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Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment
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Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment

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 2018) | Viewed by 101200

Special Issue Editors

Prof. Dr. Laura Gatti

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Guest Editor
Cell Therapy Production Unit-UPTC and Cerebrovascular Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
Interests: ntitumor agents; platinum compounds; drug resistance; apoptosis; liquid biopsy; ovarian cancer treatment; unfolded protein response; proteasome pathway; cerebrovascular diseases; RNA-seq
Special Issues, Collections and Topics in MDPI journals
Dr. Giovanni Luca Beretta

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Guest Editor
Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133 Milan, Italy
Interests: cancer research; cancer chemotherapy; molecular biology; cell biology; pharmacology; nanomedicine; drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Ovarian carcinoma is the most lethal gynaecological disease and the seventh most common cancer in women. Due to the lack of symptoms associated with tumor development and the absence of a reliable screening regimen, most patients are diagnosed at later times, making the disease hard to treat. Since the measure of serum tumor biomarkers (e.g., CA125 and HE4) is not sufficiently sensitive and specific for early detection, there is the urgent need to identify others variables and recently many studies focused on the identification of specific miRNAs in tumour specimens and serum samples of patients. As far as the treatment of ovarian cancer is concerned, the surgery in combination with radio-chemotherapy (paclitaxel and platinum compounds) is still the first choice in medical practice. However, in spite of the recently acquired knowledge achieved at molecular level, including the identification of the major pathways accounting for reduced drug efficacy, no substantial progresses have been introduced for disease treatment. This finding accounts for a poor survival rate which is often associated with aggressive tumor cell behaviour and increased metastatic potential. Moreover, despite the availability of various effective second-line treatments and of PARP inhibitors (for selected patients harbouring BRCA mutations), there is a need for novel therapeutic approaches. Among these, the administration of antitumor agents encapsulated into nanovectors emerged as an intriguing strategy that already proved its efficacy, as demonstrated by the clinical success of Doxil (liposomal doxorubicin) and Abraxane (albumin-based paclitaxel).

We warmly welcome submissions, including original papers and reviews, on this Special Issue focused on “pathogenesis, diagnosis and treatment of ovarian cancer”.

Dr. Laura Gatti
Dr. Giovanni Luca Beretta
Guest Editors

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Keywords

  • Ovarian cancer
  • Tumor biomarkers on ovarian cancer
  • Survival pathways
  • Nanomedicine
  • Metastasis
  • Drug resistance
  • Pre-clinical studies

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Published Papers (16 papers)

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13 pages, 621 KiB  
Article
rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology
by Linda E. Kelemen, Madalene Earp, Brooke L. Fridley, Georgia Chenevix-Trench, On behalf of Australian Ovarian Cancer Study Group, Peter A. Fasching, Matthias W. Beckmann, Arif B. Ekici, Alexander Hein, Diether Lambrechts, Sandrina Lambrechts, Els Van Nieuwenhuysen, Ignace Vergote, Mary Anne Rossing, Jennifer A. Doherty, Jenny Chang-Claude, Sabine Behrens, Kirsten B. Moysich, Rikki Cannioto, Shashikant Lele, Kunle Odunsi, Marc T. Goodman, Yurii B. Shvetsov, Pamela J. Thompson, Lynne R. Wilkens, Thilo Dörk, Natalia Antonenkova, Natalia Bogdanova, Peter Hillemanns, Ingo B. Runnebaum, Andreas Du Bois, Philipp Harter, Florian Heitz, Ira Schwaab, Ralf Butzow, Liisa M. Pelttari, Heli Nevanlinna, Francesmary Modugno, Robert P. Edwards, Joseph L. Kelley, Roberta B. Ness, Beth Y. Karlan, Jenny Lester, Sandra Orsulic, Christine Walsh, Susanne K. Kjaer, Allan Jensen, Julie M. Cunningham, Robert A. Vierkant, Graham G. Giles, Fiona Bruinsma, Melissa C. Southey, Michelle A.T. Hildebrandt, Dong Liang, Karen Lu, Xifeng Wu, Thomas A. Sellers, Douglas A. Levine, Joellen M. Schildkraut, Edwin S. Iversen, Kathryn L. Terry, Daniel W. Cramer, Shelley S. Tworoger, Elizabeth M. Poole, Elisa V. Bandera, Sara H. Olson, Irene Orlow, Liv Cecilie Vestrheim Thomsen, Line Bjorge, Camilla Krakstad, Ingvild L. Tangen, Lambertus A. Kiemeney, Katja K.H. Aben, Leon F.A.G. Massuger, Anne M. Van Altena, Tanja Pejovic, Yukie Bean, Melissa Kellar, Linda S. Cook, Nhu D. Le, Angela Brooks-Wilson, Jacek Gronwald, Cezary Cybulski, Anna Jakubowska, Jan Lubiński, Nicolas Wentzensen, Louise A. Brinton, Jolanta Lissowska, Estrid Hogdall, Svend Aage Engelholm, Claus Hogdall, Lene Lundvall, Lotte Nedergaard, Paul D.P. Pharoah, Ed Dicks, Honglin Song, Jonathan P. Tyrer, Iain McNeish, Nadeem Siddiqui, Karen Carty, Rosalind Glasspool, James Paul, Ian G. Campbell, Diana Eccles, Alice S. Whittemore, Valerie McGuire, Joseph H. Rothstein, Weiva Sieh, Steven A. Narod, Catherine M. Phelan, John R. McLaughlin, Harvey A. Risch, Hoda Anton-Culver, Argyrios Ziogas, Usha Menon, Simon A. Gayther, Aleksandra Gentry-Maharaj, Susan J. Ramus, Anna H. Wu, Celeste Leigh Pearce, Alice W. Lee, Malcolm C. Pike, Jolanta Kupryjanczyk, Agnieszka Podgorska, Joanna Plisiecka-Halasa, Wlodzimierz Sawicki, Ellen L. Goode, Andrew Berchuck and Ovarian Cancer Association Consortiumadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2018, 19(9), 2473; https://doi.org/10.3390/ijms19092473 - 21 Aug 2018
Cited by 3 | Viewed by 7185
Abstract
Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3′ [...] Read more.
Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3′ gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97–1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03–1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10−28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
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15 pages, 981 KiB  
Article
Understanding Ovarian Cancer: iTRAQ-Based Proteomics for Biomarker Discovery
by Agata Swiatly, Agnieszka Horala, Jan Matysiak, Joanna Hajduk, Ewa Nowak-Markwitz and Zenon J. Kokot
Int. J. Mol. Sci. 2018, 19(8), 2240; https://doi.org/10.3390/ijms19082240 - 31 Jul 2018
Cited by 33 | Viewed by 5526
Abstract
Despite many years of studies, ovarian cancer remains one of the top ten cancers worldwide. Its high mortality rate is mainly due to lack of sufficient diagnostic methods. For this reason, our research focused on the identification of blood markers whose appearance would [...] Read more.
Despite many years of studies, ovarian cancer remains one of the top ten cancers worldwide. Its high mortality rate is mainly due to lack of sufficient diagnostic methods. For this reason, our research focused on the identification of blood markers whose appearance would precede the clinical manifestation of the disease. ITRAQ-tagging (isobaric Tags for Relative and Absolute Quantification) coupled with mass spectrometry technology was applied. Three groups of samples derived from patients with: ovarian cancer, benign ovarian tumor, and healthy controls, were examined. Mass spectrometry analysis allowed for highlighting the dysregulation of several proteins associated with ovarian cancer. Further validation of the obtained results indicated that five proteins (Serotransferrin, Amyloid A1, Hemopexin, C-reactive protein, Albumin) were differentially expressed in ovarian cancer group. Interestingly, the addition of Albumin, Serotransferrin, and Amyloid A1 to CA125 (cancer antigen 125) and HE4 (human epididymis protein4) improved the diagnostic performance of the model discriminating between benign and malignant tumors. Identified proteins shed light on the molecular signaling pathways that are associated with ovarian cancer development and should be further investigated in future studies. Our findings indicate five proteins with a strong potential to use in a multimarker test for screening and detection of ovarian cancer. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
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26 pages, 6670 KiB  
Article
Establishment and Characterization of the Novel High-Grade Serous Ovarian Cancer Cell Line OVPA8
by Patrycja Tudrej, Magdalena Olbryt, Ewa Zembala-Nożyńska, Katarzyna A. Kujawa, Alexander J. Cortez, Anna Fiszer-Kierzkowska, Wojciech Pigłowski, Barbara Nikiel, Magdalena Głowala-Kosińska, Aleksandra Bartkowska-Chrobok, Andrzej Smagur, Wojciech Fidyk and Katarzyna M. Lisowska
Int. J. Mol. Sci. 2018, 19(7), 2080; https://doi.org/10.3390/ijms19072080 - 17 Jul 2018
Cited by 27 | Viewed by 11160
Abstract
High-grade serous ovarian carcinoma (HGSOC) is the most frequent histological type of ovarian cancer and the one with worst prognosis. Unfortunately, the majority of established ovarian cancer cell lines which are used in the research have unclear histological origin and probably do not [...] Read more.
High-grade serous ovarian carcinoma (HGSOC) is the most frequent histological type of ovarian cancer and the one with worst prognosis. Unfortunately, the majority of established ovarian cancer cell lines which are used in the research have unclear histological origin and probably do not represent HGSOC. Thus, new and reliable models of HGSOC are needed. Ascitic fluid from a patient with recurrent HGSOC was used to establish a stable cancer cell line. Cells were characterized by cytogenetic karyotyping and short tandem repeat (STR) profiling. New generation sequencing was applied to test for hot-spot mutations in 50 cancer-associated genes and fluorescence in situ hybridization (FISH) analysis was used to check for TP53 status. Cells were analyzed for expression of several marker genes/proteins by reverse-transcription polymerase chain reaction (RT-PCR), fluorescence-activated cell sorting (FACS), and immunocytochemistry (ICC). Functional tests were performed to compare OVPA8 cells with five commercially available and frequently used ovarian cancer cell lines: SKOV3, A2780, OVCAR3, ES2, and OAW42. Our newly-established OVPA8 cell line shows morphologic and genetic features consistent with HGSOC, such as epithelial morphology, multiple chromosomal aberrations, TP53 mutation, BRCA1 mutation, and loss of one copy of BRCA2. The OVPA8 line has a stable STR profile. Cells are positive for EpCAM, CK19, and CD44; they have relatively low plating efficiency/ability to form spheroids, a low migration rate, and intermediate invasiveness in matrigel, as compared to other ovarian cancer lines. OVPA8 is sensitive to paclitaxel and resistant to cisplatin. We also tested two FGFR inhibitors; OVPA8 cells were resistant to AZD4547 (AstraZeneca, London, UK), but sensitive to the new inhibitor CPL304-110-01 (Celon Pharma, Łomianki/Kiełpin, Poland). We have established and characterized a novel cell line, OVPA8, which can be a valuable preclinical model for studies on high-grade serous ovarian cancer. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
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13 pages, 4427 KiB  
Article
Mucins and Truncated O-Glycans Unveil Phenotypic Discrepancies between Serous Ovarian Cancer Cell Lines and Primary Tumours
by Ricardo Coelho, Lara Marcos-Silva, Nuno Mendes, Daniela Pereira, Catarina Brito, Francis Jacob, Catharina Steentoft, Ulla Mandel, Henrik Clausen, Leonor David and Sara Ricardo
Int. J. Mol. Sci. 2018, 19(7), 2045; https://doi.org/10.3390/ijms19072045 - 13 Jul 2018
Cited by 24 | Viewed by 6007
Abstract
Optimal research results rely on the selection of cellular models capable of recapitulating the characteristics of primary tumours from which they originate. The expression of mucins (MUC16 and MUC1) and truncated O-glycans (Tn, STn and T) represents a characteristic footprint of serous [...] Read more.
Optimal research results rely on the selection of cellular models capable of recapitulating the characteristics of primary tumours from which they originate. The expression of mucins (MUC16 and MUC1) and truncated O-glycans (Tn, STn and T) represents a characteristic footprint of serous ovarian carcinomas (SOCs). Therefore, selecting ovarian cancer (OVCA) cell lines that reflect this phenotype is crucial to explore the putative biological role of these biomarkers in the SOC setting. Here, we investigated a panel of OVCA cell lines commonly used as SOC models, and tested whether, when cultured in 2D and 3D conditions, these recapitulate the mucin and O-glycan expression profiles of SOCs. We further explored the role of truncating the O-glycosylation capacity in OVCAR3 cells through knockout of the COSMC chaperone, using in vitro and in vivo assays. We found that the majority of OVCA cell lines of serous origin do not share the mucin and truncated O-glycan footprint of SOCs, although 3D cultures showed a higher resemblance. We also found that genetic truncation of the O-glycosylation capacity of OVCAR3 cells did not enhance oncogenic features either in vitro or in vivo. This study underscores the importance of well-characterized cellular models to study specific features of ovarian cancer. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
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16 pages, 1625 KiB  
Article
Distinct DNA Methylation Profiles in Ovarian Tumors: Opportunities for Novel Biomarkers
by Lorena Losi, Sergio Fonda, Sara Saponaro, Sonia T. Chelbi, Cesare Lancellotti, Gaia Gozzi, Loredana Alberti, Luca Fabbiani, Laura Botticelli and Jean Benhattar
Int. J. Mol. Sci. 2018, 19(6), 1559; https://doi.org/10.3390/ijms19061559 - 24 May 2018
Cited by 24 | Viewed by 4350
Abstract
Aberrant methylation of multiple promoter CpG islands could be related to the biology of ovarian tumors and its determination could help to improve treatment strategies. DNA methylation profiling was performed using the Methylation Ligation-dependent Macroarray (MLM), an array-based analysis. Promoter regions of 41 [...] Read more.
Aberrant methylation of multiple promoter CpG islands could be related to the biology of ovarian tumors and its determination could help to improve treatment strategies. DNA methylation profiling was performed using the Methylation Ligation-dependent Macroarray (MLM), an array-based analysis. Promoter regions of 41 genes were analyzed in 102 ovarian tumors and 17 normal ovarian samples. An average of 29% of hypermethylated promoter genes was observed in normal ovarian tissues. This percentage increased slightly in serous, endometrioid, and mucinous carcinomas (32%, 34%, and 45%, respectively), but decreased in germ cell tumors (20%). Ovarian tumors had methylation profiles that were more heterogeneous than other epithelial cancers. Unsupervised hierarchical clustering identified four groups that are very close to the histological subtypes of ovarian tumors. Aberrant methylation of three genes (BRCA1, MGMT, and MLH1), playing important roles in the different DNA repair mechanisms, were dependent on the tumor subtype and represent powerful biomarkers for precision therapy. Furthermore, a promising relationship between hypermethylation of MGMT, OSMR, ESR1, and FOXL2 and overall survival was observed. Our study of DNA methylation profiling indicates that the different histotypes of ovarian cancer should be treated as separate diseases both clinically and in research for the development of targeted therapies. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
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18 pages, 6392 KiB  
Article
Functional Analyses of RUNX3 and CaMKIINα in Ovarian Cancer Cell Lines Reveal Tumor-Suppressive Functions for CaMKIINα and Dichotomous Roles for RUNX3 Transcript Variants
by Karolin Heinze, Daniel Kritsch, Alexander S. Mosig, Matthias Dürst, Norman Häfner and Ingo B. Runnebaum
Int. J. Mol. Sci. 2018, 19(1), 253; https://doi.org/10.3390/ijms19010253 - 15 Jan 2018
Cited by 8 | Viewed by 6154
Abstract
(1) Background: Epithelial ovarian cancer (EOC) is the most lethal cancer of the female reproductive system. In an earlier study, we identified multiple genes as hypermethylated in tumors of patients with poor prognosis. The most promising combination of markers to predict a patient’s [...] Read more.
(1) Background: Epithelial ovarian cancer (EOC) is the most lethal cancer of the female reproductive system. In an earlier study, we identified multiple genes as hypermethylated in tumors of patients with poor prognosis. The most promising combination of markers to predict a patient’s outcome was CaMKIINα and RUNX3. Aim of this study was to functionally validate the importance of both genes. (2) Methods: IC50 measurements, cell cycle distribution-, proliferation, and migration experiments were conducted after transgene overexpression in two EOC cell lines. (3) Results: We showed that CaMKIINα has tumor suppressive functions in vitro and reduces proliferation, migration, and colony formation. However, it had no effect on the reversion of the resistance to cisplatin. RUNX3 exhibited dualistic functions related to cisplatin sensitivity and migration capacity, depending on the respective transcript variant (TV). A2780 cells expressing RUNX3 TV2—the promoter of which harbors a CpG (5′-C-phosphate-G-3′) island and is potentially inactivated by hypermethylation—exhibited increased cisplatin sensitivity and reduced migration properties. However, RUNX3 TV1, not affected by CpG island methylation could be characterized as mediating resistance and enhancing migration in A2780. The higher resistance of RUNX3 TV1 transfected cells correlates with a reduction of cell proliferation. Moreover, RUNX3 TV1 expressing cells exhibit a reduced cell cycle arrest at the gap-2 or mitosis phase (G2/M) under cisplatin treatment comparable to resistant A2780 subcultures. (4) Conclusion: It appears that CaMKIINα and RUNX3 TV2 can reduce the malignant potential of EOC cells. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
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2139 KiB  
Article
Usefulness of Amino Acid Profiling in Ovarian Cancer Screening with Special Emphasis on Their Role in Cancerogenesis
by Szymon Plewa, Agnieszka Horała, Paweł Dereziński, Agnieszka Klupczynska, Ewa Nowak-Markwitz, Jan Matysiak and Zenon J. Kokot
Int. J. Mol. Sci. 2017, 18(12), 2727; https://doi.org/10.3390/ijms18122727 - 16 Dec 2017
Cited by 42 | Viewed by 5544
Abstract
The aim of this study was to quantitate 42 serum-free amino acids, propose the biochemical explanation of their role in tumor development, and identify new ovarian cancer (OC) biomarkers for potential use in OC screening. The additional value of this work is the [...] Read more.
The aim of this study was to quantitate 42 serum-free amino acids, propose the biochemical explanation of their role in tumor development, and identify new ovarian cancer (OC) biomarkers for potential use in OC screening. The additional value of this work is the schematic presentation of the interrelationship between metabolites which were identified as significant for OC development and progression. The liquid chromatography-tandem mass spectrometry technique using highly-selective multiple reaction monitoring mode and labeled internal standards for each analyzed compound was applied. Performed statistical analyses showed that amino acids are potentially useful as OC biomarkers, especially as variables in multi-marker models. For the distinguishing metabolites the following metabolic pathways involved in cancer growth and development were proposed: histidine metabolism; tryptophan metabolism; arginine biosynthesis; arginine and proline metabolism; and alanine, aspartate and glutamine metabolism. The presented research identifies histidine and citrulline as potential new OC biomarkers. Furthermore, it provides evidence that amino acids are involved in metabolic pathways related to tumor growth and play an important role in cancerogenesis. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
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Review

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18 pages, 289 KiB  
Review
Translational Research Opportunities Regarding Homologous Recombination in Ovarian Cancer
by Margarita Romeo, Juan Carlos Pardo, Anna Martínez-Cardús, Eva Martínez-Balibrea, Vanesa Quiroga, Sergio Martínez-Román, Francesc Solé, Mireia Margelí and Ricard Mesía
Int. J. Mol. Sci. 2018, 19(10), 3249; https://doi.org/10.3390/ijms19103249 - 19 Oct 2018
Cited by 6 | Viewed by 3892
Abstract
Homologous recombination (HR) is a DNA repair pathway that is deficient in 50% of high-grade serous ovarian carcinomas (HGSOC). Deficient HR (DHR) constitutes a therapeutic opportunity for these patients, thanks to poly (ADP-ribose) polymerases (PARP) inhibitors (PARPi; olaparib, niraparib, and rucaparib are already [...] Read more.
Homologous recombination (HR) is a DNA repair pathway that is deficient in 50% of high-grade serous ovarian carcinomas (HGSOC). Deficient HR (DHR) constitutes a therapeutic opportunity for these patients, thanks to poly (ADP-ribose) polymerases (PARP) inhibitors (PARPi; olaparib, niraparib, and rucaparib are already commercialized). Although initially, PARPi were developed for patients with BRCA1/2 mutations, robust clinical data have shown their benefit in a broader population without DHR. This breakthrough in daily practice has raised several questions that necessitate further research: How can populations that will most benefit from PARPi be selected? At which stage of ovarian cancer should PARPi be used? Which strategies are reasonable to overcome PARPi resistance? In this paper, we present a summary of the literature and discuss the present clinical research involving PARPi (after reviewing ClinicalTrials.gov) from a translational perspective. Research into the functional biomarkers of DHR and clinical trials testing PARPi benefits as first-line setting or rechallenge are currently ongoing. Additionally, in the clinical setting, only secondary restoring mutations of BRCA1/2 have been identified as events inducing resistance to PARPi. The clinical frequency of this and other mechanisms that have been described in preclinics is unknown. It is of great importance to study mechanisms of resistance to PARPi to guide the clinical development of drug combinations. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
12 pages, 583 KiB  
Review
METCAM/MUC18 Decreases the Malignant Propensity of Human Ovarian Carcinoma Cells
by Guang-Jer Wu
Int. J. Mol. Sci. 2018, 19(10), 2976; https://doi.org/10.3390/ijms19102976 - 29 Sep 2018
Cited by 2 | Viewed by 2707
Abstract
METCAM/MUC18 is an integral membrane cell adhesion molecule (CAM) in the Ig-like gene super-family. It can carry out common functions of CAMs which is to perform intercellular interactions and interaction of cell with extracellular matrix in tumor microenvironment, to interact with various signaling [...] Read more.
METCAM/MUC18 is an integral membrane cell adhesion molecule (CAM) in the Ig-like gene super-family. It can carry out common functions of CAMs which is to perform intercellular interactions and interaction of cell with extracellular matrix in tumor microenvironment, to interact with various signaling pathways and to regulate general behaviors of cells. We and other two groups previously suggested that METCAM/MUC18 probably be utilized as a biomarker for predicting the malignant tendency of clinical ovarian carcinomas, since METAM/MUC18 expression appears to associate with the carcinoma at advanced stages. It has been further postulated to promote the malignant tendency of the carcinoma. However, our recent research results appear to support the conclusion that the above positive correlation is fortuitous; actually METCAM/MUC18 acts as a tumor and metastasis suppressor for the ovarian carcinoma cells. We also suggest possible mechanisms in the METCAM/MUC18-mediated early tumor development and metastasis of ovarian carcinoma. Moreover, we propose to employ recombinant METCAM/MUC18 proteins and other derived products as therapeutic agents to treat the ovarian cancer patients by decreasing the malignant potential of ovarian carcinoma. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
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22 pages, 893 KiB  
Review
Exploring the Role of Fallopian Ciliated Cells in the Pathogenesis of High-Grade Serous Ovarian Cancer
by Michela Coan, Gian Luca Rampioni Vinciguerra, Laura Cesaratto, Emanuela Gardenal, Riccardo Bianchet, Erik Dassi, Andrea Vecchione, Gustavo Baldassarre, Riccardo Spizzo and Milena Sabrina Nicoloso
Int. J. Mol. Sci. 2018, 19(9), 2512; https://doi.org/10.3390/ijms19092512 - 24 Aug 2018
Cited by 30 | Viewed by 6848
Abstract
High-grade serous epithelial ovarian cancer (HGSOC) is the fifth leading cause of cancer death in women and the first among gynecological malignancies. Despite an initial response to standard chemotherapy, most HGSOC patients relapse. To improve treatment options, we must continue investigating tumor biology. [...] Read more.
High-grade serous epithelial ovarian cancer (HGSOC) is the fifth leading cause of cancer death in women and the first among gynecological malignancies. Despite an initial response to standard chemotherapy, most HGSOC patients relapse. To improve treatment options, we must continue investigating tumor biology. Tumor characteristics (e.g., risk factors and epidemiology) are valuable clues to accomplish this task. The two most frequent risk factors for HGSOC are the lifetime number of ovulations, which is associated with increased oxidative stress in the pelvic area caused by ovulation fluid, and a positive family history due to genetic factors. In the attempt to identify novel genetic factors (i.e., genes) associated with HGSOC, we observed that several genes in linkage with HGSOC are expressed in the ciliated cells of the fallopian tube. This finding made us hypothesize that ciliated cells, despite not being the cell of origin for HGSOC, may take part in HGSOC tumor initiation. Specifically, malfunction of the ciliary beat impairs the laminar fluid flow above the fallopian tube epithelia, thus likely reducing the clearance of oxidative stress caused by follicular fluid. Herein, we review the up-to-date findings dealing with HGSOC predisposition with the hypothesis that fallopian ciliated cells take part in HGSOC onset. Finally, we review the up-to-date literature concerning genes that are located in genomic loci associated with epithelial ovarian cancer (EOC) predisposition that are expressed by the fallopian ciliated cells. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
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16 pages, 921 KiB  
Review
One-Carbon Metabolism: Biological Players in Epithelial Ovarian Cancer
by Andrea Rizzo, Alessandra Napoli, Francesca Roggiani, Antonella Tomassetti, Marina Bagnoli and Delia Mezzanzanica
Int. J. Mol. Sci. 2018, 19(7), 2092; https://doi.org/10.3390/ijms19072092 - 19 Jul 2018
Cited by 27 | Viewed by 9209
Abstract
Metabolism is deeply involved in cell behavior and homeostasis maintenance, with metabolites acting as molecular intermediates to modulate cellular functions. In particular, one-carbon metabolism is a key biochemical pathway necessary to provide carbon units required for critical processes, including nucleotide biosynthesis, epigenetic methylation, [...] Read more.
Metabolism is deeply involved in cell behavior and homeostasis maintenance, with metabolites acting as molecular intermediates to modulate cellular functions. In particular, one-carbon metabolism is a key biochemical pathway necessary to provide carbon units required for critical processes, including nucleotide biosynthesis, epigenetic methylation, and cell redox-status regulation. It is, therefore, not surprising that alterations in this pathway may acquire fundamental importance in cancer onset and progression. Two of the major actors in one-carbon metabolism, folate and choline, play a key role in the pathobiology of epithelial ovarian cancer (EOC), the deadliest gynecological malignancy. EOC is characterized by a cholinic phenotype sustained via increased activity of choline kinase alpha, and via membrane overexpression of the alpha isoform of the folate receptor (FRα), both of which are known to contribute to generating regulatory signals that support EOC cell aggressiveness and proliferation. Here, we describe in detail the main biological processes associated with one-carbon metabolism, and the current knowledge about its role in EOC. Moreover, since the cholinic phenotype and FRα overexpression are unique properties of tumor cells, but not of normal cells, they can be considered attractive targets for the development of therapeutic approaches. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
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17 pages, 485 KiB  
Review
Potential for Mitochondrial DNA Sequencing in the Differential Diagnosis of Gynaecological Malignancies
by Anna Myriam Perrone, Giulia Girolimetti, Martina Procaccini, Lorena Marchio, Alessandra Livi, Giulia Borghese, Anna Maria Porcelli, Pierandrea De Iaco and Giuseppe Gasparre
Int. J. Mol. Sci. 2018, 19(7), 2048; https://doi.org/10.3390/ijms19072048 - 13 Jul 2018
Cited by 17 | Viewed by 3652
Abstract
In the event of multiple synchronous gynecological lesions, a fundamental piece of information to determine patient management, prognosis, and therapeutic regimen choice is whether the simultaneous malignancies arise independently or as a result of metastatic dissemination. An example of synchronous primary tumors of [...] Read more.
In the event of multiple synchronous gynecological lesions, a fundamental piece of information to determine patient management, prognosis, and therapeutic regimen choice is whether the simultaneous malignancies arise independently or as a result of metastatic dissemination. An example of synchronous primary tumors of the female genital tract most frequently described are ovarian and endometrial cancers. Surgical findings and histopathological examination aimed at resolving this conundrum may be aided by molecular analyses, although they are too often inconclusive. High mitochondrial DNA (mtDNA) variability and its propensity to accumulate mutations has been proposed by our group as a tool to define clonality. We showed mtDNA sequencing to be informative in synchronous primary ovarian and endometrial cancer, detecting tumor-specific mutations in both lesions, ruling out independence of the two neoplasms, and indicating clonality. Furthermore, we tested this method in another frequent simultaneously detected gynecological lesion type, borderline ovarian cancer and their peritoneal implants, which may be monoclonal extra-ovarian metastases or polyclonal independent masses. The purpose of this review is to provide an update on the potential use of mtDNA sequencing in distinguishing independent and metastatic lesions in gynecological cancers, and to compare the efficiency of molecular analyses currently in use with this novel method. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
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15 pages, 1669 KiB  
Review
Glutathione in Ovarian Cancer: A Double-Edged Sword
by Sofia C. Nunes and Jacinta Serpa
Int. J. Mol. Sci. 2018, 19(7), 1882; https://doi.org/10.3390/ijms19071882 - 26 Jun 2018
Cited by 80 | Viewed by 8928
Abstract
Glutathione (GSH) has several roles in a cell, such as a reactive oxygen species (ROS) scavenger, an intervenient in xenobiotics metabolism and a reservoir of cysteine. All of these activities are important in the maintenance of normal cells homeostasis but can also constitute [...] Read more.
Glutathione (GSH) has several roles in a cell, such as a reactive oxygen species (ROS) scavenger, an intervenient in xenobiotics metabolism and a reservoir of cysteine. All of these activities are important in the maintenance of normal cells homeostasis but can also constitute an advantage for cancer cells, allowing disease progression and resistance to therapy. Ovarian cancer is the major cause of death from gynaecologic disease and the second most common gynaecologic malignancy worldwide. In over 50 years, the overall survival of patients diagnosed with epithelial ovarian cancer has not changed, regardless of the efforts concerning early detection, radical surgery and new therapeutic approaches. Late diagnosis and resistance to therapy are the main causes of this outcome, and GSH is profoundly associated with chemoresistance to platinum salts, which, together with taxane-based chemotherapy and surgery, are the main therapy strategies in ovarian cancer treatment. Herein, we present some insights into the role of GSH in the poor prognosis of ovarian cancer, and also point out how some strategies underlying the dependence of ovarian cancer cells on GSH can be further used to improve the effectiveness of therapy. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
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11 pages, 255 KiB  
Review
Recent Insights into Mucinous Ovarian Carcinoma
by Francesca Ricci, Roberta Affatato, Laura Carrassa and Giovanna Damia
Int. J. Mol. Sci. 2018, 19(6), 1569; https://doi.org/10.3390/ijms19061569 - 24 May 2018
Cited by 46 | Viewed by 6598
Abstract
Ovarian mucinous tumors represent a group of rare neoplasms with a still undefined cell of origin but with an apparent progression from benign to borderline to carcinoma. Even though these tumors are different from the other histological subtypes of epithelial ovarian neoplasms, they [...] Read more.
Ovarian mucinous tumors represent a group of rare neoplasms with a still undefined cell of origin but with an apparent progression from benign to borderline to carcinoma. Even though these tumors are different from the other histological subtypes of epithelial ovarian neoplasms, they are still treated with a similar chemotherapeutic approach. Here, we review its pathogenesis, molecular alterations, (differential) diagnosis, clinical presentation and current treatment, and how recent molecular and biological information on this tumor might lead to better and more specific clinical management of patients with mucinous ovarian carcinoma. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
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27 pages, 1682 KiB  
Review
Nanotechnology and Glycosaminoglycans: Paving the Way Forward for Ovarian Cancer Intervention
by Yasar Hoosen, Priyamvada Pradeep, Pradeep Kumar, Lisa C. Du Toit, Yahya E. Choonara and Viness Pillay
Int. J. Mol. Sci. 2018, 19(3), 731; https://doi.org/10.3390/ijms19030731 - 4 Mar 2018
Cited by 7 | Viewed by 5342
Abstract
Ovarian cancer (OC) has gained a great deal of attention due to its aggressive proliferative capabilities, high death rates and poor treatment outcomes, rendering the disease the ultimate lethal gynaecological cancer. Nanotechnology provides a promising avenue to combat this malignancy by the niche [...] Read more.
Ovarian cancer (OC) has gained a great deal of attention due to its aggressive proliferative capabilities, high death rates and poor treatment outcomes, rendering the disease the ultimate lethal gynaecological cancer. Nanotechnology provides a promising avenue to combat this malignancy by the niche fabrication of optimally-structured nanomedicines that ensure potent delivery of chemotherapeutics to OC, employing nanocarriers to act as “intelligent” drug delivery vehicles, functionalized with active targeting approaches for precision delivery of chemotherapeutics to overexpressed biomarkers on cancer cells. Recently, much focus has been implemented to optimize these active targeting mechanisms for treatment/diagnostic purposes employing nanocarriers. This two-part article aims to review the latest advances in active target-based OC interventions, where the impact of the newest antibody, aptamer and folate functionalization on OC detection and treatment is discussed in contrast to the limitations of this targeting mechanism. Furthermore, we discuss the latest advances in nanocarrier based drug delivery in OC, highlighting their commercial/clinical viability of these systems beyond the realms of research. Lastly, in the second section of this review, we comprehensively discussed a focus shift in OC targeting from the well-studied OC cells to the vastly neglected extracellular matrix and motivate the potential for glycosaminoglycans (GAGs) as a more focused extracellular molecular target. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
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11 pages, 10785 KiB  
Case Report
A Whole Germline BRCA2 Gene Deletion: How to Learn from CNV In Silico Analysis
by Giovanni Luca Scaglione, Paola Concolino, Maria De Bonis, Elisa De Paolis, Angelo Minucci, Gabriella Ferrandina, Giovanni Scambia and Ettore Capoluongo
Int. J. Mol. Sci. 2018, 19(4), 961; https://doi.org/10.3390/ijms19040961 - 23 Mar 2018
Cited by 15 | Viewed by 5400
Abstract
BRCA1/2 screening in Hereditary Breast and Ovarian Syndrome (HBOC) is an essential step for effective patients’ management. Next-Generation Sequencing (NGS) can rapidly provide high throughput and reliable information about the qualitative and quantitative status of tumor-associated genes. Straightforwardly, bioinformatics methods play a key [...] Read more.
BRCA1/2 screening in Hereditary Breast and Ovarian Syndrome (HBOC) is an essential step for effective patients’ management. Next-Generation Sequencing (NGS) can rapidly provide high throughput and reliable information about the qualitative and quantitative status of tumor-associated genes. Straightforwardly, bioinformatics methods play a key role in molecular diagnostics pipelines. BRCA1/2 genes were evaluated with our NGS workflow, coupled with Multiplex Amplicon Quantification (MAQ) and Multiplex Ligation-dependent Probe Amplification (MLPA) assays. Variant calling was performed on Amplicon Suite, while Copy Number Variant (CNV) prediction by in house and commercial CNV tools, before confirmatory MAQ/MLPA testing. The germline profile of BRCA genes revealed a unique HBOC pattern. Although variant calling analysis pinpointed heterozygote and homozygote polymorphisms on BRCA1 and BRCA2, respectively, the CNV predicted by our script suggested two conflicting interpretations: BRCA1 duplication and/or BRCA2 deletion. Our commercial software reported a BRCA1 duplication, in contrast with variant calling results. Finally, the MAQ/MLPA assays assessed a whole BRCA2 copy loss. In silico CNV analysis is a time and cost-saving procedure to powerfully identify possible Large Rearrangements using robust and efficient NGS pipelines. Our layout shows as bioinformatics algorithms alone cannot completely and correctly identify whole BRCA1/2 deletions/duplications. In particular, the complete deletion of an entire gene, like in our case, cannot be solved without alternative strategies as MLPA/MAQ. These findings support the crucial role of bioinformatics in deciphering pitfalls within NGS data analysis. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
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