancer Cells
by Maritza P. Garrido, Ignacio Torres, Alba Avila, Jonás Chnaiderman, Manuel Valenzuela-Valderrama, José Aramburo, Lorena Oróstica, Eduardo Durán-Jara, Lorena Lobos-Gonzalez and Carmen Romero
Int. J. Mol. Sci. 2020, 21(20), 7657; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207657 - 16 Oct 2020
Cited by 20 | Viewed by 3631
Abstract
Nerve Growth Factor (NGF) and its high-affinity receptor tropomyosin receptor kinase A (TRKA) increase their expression during the progression of epithelial ovarian cancer (EOC), promoting cell proliferation and angiogenesis through several oncogenic proteins, such as c-MYC and vascular endothelial growth factor (VEGF). The [...] Read more.
Nerve Growth Factor (NGF) and its high-affinity receptor tropomyosin receptor kinase A (TRKA) increase their expression during the progression of epithelial ovarian cancer (EOC), promoting cell proliferation and angiogenesis through several oncogenic proteins, such as c-MYC and vascular endothelial growth factor (VEGF). The expression of these proteins is controlled by microRNAs (miRs), such as miR-145, whose dysregulation has been related to cancer. The aims of this work were to evaluate in EOC cells whether NGF/TRKA decreases miR-145 levels, and the effect of miR-145 upregulation. The levels of miR-145-5p were assessed by qPCR in ovarian biopsies and ovarian cell lines (human ovarian surface epithelial cells (HOSE), A2780 and SKOV3) stimulated with NGF. Overexpression of miR-145 in ovarian cells was used to evaluate cell proliferation, migration, invasion, c-MYC and VEGF protein levels, as well as tumor formation and metastasis in vivo. In EOC samples, miR-145-5p levels were lower than in epithelial ovarian tumors. Overexpression of miR-145 decreased cell proliferation, migration and invasion of EOC cells, changes that were concomitant with the decrease in c-MYC and VEGF protein levels. We observed decreased tumor formation and suppressed metastasis behavior in mice injected with EOC cells that overexpressed miR-145. As expected, ovarian cell lines stimulated with NGF diminished miR-145-5p transcription and abundance. These results suggest that the tumoral effects of NGF/TRKA depend on the regulation of miR-145-5p levels in EOC cells, and that its upregulation could be used as a possible therapeutic strategy for EOC. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis 2.0)
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17 pages, 6064 KiB  
Article
Characteristics of CD133-Sustained Chemoresistant Cancer Stem-Like Cells in Human Ovarian Carcinoma
by Chao Lien Liu, Ying Jen Chen, Ming Huei Fan, Yi Jen Liao and Tsui Lien Mao
Int. J. Mol. Sci. 2020, 21(18), 6467; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186467 - 04 Sep 2020
Cited by 15 | Viewed by 3081
Abstract
Cancer stem cells (CSCs) are considered to be the origin of ovarian cancer (OC) development, recurrence, and chemoresistance. We investigated changes in expression levels of the CSC biomarker, cluster of differentiation 133 (CD133), from primary OC cell lines to induction of CSC-spheres in [...] Read more.
Cancer stem cells (CSCs) are considered to be the origin of ovarian cancer (OC) development, recurrence, and chemoresistance. We investigated changes in expression levels of the CSC biomarker, cluster of differentiation 133 (CD133), from primary OC cell lines to induction of CSC-spheres in an attempt to explore the mechanisms related to modulation of stemness, drug resistance, and tumorigenesis in CSCs, thus facilitating the search for new therapeutics for OC. The effect of CD133 overexpression on the induction of CSC properties was evaluated by sphere-forming assays, RT-qPCR, flow cytometry, cell viability assays, and in vivo xenograft experiments. Moreover, the potential signaling molecules that participate in CD133 maintenance of stemness were screened by RNA-sequencing. CD133 expression was upregulated during OCSC induction and chemotherapeutic drug treatment over time, which increased the expressions of stemness-related markers (SOX2, OCT4, and Nanog). CD133 overexpression also promoted tumorigenesis in NOD/SCID mice. Several signalings were controlled by CD133 spheres, including extracellular matrix receptor interactions, chemokine signaling, and Wnt signaling, all of which promote cell survival and cell cycle progression. Our findings suggest that CD133 possesses the ability to maintain functional stemness and tumorigenesis of OCSCs by promoting cell survival signaling and may serve as a potential target for stem cell-targeted therapy of OC. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis 2.0)
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Review

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17 pages, 2279 KiB  
Review
The Cancer Stem Cell Niche in Ovarian Cancer and Its Impact on Immune Surveillance
by Srishti Jain, Stephanie L. Annett, Maria P. Morgan and Tracy Robson
Int. J. Mol. Sci. 2021, 22(8), 4091; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084091 - 15 Apr 2021
Cited by 14 | Viewed by 4470
Abstract
Ovarian cancer is an aggressive gynaecological cancer with extremely poor prognosis, due to late diagnosis as well as the development of chemoresistance after first-line therapy. Research advances have found stem-like cells present in ovarian tumours, which exist in a dynamic niche and persist [...] Read more.
Ovarian cancer is an aggressive gynaecological cancer with extremely poor prognosis, due to late diagnosis as well as the development of chemoresistance after first-line therapy. Research advances have found stem-like cells present in ovarian tumours, which exist in a dynamic niche and persist through therapy. The stem cell niche interacts extensively with the immune and non-immune components of the tumour microenvironment. Significant pathways associated with the cancer stem cell niche have been identified which interfere with the immune component of the tumour microenvironment, leading to immune surveillance evasion, dysfunction and suppression. This review aims to summarise current evidence-based knowledge on the cancer stem cell niche within the ovarian cancer tumour microenvironment and its effect on immune surveillance. Furthermore, the review seeks to understand the clinical consequences of this dynamic interaction by highlighting current therapies which target these processes. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis 2.0)
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44 pages, 1496 KiB  
Review
The Role of microRNAs in Epithelial Ovarian Cancer Metastasis
by Vu Hong Loan Nguyen, Chenyang Yue, Kevin Y. Du, Mohamed Salem, Jacob O'Brien and Chun Peng
Int. J. Mol. Sci. 2020, 21(19), 7093; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197093 - 25 Sep 2020
Cited by 31 | Viewed by 4624
Abstract
Epithelial ovarian cancer (EOC) is the deadliest gynecological cancer, and the major cause of death is mainly attributed to metastasis. MicroRNAs (miRNAs) are a group of small non-coding RNAs that exert important regulatory functions in many biological processes through their effects on regulating [...] Read more.
Epithelial ovarian cancer (EOC) is the deadliest gynecological cancer, and the major cause of death is mainly attributed to metastasis. MicroRNAs (miRNAs) are a group of small non-coding RNAs that exert important regulatory functions in many biological processes through their effects on regulating gene expression. In most cases, miRNAs interact with the 3′ UTRs of target mRNAs to induce their degradation and suppress their translation. Aberrant expression of miRNAs has been detected in EOC tumors and/or the biological fluids of EOC patients. Such dysregulation occurs as the result of alterations in DNA copy numbers, epigenetic regulation, and miRNA biogenesis. Many studies have demonstrated that miRNAs can promote or suppress events related to EOC metastasis, such as cell migration, invasion, epithelial-to-mesenchymal transition, and interaction with the tumor microenvironment. In this review, we provide a brief overview of miRNA biogenesis and highlight some key events and regulations related to EOC metastasis. We summarize current knowledge on how miRNAs are dysregulated, focusing on those that have been reported to regulate metastasis. Furthermore, we discuss the role of miRNAs in promoting and inhibiting EOC metastasis. Finally, we point out some limitations of current findings and suggest future research directions in the field. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis 2.0)
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