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J N Sheets, M Iwanicki, J F Liu, B E Howitt, M S Hirsch, J A A Gubbels, R Drapkin, K A Egland
The cause of death among the majority of epithelial ovarian cancer (EOC) patients involves passive dissemination of cancer cells within the peritoneal cavity and subsequent implantation of cancer spheroids into adjacent organs. Thus, it is important to identify the factors that mediate EOC metastasis and implantation, including clearance of the mesothelium. Sushi domain containing 2 (SUSD2) encodes a type I transmembrane protein containing several functional domains inherent to adhesion molecules. Immunohistochemical analysis determined the presence of SUSD2 in several subtypes of EOC, with the strongest staining observed in high-grade serous ovarian carcinomas (HGSOCs)...
October 24, 2016: Oncogenesis
Tushar Tomar, Steven de Jong, Nicolette G Alkema, Rieks L Hoekman, Gert Jan Meersma, Harry G Klip, Ate Gj van der Zee, G Bea A Wisman
BACKGROUND: In high-grade serous ovarian cancer (HGSOC), intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations but frequent epigenetic alterations, including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs) supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated so far...
October 20, 2016: Genome Medicine
Tatiana Pochechueva, Alexander Chinarev, Andreas Schoetzau, André Fedier, Nicolai V Bovin, Neville F Hacker, Francis Jacob, Viola Heinzelmann-Schwarz
Altered levels of naturally occurring anti-glycan antibodies (AGA) circulating in human blood plasma are found in different pathologies including cancer. Here the levels of AGA directed against 22 negatively charged (sialylated and sulfated) glycans were assessed in high-grade serous ovarian cancer (HGSOC, n = 22) patients and benign controls (n = 31) using our previously developed suspension glycan array (SGA). Specifically, the ability of AGA to differentiate between controls and HGSOC, the most common and aggressive type of ovarian cancer with a poor outcome was determined...
2016: PloS One
Anselmo Papa, Davide Caruso, Martina Strudel, Silverio Tomao, Federica Tomao
BACKGROUND: Despite standard treatment for epithelial ovarian cancer (EOC), that involves cytoreductive surgery followed by platinum-based chemotherapy, and initial high response rates to these, up to 80 % of patients experience relapses with a median progression-free survival of 12-18 months. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. Of the many targeted therapies currently under evaluation, the most promising strategies developed thus far are antiangiogenic agents and Poly(ADP-ribose) polymerase (PARP) inhibitors...
2016: Journal of Translational Medicine
Kevin M Elias, Megan M Emori, Thomas Westerling, Henry Long, Anna Budina-Kolomets, Fugen Li, Emily MacDuffie, Michelle R Davis, Alexander Holman, Brian Lawney, Matthew L Freedman, John Quackenbush, Myles Brown, Ronny Drapkin
Regulation of lineage-restricted transcription factors has been shown to influence malignant transformation in several types of cancer. Whether similar mechanisms are involved in ovarian cancer pathogenesis is unknown. PAX8 is a nuclear transcription factor that controls the embryologic development of the Müllerian system, including the fallopian tubes. Recent studies have shown that fallopian tube secretory epithelial cells (FTSECs) give rise to the most common form of ovarian cancer, high-grade serous ovarian carcinomas (HGSOCs)...
August 18, 2016: JCI Insight
Mariam M AlHilli, Marc A Becker, S John Weroha, Karen S Flatten, Rachel M Hurley, Maria I Harrell, Ann L Oberg, Matt J Maurer, Kieran M Hawthorne, Xiaonan Hou, Sean C Harrington, Sarah McKinstry, X Wei Meng, Keith M Wilcoxen, Kimberly R Kalli, Elizabeth M Swisher, Scott H Kaufmann, Paul Haluska
OBJECTIVE: Poly(ADP-ribose) polymerase (PARP) inhibitors have yielded encouraging responses in high-grade serous ovarian carcinomas (HGSOCs), but the optimal treatment setting remains unknown. We assessed the effect of niraparib on HGSOC patient-derived xenograft (PDX) models as well as the relationship between certain markers of homologous recombination (HR) status, including BRCA1/2 mutations and formation of RAD51 foci after DNA damage, and response of these PDXs to niraparib in vivo...
September 7, 2016: Gynecologic Oncology
Yuanyuan Hua, Pui-Wah Choi, Alexander J Trachtenberg, Allen C Ng, Winston P Kuo, Shu-Kay Ng, Daniela M Dinulescu, Martin M Matzuk, Ross S Berkowitz, Shu-Wing Ng
Epithelial ovarian carcinoma accounts for 90% of all ovarian cancer and is the most deadly gynecologic malignancy. Recent studies have suggested that fallopian tube fimbriae can be the origin of cells for high-grade serous subtype of epithelial ovarian carcinoma (HGSOC). A mouse HGSOC model with conditional Dicer-Pten double knockout (Dicer-Pten DKO) developed primary tumors, intriguingly, from the fallopian tube stroma. We examined the growth and epithelial phenotypes of the Dicer-Pten DKO mouse tumor cells contributable by each gene knockout...
September 1, 2016: Oncotarget
Subbulakshmi Karthikeyan, Daniel D Lantvit, Dam Hee Chae, Joanna E Burdette
High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy and may arise in either the fallopian tube epithelium (FTE) or ovarian surface epithelium (OSE). A mutation in p53 is reported in 96% of HGSOC, most frequently at R273 and R248. The goal of this study was to identify specific gene targets in the FTE that are altered by mutant p53, but not in the OSE. Gene analysis revealed that both R273 and R248 mutant p53 reduces CDH6 expression in the oviduct, but CDH6 was not detected in murine OSE cells...
August 22, 2016: Oncotarget
F Coscia, K M Watters, M Curtis, M A Eckert, C Y Chiang, S Tyanova, A Montag, R R Lastra, E Lengyel, M Mann
A cell line representative of human high-grade serous ovarian cancer (HGSOC) should not only resemble its tumour of origin at the molecular level, but also demonstrate functional utility in pre-clinical investigations. Here, we report the integrated proteomic analysis of 26 ovarian cancer cell lines, HGSOC tumours, immortalized ovarian surface epithelial cells and fallopian tube epithelial cells via a single-run mass spectrometric workflow. The in-depth quantification of >10,000 proteins results in three distinct cell line categories: epithelial (group I), clear cell (group II) and mesenchymal (group III)...
2016: Nature Communications
Paul A Cohen, Nicola Flowers, Stephen Tong, Natalie Hannan, Mark D Pertile, Lisa Hui
BACKGROUND: Non-invasive prenatal testing (NIPT) identifies fetal aneuploidy by sequencing cell-free DNA in the maternal plasma. Pre-symptomatic maternal malignancies have been incidentally detected during NIPT based on abnormal genomic profiles. This low coverage sequencing approach could have potential for ovarian cancer screening in the non-pregnant population. Our objective was to investigate whether plasma DNA sequencing with a clinical whole genome NIPT platform can detect early- and late-stage high-grade serous ovarian carcinomas (HGSOC)...
August 24, 2016: BMC Medicine
Karin Hellner, Fabrizio Miranda, Donatien Fotso Chedom, Sandra Herrero-Gonzalez, Daniel M Hayden, Rick Tearle, Mara Artibani, Mohammad KaramiNejadRanjbar, Ruth Williams, Kezia Gaitskell, Samar Elorbany, Ruoyan Xu, Alex Laios, Petronela Buiga, Karim Ahmed, Sunanda Dhar, Rebecca Yu Zhang, Leticia Campo, Kevin A Myers, María Lozano, María Ruiz-Miró, Sónia Gatius, Alba Mota, Gema Moreno-Bueno, Xavier Matias-Guiu, Javier Benítez, Lorna Witty, Gil McVean, Simon Leedham, Ian Tomlinson, Radoje Drmanac, Jean-Baptiste Cazier, Robert Klein, Kevin Dunne, Robert C Bast, Stephen H Kennedy, Bassim Hassan, Stefano Lise, María José Garcia, Brock A Peters, Christopher Yau, Tatjana Sauka-Spengler, Ahmed Ashour Ahmed
Current screening methods for ovarian cancer can only detect advanced disease. Earlier detection has proved difficult because the molecular precursors involved in the natural history of the disease are unknown. To identify early driver mutations in ovarian cancer cells, we used dense whole genome sequencing of micrometastases and microscopic residual disease collected at three time points over three years from a single patient during treatment for high-grade serous ovarian cancer (HGSOC). The functional and clinical significance of the identified mutations was examined using a combination of population-based whole genome sequencing, targeted deep sequencing, multi-center analysis of protein expression, loss of function experiments in an in-vivo reporter assay and mammalian models, and gain of function experiments in primary cultured fallopian tube epithelial (FTE) cells...
August 2016: EBioMedicine
Alessandra Ciucci, Gian Franco Zannoni, Marianna Buttarelli, Enrica Martinelli, Floriana Mascilini, Marco Petrillo, Gabriella Ferrandina, Giovanni Scambia, Daniela Gallo
Only recently low-grade serous carcinoma (LGSOC) of the ovary has been recognized as a disease entity distinct from the more common high-grade serous carcinoma (HGSOC), with significant differences in pathogenesis and clinical and pathologic features. The present study aimed at evaluating whether the different natural histories and patterns of response to therapy demonstrated for LGSOC and HGSOC, along with a diverse genomic landscape, may also reside in the supporting tumor stroma, specifically in the state of differentiation and activation of tumor associated macrophages (TAMs)...
July 23, 2016: Oncotarget
Margarita Romeo, Niki Karachaliou, Imane Chaid, Cristina Queralt, Itziar De Aguirre, María Del Carmen Gómez, María Sanchez-Ronco, Joaquim Radua, José Luís Ramírez, Rafael Rosell
OBJECTIVE: Homologous recombination (HR) is frequently impaired in sporadic high-grade serous ovarian carcinoma (sHGSOC) due to deficiencies in BRCA1/2 genes, a situation associated with hypersensitivity to platinum compounds. Alterations in other genes can also cause HR deficiency. Preclinical data show that RAP80 is an HR-pathway-related gene that influences BRCA1 activity. RAP80 has been reported to affect outcome in some solid neoplasms. This study investigates the role of RAP80 in sHGSOC survival...
July 18, 2016: International Journal of Biological Markers
Reto S Kohler, Merrina Anugraham, Mónica Núñez López, Christina Xiao, Andreas Schoetzau, Timm Hettich, Goetz Schlotterbeck, André Fedier, Francis Jacob, Viola Heinzelmann-Schwarz
Bisecting GlcNAc on N-glycoproteins is described in E-cadherin-, EGF-, Wnt- and integrin- cancer-associated signaling pathways. However, the mechanisms regulating bisecting GlcNAc expression are not clear. Bisecting GlcNAc is attached to N-glycans through beta 1-4 N-acetylglucosaminyl transferase III (MGAT3), which is encoded by two exons flanked by high-density CpG islands. Despite a recently described correlation of MGAT3 and bisecting GlcNAc in ovarian cancer cells, it remains unknown whether DNA methylation is causative for the presence of bisecting GlcNAc...
July 12, 2016: Oncotarget
Naoki Horikawa, Kaoru Abiko, Noriomi Matsumura, Junzo Hamanishi, Tsukasa Baba, Ken Yamaguchi, Yumiko Yoshioka, Masafumi Koshiyama, Ikuo Konishi
PURPOSE: High vascular endothelial growth factor (VEGF) expression in ovarian cancer is an unfavorable prognostic factor. However, the role of VEGF in tumor immunity remains unclear. Here, we examined the impact of VEGF on local immunity, including induction of myeloid-derived suppressor cells (MDSCs), in ovarian cancer. EXPERIMENTAL DESIGN: High-grade serous ovarian cancer (HGSOC) cases were analyzed by gene expression microarray and immunohistochemistry for VEGF, CD8, and CD33...
July 11, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Anne Montfort, Oliver M T Pearce, Eleni Maniati, Benjamin Vincent, Lisa M Bixby, Steffen Böhm, Thomas Dowe, Edmund H Wilkes, Probir Chakravarty, Richard Thompson, Joanne Topping, Pedro R Cutillas, Michelle Lockley, Jonathan S Serody, Melania Capasso, Frances R Balkwill
PURPOSE: In high-grade serous ovarian cancer (HGSOC), higher densities of both B cells and the CD8+ T cell infiltrate were associated with a better prognosis. However, the precise role of B cells in the anti-tumor response remains unknown. As peritoneal metastases are often responsible for relapse, our aim was to characterize the role of B cells in the anti-tumor immune response in HGSOC metastases. EXPERIMENTAL DESIGN: Unmatched pre and post-chemotherapy HGSOC metastases were studied...
June 27, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Kelsie L Thu, Mahboubeh Papari-Zareei, Victor Stastny, Kai Song, Michael Peyton, Victor D Martinez, Yu-An Zhang, Isabel B Castro, Marileila Varella-Garcia, Hanquan Liang, Chao Xing, Ralf Kittler, Sara Milchgrub, Diego H Castrillon, Heather L Davidson, C Patrick Reynolds, Wan L Lam, Jayanthi Lea, Adi F Gazdar
Recent literature suggests that most widely used ovarian cancer (OVCA) cell models do not recapitulate the molecular features of clinical tumors. To address this limitation, we generated 18 cell lines and 3 corresponding patient-derived xenografts predominantly from high-grade serous carcinoma (HGSOC) peritoneal effusions. Comprehensive genomic characterization and comparison of each model to its parental tumor demonstrated a high degree of molecular similarity. Our characterization included whole exome-sequencing and copy number profiling for cell lines, xenografts, and matched non-malignant tissues, and DNA methylation, gene expression, and spectral karyotyping for a subset of specimens...
June 10, 2016: Oncotarget
Dana-Adriana Botesteanu, Jung-Min Lee, Doron Levy
High-grade serous ovarian cancer (HGSOC) represents the majority of ovarian cancers and accounts for the largest proportion of deaths from the disease. A timely detection of low volume HGSOC should be the goal of any screening studies. However, numerous transvaginal ultrasound (TVU) detection-based population studies aimed at detecting low-volume disease have not yielded reduced mortality rates. A quantitative invalidation of TVU as an effective HGSOC screening strategy is a necessary next step. Herein, we propose a mathematical model for a quantitative explanation on the reported failure of TVU-based screening to improve HGSOC low-volume detectability and overall survival...
2016: PloS One
Katherine Karakasis, Julia V Burnier, Valerie Bowering, Amit M Oza, Stephanie Lheureux
Without prevention or screening options available, ovarian cancer is the most lethal malignancy of the female reproductive tract. High-grade serous ovarian cancer (HGSOC) is the most common histologic subtype, and the role of germline BRCA1/2 mutation in predisposition and prognosis is established. Given the targeted treatment opportunities with PARP inhibitors, a predictive role for BRCA1/2 mutation has emerged. Despite recommendations to provide BRCA1/2 testing to all women with histologically confirmed HGSOC, uniform implementation remains challenging...
2016: Frontiers in Oncology
Lorenza Mittempergher
High-grade serous ovarian carcinoma (HGSOC) accounts for the majority of the ovarian cancer deaths, but over the last years little improvement in overall survival has been achieved. HGSOC is a molecularly and clinically heterogeneous disease. At genomic level, it represents a C-class malignancy having frequent gene losses (NF1, RB1, PTEN) and gains (CCNE1, MYC). HGSOC shows a simple mutational profile with TP53 nearly always mutated and with other genes mutated at low frequency. Importantly, 50 % of all HGSOCs have genetic features indicating a homologous recombination (HR) deficiency...
July 2016: Current Oncology Reports
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