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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 108079

Special Issue Editors

Prof. Dr. Laura Gatti

E-Mail Website
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

E-Mail Website
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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18 pages, 289 KiB  
Review
Translational Research Opportunities Regarding Homologous Recombination in Ovarian Cancer
by Margarita Romeo 1,2,*, Juan Carlos Pardo 1, Anna Martínez-Cardús 3, Eva Martínez-Balibrea 4, Vanesa Quiroga 1, Sergio Martínez-Román 5, Francesc Solé 6, Mireia Margelí 1 and Ricard Mesía 1
1 Medical Oncology Department, B-ARGO Group, Institut Català d’Oncologia Badalona, Carretera del Canyet s/n, 08916 Badalona, Spain
2 Campus de la UAB, Universitat Autónoma de Barcelona, Plaça Cívica, 08193 Bellaterra, Spain
3 Health Sciences Research Institute of the Germans Trias i Pujol Foundation (IGTP), B-ARGO Group, Carretera del Canyet s/n, 08916 Badalona, Spain
4 Program against Cancer Therapeutic Resistance (ProCURE), Institut Català d’Oncologia Badalona, Program for Predictive and Personalized Cancer Medicine (PMPPC), Health Sciences Research Institute Germans Trias i Pujo (IGTP), Carretera de Can Ruti, Camí de les Escoles s/n, 08916 Badalona, Spain
5 Gynecology Department, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain
6 Institut de Recerca contra la Leucemia Josep Carreras, 08916 Badalona, Spain
Int. J. Mol. Sci. 2018, 19(10), 3249; https://doi.org/10.3390/ijms19103249 - 19 Oct 2018
Cited by 6 | Viewed by 4129
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 1,2
1 Department of Bioscience Technology and Center for Biomedical Technology, Chung Yuan Christian University, Chung Li 32023, Taiwan
2 Department of Microbiology & Immunology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA
Int. J. Mol. Sci. 2018, 19(10), 2976; https://doi.org/10.3390/ijms19102976 - 29 Sep 2018
Cited by 2 | Viewed by 2891
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 1, Gian Luca Rampioni Vinciguerra 1, Laura Cesaratto 1, Emanuela Gardenal 2, Riccardo Bianchet 3, Erik Dassi 4, Andrea Vecchione 5, Gustavo Baldassarre 1, Riccardo Spizzo 1,* and Milena Sabrina Nicoloso 1
1 Division of Molecular Oncology, Department of Translational Research, IRCCS CRO Aviano-National Cancer Institute, Via Franco Gallini, 2 33081 Aviano PN, Italy
2 Azienda Ospedaliera Universitaria Integrata, University of Verona, 37129 Verona, Italy
3 Scientific Direction, CRO Aviano Italy, Via Franco Gallini, 2 33081 Aviano, Italy
4 Centre for Integrative Biology, University of Trento, 38122 Trento, Italy
5 Department of clinical and molecular medicine, university of Rome “Sapienza”, c/o sant andrea hospital, Via di Grottarossa 1035, 00189 Rome, Italy
Int. J. Mol. Sci. 2018, 19(9), 2512; https://doi.org/10.3390/ijms19092512 - 24 Aug 2018
Cited by 34 | Viewed by 7353
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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13 pages, 621 KiB  
Article
rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology
by Linda E. Kelemen 1,2,*, Madalene Earp 3, Brooke L. Fridley 4, Georgia Chenevix-Trench 5, On behalf of Australian Ovarian Cancer Study Group 5,6, Peter A. Fasching 7,8, Matthias W. Beckmann 7, Arif B. Ekici 9, Alexander Hein 7, Diether Lambrechts 10,11, Sandrina Lambrechts 12, Els Van Nieuwenhuysen 12, Ignace Vergote 12, Mary Anne Rossing 13,14, Jennifer A. Doherty 15, Jenny Chang-Claude 16,17, Sabine Behrens 16, Kirsten B. Moysich 18, Rikki Cannioto 18, Shashikant Lele 19, Kunle Odunsi 19, Marc T. Goodman 20,21, Yurii B. Shvetsov 22, Pamela J. Thompson 20,21, Lynne R. Wilkens 22, Thilo Dörk 23, Natalia Antonenkova 24, Natalia Bogdanova 23, Peter Hillemanns 25, Ingo B. Runnebaum 26, Andreas Du Bois 27,28, Philipp Harter 27,28, Florian Heitz 27,28, Ira Schwaab 29, Ralf Butzow 30,31, Liisa M. Pelttari 31, Heli Nevanlinna 31, Francesmary Modugno 32,33,34, Robert P. Edwards 32, Joseph L. Kelley 32, Roberta B. Ness 35, Beth Y. Karlan 36, Jenny Lester 36, Sandra Orsulic 36, Christine Walsh 36, Susanne K. Kjaer 37,38, Allan Jensen 38, Julie M. Cunningham 39, Robert A. Vierkant 40, Graham G. Giles 41,42,43, Fiona Bruinsma 42, Melissa C. Southey 44, Michelle A.T. Hildebrandt 45, Dong Liang 46, Karen Lu 47, Xifeng Wu 45, Thomas A. Sellers 48, Douglas A. Levine 49, Joellen M. Schildkraut 50, Edwin S. Iversen 51, Kathryn L. Terry 52,53, Daniel W. Cramer 52,53, Shelley S. Tworoger 48,52, Elizabeth M. Poole 54, Elisa V. Bandera 55, Sara H. Olson 56, Irene Orlow 56, Liv Cecilie Vestrheim Thomsen 57,58, Line Bjorge 57,58, Camilla Krakstad 57,58, Ingvild L. Tangen 57,58, Lambertus A. Kiemeney 59, Katja K.H. Aben 59,60, Leon F.A.G. Massuger 61, Anne M. Van Altena 61, Tanja Pejovic 62,63, Yukie Bean 62,63, Melissa Kellar 62,63, Linda S. Cook 64, Nhu D. Le 65, Angela Brooks-Wilson 66,67, Jacek Gronwald 68, Cezary Cybulski 68, Anna Jakubowska 68,69, Jan Lubiński 68, Nicolas Wentzensen 70, Louise A. Brinton 70, Jolanta Lissowska 71, Estrid Hogdall 38,72, Svend Aage Engelholm 73, Claus Hogdall 37, Lene Lundvall 37, Lotte Nedergaard 74, Paul D.P. Pharoah 75,76, Ed Dicks 76, Honglin Song 76, Jonathan P. Tyrer 76, Iain McNeish 77, Nadeem Siddiqui 78, Karen Carty 79, Rosalind Glasspool 79, James Paul 79, Ian G. Campbell 44,80,81, Diana Eccles 82, Alice S. Whittemore 83, Valerie McGuire 83, Joseph H. Rothstein 84,85, Weiva Sieh 84,85, Steven A. Narod 86, Catherine M. Phelan 48, John R. McLaughlin 87, Harvey A. Risch 88, Hoda Anton-Culver 89, Argyrios Ziogas 89, Usha Menon 90, Simon A. Gayther 91, Aleksandra Gentry-Maharaj 90, Susan J. Ramus 92,93, Anna H. Wu 94, Celeste Leigh Pearce 94,95, Alice W. Lee 96, Malcolm C. Pike 56,94, Jolanta Kupryjanczyk 97, Agnieszka Podgorska 97, Joanna Plisiecka-Halasa 97, Wlodzimierz Sawicki 98, Ellen L. Goode 3, Andrew Berchuck 99 and Ovarian Cancer Association Consortiumadd Show full author list remove Hide full author list
1 Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
2 Department of Public Health Sciences, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
3 Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Rochester, MN 55905, USA
4 Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 USA
5 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
6 Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
7 Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center, 91054 Erlangen, Germany
8 Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
9 Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen Nuremberg, Erlangen 91054, Germany
10 Vesalius Research Center, University of Leuven, Leuven 3001, Belgium
11 Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven 3000, Belgium
12 Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven 3000, Belgium
13 Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
14 Department of Epidemiology, University of Washington, Seattle, WA 98402, USA
15 Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT 84112, USA
16 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
17 University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
18 Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
19 Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
20 Department of Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
21 Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
22 Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
23 Gynaecology Research Unit, Hannover Medical School, Hannover 30625, Germany
24 Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk 223040, Belarus
25 Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover 30625, Germany
26 Department of Gynecology, Jena University Hospital-Friedrich Schiller University, Jena 07743, Germany
27 Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte (KEM), Essen 45136, Germany
28 Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden 65199, Germany
29 Praxis für Humangenetik, Wiesbaden 65187, Germany
30 Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki 00290, Finland
31 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki 00290, Finland
32 Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
33 Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15213, USA
34 Women’s Cancer Research Program, Magee-Women's Research Institute and Hillman Cancer Center, Pittsburgh, PA 15213, USA
35 School of Public Health, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA
36 Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
37 Department of Gynaecology, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark
38 Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Centre, DK-2100 Copenhagen, Denmark
39 Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN 55905, USA
40 Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA
41 Centre for Epidemiology and Biostatistics, University of Melbourne, VIC 3010, Australia
42 Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC 3004, Australia
43 Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC 3800, Australia
44 Department of Pathology, University of Melbourne, Melbourne, VIC 3010, Australia
45 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
46 College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA
47 Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
48 Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
49 Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA
50 Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA
51 Department of Statistical Science, Duke University, Durham, NC 27708, USA
52 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
53 Obstetrics and Gynecology Epidemiology Center, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
54 Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
55 Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
56 Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY 10065, USA
57 Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen 5021, Norway
58 Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen 5020, Norway
59 Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen 6525 EZ, The Netherlands
60 Netherlands Comprehensive Cancer Organisation, Utrecht 3511 DT, The Netherlands
61 Radboud University Medical Centre, Department of Obstetrics and Gynecology, Nijmegen 6525 GA, The Netherlands
62 Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR 97239, USA
63 Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA
64 Division of Epidemiology, Biostatistics and Preventive Medicine, Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA
65 Cancer Control Research, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
66 Canada’s Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
67 Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC V5A 1S6, Canada
68 International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 71-252, Poland
69 Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin 70-111, Poland
70 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA
71 Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Institute-Oncology Center, Warsaw 02-034, Poland
72 Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen DK-2100, Denmark
73 Department of Radiation Oncology, Rigshospitalet, University of Copenhagen, Copenhagen DK-2100, Denmark
74 Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen DK-2100, Denmark
75 The Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
76 The Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
77 Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK
78 Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow G4 0SF, UK
79 Cancer Research UK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK
80 Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC 3000, Australia
81 Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3000, Australia
82 Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK
83 Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA 94305, USA
84 Department of Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
85 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
86 Women’s College Research Institute, University of Toronto, Toronto, ON M5S 1A8, Canada
87 Public Health Ontario, Samuel Lunenfeld Research Institute, Toronto, ON M5T 3L9, Canada
88 Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT 06510, USA
89 Department of Epidemiology, Genetic Epidemiology Research Institute, School of Medicine, University of California Irvine, Irvine, CA 92617, USA
90 MRC Clinical Trials at UCL, Institute of Clinical Trials & Methodology, Population Health Sciences, University College London, London, WC1V 6LJ, UK
91 Department of Biomedical Sciences and Center for Cancer Prevention and Translational Genomics, Samuel Oschin Comprensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
92 School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
93 The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia
94 Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
95 Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA
96 Department of Public Health, California State University, Fullerton, CA 92831, USA
97 Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Institute-Oncology Center, Warsaw 02-034, Poland
98 Department of Obstetrics, Gynecology and Oncology, Second Faculty of Medicine, Medical University of Warsaw, Mazovian Bródno Hospital, Warsaw 03-242, Poland
99 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710, USA
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Int. J. Mol. Sci. 2018, 19(9), 2473; https://doi.org/10.3390/ijms19092473 - 21 Aug 2018
Cited by 3 | Viewed by 7478
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 1, Agnieszka Horala 2, Jan Matysiak 1, Joanna Hajduk 1, Ewa Nowak-Markwitz 2 and Zenon J. Kokot 1,*
1 Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, ul. Grunwaldzka 6, 60-780 Poznań, Poland
2 Gynecologic Oncology Department, Poznan University of Medical Sciences, ul. Polna 33, 60-535 Poznań, Poland
Int. J. Mol. Sci. 2018, 19(8), 2240; https://doi.org/10.3390/ijms19082240 - 31 Jul 2018
Cited by 34 | Viewed by 5846
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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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 *
Unit of Molecular Therapies, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy
Int. J. Mol. Sci. 2018, 19(7), 2092; https://doi.org/10.3390/ijms19072092 - 19 Jul 2018
Cited by 28 | Viewed by 9591
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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26 pages, 6670 KiB  
Article
Establishment and Characterization of the Novel High-Grade Serous Ovarian Cancer Cell Line OVPA8
by Patrycja Tudrej 1, Magdalena Olbryt 1, Ewa Zembala-Nożyńska 2, Katarzyna A. Kujawa 1, Alexander J. Cortez 1, Anna Fiszer-Kierzkowska 3, Wojciech Pigłowski 3, Barbara Nikiel 2, Magdalena Głowala-Kosińska 4, Aleksandra Bartkowska-Chrobok 5, Andrzej Smagur 4, Wojciech Fidyk 4 and Katarzyna M. Lisowska 1,*
1 Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowskaj-Curie Institute—Oncology Center, Gliwice Branch, ul. Wybrzeże Armii Krajowej 15, 44-101 Gliwice, Poland
2 Thumor Pathology Department, Maria Skłodowskaj-Curie Institute—Oncology Center, Gliwice Branch, ul. Wybrzeże Armii Krajowej 15, 44-101 Gliwice, Poland
3 Molecular Diagnostics Laboratory, Maria Skłodowskaj-Curie Institute—Oncology Center, Gliwice Branch, ul. Wybrzeże Armii Krajowej 15, 44-101 Gliwice, Poland
4 Department of Bone Marrow Transplantation and Hematology-Oncology, Maria Skłodowskaj-Curie Institute—Oncology Center, Gliwice Branch, ul. Wybrzeże Armii Krajowej 15, 44-101 Gliwice, Poland
5 Department of Hematology and Bone Marrow Transplantation, Andrzej Mielęcki Independent Public Hospital, ul. Dąbrowskiego 25, 40-032 Katowice, Poland
Int. J. Mol. Sci. 2018, 19(7), 2080; https://doi.org/10.3390/ijms19072080 - 17 Jul 2018
Cited by 28 | Viewed by 12743
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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17 pages, 485 KiB  
Review
Potential for Mitochondrial DNA Sequencing in the Differential Diagnosis of Gynaecological Malignancies
by Anna Myriam Perrone 1,*,†, Giulia Girolimetti 2,†, Martina Procaccini 1, Lorena Marchio 2, Alessandra Livi 1, Giulia Borghese 1, Anna Maria Porcelli 3, Pierandrea De Iaco 1 and Giuseppe Gasparre 2,4,*
1 Unit of Oncologic Gynecology, Sant Orsola-Malpighi Hospital, via Massarenti 13, 40138 Bologna, Italy
2 Unit of Medical Genetics, Department of Medical and Surgical Sciences (DIMEC), Sant Orsola Hospital, Pav.11, via Massarenti 9, 40138 Bologna, Italy
3 Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40138 Bologna, Italy
4 Center for Applied Biomedical Research (CRBA), University of Bologna, 40138 Bologna, Italy
† These authors contributed equally to this work.
Int. J. Mol. Sci. 2018, 19(7), 2048; https://doi.org/10.3390/ijms19072048 - 13 Jul 2018
Cited by 17 | Viewed by 3816
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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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 1,2,3, Lara Marcos-Silva 1,2,4,5, Nuno Mendes 1,2, Daniela Pereira 1,2,†, Catarina Brito 4,5, Francis Jacob 6, Catharina Steentoft 7, Ulla Mandel 7, Henrik Clausen 7, Leonor David 1,2,3 and Sara Ricardo 1,2,3,*
1 Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4099-002 Porto, Portugal
2 Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4099-002 Porto, Portugal
3 Faculty of Medicine, University of Porto, 4099-002 Porto, Portugal
4 Instituto de Biologia Experimental e Tecnológica (iBET), 2780-901 Oeiras, Portugal
5 Instituto de Tecnologia Química e Biológica (ITQB) António Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal
6 Glyco-Oncology, Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland
7 Copenhagen Center for Glycomics, Department of Odontology, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
† Present work address: Portsmouth Hospitals NHS Trust, United Kingdom.
Int. J. Mol. Sci. 2018, 19(7), 2045; https://doi.org/10.3390/ijms19072045 - 13 Jul 2018
Cited by 26 | Viewed by 6395
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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15 pages, 1669 KiB  
Review
Glutathione in Ovarian Cancer: A Double-Edged Sword
by Sofia C. Nunes 1,2 and Jacinta Serpa 1,2,*
1 Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal
2 Unidade de Investigação em Patobiologia Molecular do Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof. Lima Basto, 1099-023 Lisboa, Portugal
Int. J. Mol. Sci. 2018, 19(7), 1882; https://doi.org/10.3390/ijms19071882 - 26 Jun 2018
Cited by 81 | Viewed by 9397
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 *
IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Laboratory of Molecular Pharmacology, Via Giuseppe La Masa 19, 20156 Milan, Italy
Int. J. Mol. Sci. 2018, 19(6), 1569; https://doi.org/10.3390/ijms19061569 - 24 May 2018
Cited by 51 | Viewed by 7094
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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16 pages, 1625 KiB  
Article
Distinct DNA Methylation Profiles in Ovarian Tumors: Opportunities for Novel Biomarkers
by Lorena Losi 1,2,*, Sergio Fonda 1, Sara Saponaro 1,3, Sonia T. Chelbi 3, Cesare Lancellotti 1, Gaia Gozzi 1, Loredana Alberti 3, Luca Fabbiani 2, Laura Botticelli 2 and Jean Benhattar 3,4
1 Department of Life Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy
2 Unit of Pathology, Azienda Ospedaliero-Universitaria Policlinico, 41124 Modena, Italy
3 Institute of Pathology, Lausanne University Hospital, 1011 Lausanne, Switzerland
4 Aurigen, Centre de Génétique et Pathologie, 1004 Lausanne, Switzerland
Int. J. Mol. Sci. 2018, 19(6), 1559; https://doi.org/10.3390/ijms19061559 - 24 May 2018
Cited by 25 | Viewed by 4599
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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11 pages, 10785 KiB  
Case Report
A Whole Germline BRCA2 Gene Deletion: How to Learn from CNV In Silico Analysis
by Giovanni Luca Scaglione 1,2, Paola Concolino 3, Maria De Bonis 3, Elisa De Paolis 3, Angelo Minucci 3, Gabriella Ferrandina 4, Giovanni Scambia 1,4 and Ettore Capoluongo 2,5,*
1 Fondazione di Ricerca e Cura Giovanni Paolo II, Laboratorio di Oncologia Molecolare, Molipharma a spin-off of Fondazione di Ricerca e Cura Giovanni Paolo II, Contrada Tappino, 86100 Campobasso, Italy
2 Istituto Dermopatico dell’Immacolata—Istituto di Ricovero e Cura a Carattere Scientifico, Dipartimento di Diagnostica di Laboratorio e Biologia Molecolare Clinica, 00168 Roma, Italy
3 Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, Polo Scienze delle Immagini, di Laboratorio ed Infettivologiche, 00168 Rome, Italy
4 Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, Polo Scienze della Salute della Donna e del Bambino, 00168 Rome, Italy
5 Laboratory of Molecular Genomics XBiogem, Catholic University of Rome, 00168 Rome, Italy
Int. J. Mol. Sci. 2018, 19(4), 961; https://doi.org/10.3390/ijms19040961 - 23 Mar 2018
Cited by 15 | Viewed by 5635
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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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 *
Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa
Int. J. Mol. Sci. 2018, 19(3), 731; https://doi.org/10.3390/ijms19030731 - 4 Mar 2018
Cited by 9 | Viewed by 5589
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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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 1, Daniel Kritsch 1, Alexander S. Mosig 2, Matthias Dürst 1, Norman Häfner 1,* and Ingo B. Runnebaum 1,*
1 Department of Gynecology, Jena University Hospital—Friedrich Schiller University Jena, 07747 Jena, Germany
2 Department of Biochemistry II, Jena University Hospital—Friedrich Schiller University Jena, 07747 Jena, Germany
Int. J. Mol. Sci. 2018, 19(1), 253; https://doi.org/10.3390/ijms19010253 - 15 Jan 2018
Cited by 9 | Viewed by 6513
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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11 pages, 2139 KiB  
Article
Usefulness of Amino Acid Profiling in Ovarian Cancer Screening with Special Emphasis on Their Role in Cancerogenesis
by Szymon Plewa 1, Agnieszka Horała 2, Paweł Dereziński 1, Agnieszka Klupczynska 1, Ewa Nowak-Markwitz 2, Jan Matysiak 1 and Zenon J. Kokot 1,*
1 Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, 6 Grunwaldzka Street, 60-780 Poznan, Poland
2 Gynecologic Oncology Department, Poznan University of Medical Sciences, 33 Polna Street, 60-535 Poznan, Poland
Int. J. Mol. Sci. 2017, 18(12), 2727; https://doi.org/10.3390/ijms18122727 - 16 Dec 2017
Cited by 44 | Viewed by 5785
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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