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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 34628

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Dr. Michalis Liontos

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Department of Clinical Therapeutics, Division of Oncology, Alexandra Hospital, National and Kapodistrian University of Athens, 10679 Athens, Greece
Interests: ovarian cancer; personalized medicine; DNA damage response; DNA repair mechanisms; uterine cancer
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Clinical management of gynecological cancers has developed rapidly during the last few years due to the identification of their molecular pathogeneses. Novel compounds have provided a survival benefit through randomized clinical trials and have been approved by regulatory authorities. However, the progress has a major impact on patients with a deficiency in DNA repair mechanisms that bear sensitivity to either PARP inhibitors or immune checkpoint inhibitors. There is an unmet medical need to gain insight into the molecular pathogenesis in DNA repair-proficient patients as well as to understand the mechanisms of resistance in novel compounds. Under this perspective, this Special Issue aims to describe current advances in the diagnosis and management of gynecological cancers as well as challenges in clinical and translational research that will lead to improvements in the survival of patients.

Prof. Dr. Michalis Liontos
Guest Editor

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Keywords

ovarian cancer
BRCA1/2 mutations
uterine cancer
microsatellite instability
cervical cancer
angiogenesis
TP53 mutations

Published Papers (10 papers)

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Editorial

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3 pages, 166 KiB

Open AccessEditorial

Advances in Gynecological Cancers

by Michalis Liontos, Oraianthi Fiste, Flora Zagouri and Meletios-Athanasios Dimopoulos

Int. J. Mol. Sci. 2022, 23(11), 6152; https://doi.org/10.3390/ijms23116152 - 31 May 2022

Cited by 1 | Viewed by 1536

Abstract

The burden of gynecological cancer constitutes a major focus of public health efforts, as it continues to represent a significant cause of cancer mortality, exerting not only physical and emotional distress but also serious financial strain upon individuals, caregivers, and communities [...] Full article

(This article belongs to the Special Issue Advances in Gynecological Cancers)

Research

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15 pages, 6064 KiB

Open AccessArticle

EGFR Transgene Stimulates Spontaneous Formation of MCF7 Breast Cancer Cells Spheroids with Partly Loss of HER3 Receptor

by Olga Troitskaya, Diana Novak, Anna Nushtaeva, Maria Savinkova, Mikhail Varlamov, Mikhail Ermakov, Vladimir Richter and Olga Koval

Int. J. Mol. Sci. 2021, 22(23), 12937; https://doi.org/10.3390/ijms222312937 - 29 Nov 2021

Cited by 10 | Viewed by 3322

Abstract

Multicellular spheroids with 3D cell–cell interactions are a useful model to simulate the growth conditions of cancer. There is evidence that in tumor spheroids, the expression of various essential molecules is changed compared to the adherent form of cell cultures. These changes include growth factor receptors and ABC transporters and result in the enhanced invasiveness of the cells and drug resistance. It is known that breast adenocarcinoma MCF7 cells can spontaneously form 3D spheroids and such spheroids are characterized by high expression of EGFR/HER2, while the natural phenotype of MCF7 cells is EGFR^low/HER2^low. Therefore, it was interesting to reveal if high epidermal growth factor receptor (EGFR) expression is sufficient for the conversion of adherent MCF7 to spheroids. In this study, an MCF7 cell line with high expression of EGFR was engineered using the retroviral transduction method. These MCF7-EGFR cells assembled in spheroids very quickly and grew predominantly as a 3D suspension culture with no special plates, scaffolds, growth supplements, or exogenous matrixes. These spheroids were characterized by a rounded shape with a well-defined external border and 100 µM median diameter. The sphere-forming ability of MCF7-EGFR cells was up to 5 times stronger than in MCF7^wt cells. Thus, high EGFR expression was the initiation factor of conversion of adherent MCF7^wt cells to spheroids. MCF7-EGFR spheroids were enriched by the cells with a cancer stem cell (CSC) phenotype CD24^−/low/CD44⁻ in comparison with parental MCF7^wt cells and MCF7-EGFR adhesive cells. We suppose that these properties of MCF7-EGFR spheroids originate from the typical features of parental MCF7 cells. We showed the decreasing of HER3 receptors in MCF7-EGFR spheroids compared to that in MCF^wt and in adherent MCF7-EGFR cells, and the same decrease was observed in the MCF7^wt spheroids growing under the growth factors stimulation. To summarize, the expression of EGFR transgene in MCF7 cells stimulates rapid spheroids formation; these spheroids are enriched by CSC-like CD24⁻/CD44⁻ cells, they partly lose HER3 receptors, and are characterized by a lower potency in drug resistance pomp activation compared to MCF7^wt. These MCF7-EGFR spheroids are a useful cancer model for the development of anticancer drugs, including EGFR-targeted therapeutics. Full article

(This article belongs to the Special Issue Advances in Gynecological Cancers)

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21 pages, 5097 KiB

Open AccessArticle

Metformin Affects Olaparib Sensitivity through Induction of Apoptosis in Epithelial Ovarian Cancer Cell Lines

by Patrycja Gralewska, Arkadiusz Gajek, Agnieszka Marczak and Aneta Rogalska

Int. J. Mol. Sci. 2021, 22(19), 10557; https://doi.org/10.3390/ijms221910557 - 29 Sep 2021

Cited by 12 | Viewed by 3053

Abstract

This study examined the effect of combination treatment with the poly (ADP-ribose) polymerase inhibitor olaparib and metformin on homologous recombination (HR)-proficient epithelial ovarian cancer (EOC). Ovarian cancer cell lines (OV-90 and SKOV-3) were treated with olaparib, metformin, or a combination of both. Cell viability was assessed by MTT and colony formation assays. The production of reactive oxygen species (ROS) and changes in mitochondrial membrane potential were examined using the specific fluorescence probes, DCFH2-DA (2′,7′-dichloro-dihydrofluorescein diacetate) and JC-1 (5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbocyanine). Apoptotic and necrotic changes were measured by double staining with Hoechst 33258 and propidium iodide, orange acridine and ethidium bromide staining, phosphatidylserine externalization, TUNEL assay, caspase 3/7 activity, and cytochrome c and p53 expression. Compared with single-drug treatment, the combination of olaparib and metformin significantly inhibited cell proliferation and colony formation in HR-proficient ovarian cancer cells. ROS production preceded a decrease in mitochondrial membrane potential. The changes in ROS levels suggested their involvement in inducing apoptosis in response to combination treatment. The present results indicate a shift towards synergism in cells with mutant or null p53, treated with olaparib combined with metformin, providing a new approach to the treatment of gynecologic cancers. Taken together, the results support the use of metformin to sensitize EOC to olaparib therapy. Full article

(This article belongs to the Special Issue Advances in Gynecological Cancers)

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14 pages, 3165 KiB

Open AccessArticle

Difluoromethylornithine Induces Apoptosis through Regulation of AP-1 Signaling via JNK Phosphorylation in Epithelial Ovarian Cancer

by Woo Yeon Hwang, Wook Ha Park, Dong Hoon Suh, Kidong Kim, Yong Beom Kim and Jae Hong No

Int. J. Mol. Sci. 2021, 22(19), 10255; https://doi.org/10.3390/ijms221910255 - 23 Sep 2021

Cited by 5 | Viewed by 3099

Abstract

Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), has promising activity against various cancers and a tolerable safety profile for long-term use as a chemopreventive agent. However, the anti-tumor effects of DFMO in ovarian cancer cells have not been entirely understood. Our study aimed to identify the effects and mechanism of DFMO in epithelial ovarian cancer cells using SKOV-3 cells. Treatment with DFMO resulted in a significantly reduced cell viability in a time- and dose-dependent manner. DFMO treatment inhibited the activity and downregulated the expression of ODC in ovarian cancer cells. The reduction in cell viability was reversed using polyamines, suggesting that polyamine depletion plays an important role in the anti-tumor activity of DFMO. Additionally, significant changes in Bcl-2, Bcl-xL, Bax protein levels, activation of caspase-3, and cleavage of poly (ADP-ribose) polymerase were observed, indicating the apoptotic effects of DFMO. We also found that the effect of DFMO was mediated by AP-1 through the activation of upstream JNK via phosphorylation. Moreover, DFMO enhanced the effect of cisplatin, thus showing a possibility of a synergistic effect in treatment. In conclusion, treatment with DFMO alone, or in combination with cisplatin, could be a promising treatment for ovarian cancer. Full article

(This article belongs to the Special Issue Advances in Gynecological Cancers)

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18 pages, 24065 KiB

Open AccessArticle

LncRNA MALAT1 Facilitates Ovarian Cancer Progression through Promoting Chemoresistance and Invasiveness in the Tumor Microenvironment

by Tsui-Lien Mao, Ming-Huei Fan, Nhlanhla Dlamini and Chao-Lien Liu

Int. J. Mol. Sci. 2021, 22(19), 10201; https://doi.org/10.3390/ijms221910201 - 22 Sep 2021

Cited by 26 | Viewed by 3042

Abstract

Upregulation of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1, also known as nuclear-enriched abundant transcript 2 (NEAT2) or LINC00047) was found in various solid tumors, including epithelial ovarian cancer (EOC). MALAT1 is a long noncoding (lnc)RNA that regulates many functional signaling pathways, including tumorigenesis. Herein, we observed the consistent upregulation of MALAT1 in MYST4-overexpressing cell lines, while MALAT1 was frequently found to be upregulated in various types of clinical carcinoma tissues, especially EOC. To further investigate the lncRNA MALAT1 in EOC progression, the transduced overexpression of MALAT1 in EOC cell lines and cancer-associated fibroblasts (CAFs) was employed. We found that MALAT1 overexpression in EOC cell lines significantly increased drug resistance, cell migration, and invasion. Furthermore, the concomitant overexpression of MALAT1 in EOC cells and CAFs dramatically increased EOC cell invasion. Accordingly, a mechanistic investigation of MALAT1 overexpression in EOC cells showed that expressions of the cytokines interleukin (IL)-1β and p-P38/p-NFκB/Cox2/prostaglandin E2 (PGE2) signaling were significantly increased, which stimulated inflammatory responses, whereas cell apoptosis was inhibited due to increased Bcl-2 levels and reduced Caspase3 levels. After MALAT1 was overexpressed in EOC cells, and the cyclin D1, p-PI3K, and p-Akt expressions increased, suggesting the promotion of tumor cell proliferation, while increased zinc finger E-box-binding homeobox-2 (ZEB2), yes-associated protein (YAP), and vimentin expression with E-cadherin downregulation indicated the enhancement of the epithelial-to-mesenchymal transition (EMT) in terms of metastasis, thereby triggering EOC progression. Together, our findings demonstrate how MALAT1 overexpression facilitates an oncogenic function through inhibiting tumor cell apoptosis, combined with increasing tumor cell inflammation, proliferation, and invasion in the EOC tumor microenvironment. MALAT1 is thus a potential diagnostic marker and therapeutic for this malignancy. Full article

(This article belongs to the Special Issue Advances in Gynecological Cancers)

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12 pages, 1379 KiB

Open AccessArticle

Tumor Promoting Effect of BMP Signaling in Endometrial Cancer

by Tomohiko Fukuda, Risa Fukuda, Kohei Miyazono and Carl-Henrik Heldin

Int. J. Mol. Sci. 2021, 22(15), 7882; https://doi.org/10.3390/ijms22157882 - 23 Jul 2021

Cited by 15 | Viewed by 2739

Abstract

The effects of bone morphogenetic proteins (BMPs), members of the transforming growth factor-β (TGF-β) family, in endometrial cancer (EC) have yet to be determined. In this study, we analyzed the TCGA and MSK-IMPACT datasets and investigated the effects of BMP2 and of TWSG1, a BMP antagonist, on Ishikawa EC cells. Frequent ACVR1 mutations and high mRNA expressions of BMP ligands and receptors were observed in EC patients of the TCGA and MSK-IMPACT datasets. Ishikawa cells secreted higher amounts of BMP2 compared with ovarian cancer cell lines. Exogenous BMP2 stimulation enhanced EC cell sphere formation via c-KIT induction. BMP2 also induced EMT of EC cells, and promoted migration by induction of SLUG. The BMP receptor kinase inhibitor LDN193189 augmented the growth inhibitory effects of carboplatin. Analyses of mRNAs of several BMP antagonists revealed that TWSG1 mRNA was abundantly expressed in Ishikawa cells. TWSG1 suppressed BMP7-induced, but not BMP2-induced, EC cell sphere formation and migration. Our results suggest that BMP signaling promotes EC tumorigenesis, and that TWSG1 antagonizes BMP7 in EC. BMP signaling inhibitors, in combination with chemotherapy, might be useful in the treatment of EC patients. Full article

(This article belongs to the Special Issue Advances in Gynecological Cancers)

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22 pages, 4474 KiB

Open AccessArticle

Assessment of TSPAN Expression Profile and Their Role in the VSCC Prognosis

by Kelly Pedrozo Ferreira, Bruna Cristine de Almeida, Laura Gonzalez dos Anjos, Glauco Baiocchi, Fernando Augusto Soares, Rafael Malagoli Rocha, Edmund Chada Baracat, Andrey Senos Dobroff and Katia Candido Carvalho

Int. J. Mol. Sci. 2021, 22(9), 5015; https://doi.org/10.3390/ijms22095015 - 9 May 2021

Cited by 1 | Viewed by 2516

Abstract

The role and prognostic value of tetraspanins (TSPANs) in vulvar squamous cell carcinoma (VSCC) remain poorly understood. We sought to primarily determine, at both the molecular and tissue level, the expression profile of the TSPANs CD9, CD63, CD81, and CD82 in archived VSCC samples (n = 117) and further investigate their clinical relevance as prognostic markers. Our studies led us to identify CD63 as the most highly expressed TSPAN, at the gene and protein levels. Multicomparison studies also revealed that the expression of CD9 was associated with tumor size, whereas CD63 upregulation was associated with histological diagnosis and vascular invasion. Moreover, low expression of CD81 and CD82 was associated with worse prognosis. To determine the role of TSPANs in VSCC at the cellular level, we assessed the mRNA levels of CD63 and CD82 in established metastatic (SW962) and non-metastatic (SW954) VSCC human cell lines. CD82 was found to be downregulated in SW962 cells, thus supporting its metastasis suppressor role. However, CD63 was significantly upregulated in both cell lines. Silencing of CD63 by siRNA led to a significant decrease in proliferation of both SW954 and SW962. Furthermore, in SW962 particularly, CD63-siRNA also remarkably inhibited cell migration. Altogether, our data suggest that the differential expression of TSPANs represents an important feature for prognosis of VSCC patients and indicates that CD63 and CD82 are likely potential therapeutic targets in VSCC. Full article

(This article belongs to the Special Issue Advances in Gynecological Cancers)

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Review

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22 pages, 545 KiB

Open AccessReview

Cervical Carcinoma: Oncobiology and Biomarkers

by Larisa V. Volkova, Alexander I. Pashov and Nadezhda N. Omelchuk

Int. J. Mol. Sci. 2021, 22(22), 12571; https://doi.org/10.3390/ijms222212571 - 22 Nov 2021

Cited by 43 | Viewed by 7755

Abstract

Cervical cancer is one of the most common types of carcinomas causing morbidity and mortality in women in all countries of the world. At the moment, the oncology, oncobiology, and oncomorphology of cervical cancer are characterized by the accumulation of new information; various molecular biological, genetic, and immunohistochemical methods of investigation of the mechanisms of cervical carcinogenesis are tested and applied; targeted antitumour drugs and diagnostic, prognostic, and predictive biomarkers are being searched for. Many issues of the etiopathogenesis of cervical cancer have not been sufficiently studied, and the role of many biomarkers characterizing various stages of cervical carcinogenesis remains unclear. Therefore, the target of this review is to systematize and understand several problems in the pathogenesis of cervical cancer and to evaluate the significance and role of biomarkers in cervical carcinogenesis. Full article

(This article belongs to the Special Issue Advances in Gynecological Cancers)

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17 pages, 1287 KiB

Open AccessReview

Patient-Derived Xenograft Models in Cervical Cancer: A Systematic Review

by Tomohito Tanaka, Ruri Nishie, Shoko Ueda, Shunsuke Miyamoto, Sousuke Hashida, Hiromi Konishi, Shinichi Terada, Yuhei Kogata, Hiroshi Sasaki, Satoshi Tsunetoh, Kohei Taniguchi, Kazumasa Komura and Masahide Ohmichi

Int. J. Mol. Sci. 2021, 22(17), 9369; https://doi.org/10.3390/ijms22179369 - 29 Aug 2021

Cited by 15 | Viewed by 3357

Abstract

Background: Patient-derived xenograft (PDX) models have been a focus of attention because they closely resemble the tumor features of patients and retain the molecular and histological features of diseases. They are promising tools for translational research. In the current systematic review, we identify publications on PDX models of cervical cancer (CC-PDX) with descriptions of main methodological characteristics and outcomes to identify the most suitable method for CC-PDX. Methods: We searched on PubMed to identify articles reporting CC-PDX. Briefly, the main inclusion criterion for papers was description of PDX created with fragments obtained from human cervical cancer specimens, and the exclusion criterion was the creation of xenograft with established cell lines. Results: After the search process, 10 studies were found and included in the systematic review. Among 98 donor patients, 61 CC-PDX were established, and the overall success rate was 62.2%. The success rate in each article ranged from 0% to 75% and was higher when using severe immunodeficient mice such as severe combined immunodeficient (SCID), nonobese diabetic (NOD) SCID, and NOD SCID gamma (NSG) mice than nude mice. Subrenal capsule implantation led to a higher engraftment rate than orthotopic and subcutaneous implantation. Fragments with a size of 1–3 mm³ were suitable for CC-PDX. No relationship was found between the engraftment rate and characteristics of the tumor and donor patient, including histology, staging, and metastasis. The latency period varied from 10 days to 12 months. Most studies showed a strong similarity in pathological and immunohistochemical features between the original tumor and the PDX model. Conclusion: Severe immunodeficient mice and subrenal capsule implantation led to a higher engraftment rate; however, orthotopic and subcutaneous implantation were alternatives. When using nude mice, subrenal implantation may be better. Fragments with a size of 1–3 mm³ were suitable for CC-PDX. Few reports have been published about CC-PDX; the results were not confirmed because of the small sample size. Full article

(This article belongs to the Special Issue Advances in Gynecological Cancers)

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16 pages, 755 KiB

Open AccessReview

Molecular Landscape of Vulvar Squamous Cell Carcinoma

by Núria Carreras-Dieguez, José Guerrero, Maria Teresa Rodrigo-Calvo, Inmaculada Ribera-Cortada, Isabel Trias, Pedro Jares, Ricardo López del Campo, Adela Saco, Meritxell Munmany, Lorena Marimon, Melania Ferrando, Naiara Vega, Marta del Pino, Aureli Torné, Jaume Ordi and Natalia Rakislova

Int. J. Mol. Sci. 2021, 22(13), 7069; https://doi.org/10.3390/ijms22137069 - 30 Jun 2021

Cited by 12 | Viewed by 3086

Abstract

Vulvar squamous cell carcinoma (VSCC) is a rare malignancy with dual pathogenesis, Human papillomavirus (HPV)-associated and HPV-independent, with a poorly explored molecular landscape. We aimed to summarize the findings of the series analyzing molecular hallmarks of this neoplasm. In January 2021, we conducted a comprehensive literature search using Pubmed Medline and Scopus to identify publications focused on genomic profiling of VSCC. Observational studies, including both prospective and retrospective designs, evaluating molecular alterations in VSCC were deemed eligible. A total of 14 studies analyzing 749 VSCC were identified. The study series were heterogeneous in HPV testing and sequencing strategies, included small sets of tumors and cancer genes, and commonly lacked survival analysis. Only one extensive targeted next-generation sequencing-based study comprised a large cohort of 280 VSCC. The mutated genes, their number, and frequencies were highly variable between the series. Overall, TP53 and CDKN2A, followed by PIK3CA, HRAS, and PTEN, were the most frequently studied and mutated genes. Mutations involved in the PI3K/AKT/mTOR pathway, including TP53, HRAS, KRAS, and PIK3CA, have been consistently reported across the studies. However, the role of individual mutations or pathways in the development of VSCC remains unclear. In conclusion, heterogeneity and the small sample size of available molecular series contribute to a limited view of the molecular landscape of VSCC. Large-scale genome- or exome-wide studies with robust HPV testing are necessary to improve the molecular characterization of VSCC. Full article

(This article belongs to the Special Issue Advances in Gynecological Cancers)

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