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Sample records for ovarian cancer stem

  1. Epigenetic targeting of ovarian cancer stem cells.

    PubMed

    Wang, Yinu; Cardenas, Horacio; Fang, Fang; Condello, Salvatore; Taverna, Pietro; Segar, Matthew; Liu, Yunlong; Nephew, Kenneth P; Matei, Daniela

    2014-09-01

    Emerging results indicate that cancer stem-like cells contribute to chemoresistance and poor clinical outcomes in many cancers, including ovarian cancer. As epigenetic regulators play a major role in the control of normal stem cell differentiation, epigenetics may offer a useful arena to develop strategies to target cancer stem-like cells. Epigenetic aberrations, especially DNA methylation, silence tumor-suppressor and differentiation-associated genes that regulate the survival of ovarian cancer stem-like cells (OCSC). In this study, we tested the hypothesis that DNA-hypomethylating agents may be able to reset OCSC toward a differentiated phenotype by evaluating the effects of the new DNA methytransferase inhibitor SGI-110 on OCSC phenotype, as defined by expression of the cancer stem-like marker aldehyde dehydrogenase (ALDH). We demonstrated that ALDH(+) ovarian cancer cells possess multiple stem cell characteristics, were highly chemoresistant, and were enriched in xenografts residual after platinum therapy. Low-dose SGI-110 reduced the stem-like properties of ALDH(+) cells, including their tumor-initiating capacity, resensitized these OCSCs to platinum, and induced reexpression of differentiation-associated genes. Maintenance treatment with SGI-110 after carboplatin inhibited OCSC growth, causing global tumor hypomethylation and decreased tumor progression. Our work offers preclinical evidence that epigenome-targeting strategies have the potential to delay tumor progression by reprogramming residual cancer stem-like cells. Furthermore, the results suggest that SGI-110 might be administered in combination with platinum to prevent the development of recurrent and chemoresistant ovarian cancer.

  2. Epigenetic Targeting of Ovarian Cancer Stem Cells

    PubMed Central

    Wang, Yinu; Cardenas, Horacio; Fang, Fang; Condello, Salvatore; Taverna, Pietro; Segar, Matthew; Liu, Yunlong; Nephew, Kenneth P.; Matei, Daniela

    2014-01-01

    Emerging results indicate that cancer stem-like cells contribute to chemoresistance and poor clinical outcomes in many cancers, including ovarian cancer (OC). As epigenetic regulators play a major role in the control of normal stem cell differentiation, epigenetics may offer a useful arena to develop strategies to target cancer stem-like cells. Epigenetic aberrations, especially DNA methylation, silence tumor suppressor and differentiation-associated genes that regulate the survival of ovarian cancer stem-like cell (OCSC). In this study, we tested the hypothesis that DNA hypomethylating agents may be able to reset OCSC towards a differentiated phenotype, by evaluating the effects of the new DNA methytransferase inhibitor SGI-110 on OCSC phenotype, as defined by expression of the cancer stem-like marker aldehyde dehydrogenase (ALDH). We demonstrated that ALDH+ OC cells possess multiple stem cell characteristics, were highly chemoresistant, and were enriched in xenografts residual after platinum therapy. Low dose SGI-110 reduced the stem-like properties of ALDH+ cells, including their tumor initiating capacity, resensitized these OCSCs to platinum, and induced re-expression of differentiation-associated genes. Maintenance treatment with SGI-110 after carboplatin inhibited OCSC growth, causing global tumor hypomethylation and decreased tumor progression. Our work offers preclinical evidence that epigenome-targeting strategies have the potential to delay tumor progression by re-programming residual cancer stem-like cells. Further, the results suggest that SGI-110 might be administered in combination with platinum to prevent the development of recurrent and chemoresistant ovarian cancer. PMID:25035395

  3. Cisplatin induces stemness in ovarian cancer

    PubMed Central

    Thiagarajan, Praveena S.; Rao, Vinay S.; Hale, James S.; Gupta, Nikhil; Hitomi, Masahiro; Nagaraj, Anil Belur; DiFeo, Analisa; Lathia, Justin D.; Reizes, Ofer

    2016-01-01

    The mainstay of treatment for ovarian cancer is platinum-based cytotoxic chemotherapy. However, therapeutic resistance and recurrence is a common eventuality for nearly all ovarian cancer patients, resulting in poor median survival. Recurrence is postulated to be driven by a population of self-renewing, therapeutically resistant cancer stem cells (CSCs). A current limitation in CSC studies is the inability to interrogate their dynamic changes in real time. Here we utilized a GFP reporter driven by the NANOG-promoter to enrich and track ovarian CSCs. Using this approach, we identified a population of cells with CSC properties including enhanced expression of stem cell transcription factors, self-renewal, and tumor initiation. We also observed elevations in CSC properties in cisplatin-resistant ovarian cancer cells as compared to cisplatin-naïve ovarian cancer cells. CD49f, a marker for CSCs in other solid tumors, enriched CSCs in cisplatin-resistant and -naïve cells. NANOG-GFP enriched CSCs (GFP+ cells) were more resistant to cisplatin as compared to GFP-negative cells. Moreover, upon cisplatin treatment, the GFP signal intensity and NANOG expression increased in GFP-negative cells, indicating that cisplatin was able to induce the CSC state. Taken together, we describe a reporter-based strategy that allows for determination of the CSC state in real time and can be used to detect the induction of the CSC state upon cisplatin treatment. As cisplatin may provide an inductive stress for the stem cell state, future efforts should focus on combining cytotoxic chemotherapy with a CSC targeted therapy for greater clinical utility. PMID:27105520

  4. Targeting epithelial-mesenchymal transition and cancer stem cells for chemoresistant ovarian cancer

    PubMed Central

    Deng, Junli; Wang, Li; Chen, Hongmin; Hao, Jingli; Ni, Jie; Chang, Lei; Duan, Wei; Graham, Peter; Li, Yong

    2016-01-01

    Chemoresistance is the main challenge for the recurrent ovarian cancer therapy and responsible for treatment failure and unfavorable clinical outcome. Understanding mechanisms of chemoresistance in ovarian cancer would help to predict disease progression, develop new therapies and personalize systemic therapy. In the last decade, accumulating evidence demonstrates that epithelial-mesenchymal transition and cancer stem cells play important roles in ovarian cancer chemoresistance and metastasis. Treatment of epithelial-mesenchymal transition and cancer stem cells holds promise for improving current ovarian cancer therapies and prolonging the survival of recurrent ovarian cancer patients in the future. In this review, we focus on the role of epithelial-mesenchymal transition and cancer stem cells in ovarian cancer chemoresistance and explore the therapeutic implications for developing epithelial-mesenchymal transition and cancer stem cells associated therapies for future ovarian cancer treatment. PMID:27304054

  5. Targeting Aldehyde Dehydrogenase Cancer Stem Cells in Ovarian Cancer

    PubMed Central

    Landen, Charles N.; Goodman, Blake; Katre, Ashwini A.; Steg, Adam D.; Nick, Alpa M.; Stone, Rebecca L.; Miller, Lance D.; Mejia, Pablo Vivas; Jennings, Nicolas B.; Gershenson, David M.; Bast, Robert C.; Coleman, Robert L.; Lopez-Berestein, Gabriel; Sood, Anil K.

    2010-01-01

    Aldehyde dehydrogenase-1A1 (ALDH1A1) expression characterizes a subpopulation of cells with tumor initiating or cancer stem cell properties in several malignancies. Our goal was to characterize the phenotype of ALDH1A1-positive ovarian cancer cells and examine the biological effects of ALDH1A1 gene silencing. In our analysis of multiple ovarian cancer cell lines, we found that ALDH1A1 expression and activity was significantly higher in taxane and platinum-resistant cell lines. In patient samples, 72.9% of ovarian cancers had ALDH1A1 expression, in whom the percent of ALDH1A1-positive cells correlated negatively with progression-free survival (6.05 v 13.81 months, p<0.035). Subpopulations of A2780cp20 cells with ALDH1A1 activity were isolated for orthotopic tumor initiating studies, where tumorigenicity was approximately 50-fold higher with ALDH1A1-positive cells. Interestingly, tumors derived from ALDH1A1-positive cells gave rise to both ALDH1A1-positive and ALDH1A1-negative populations, but ALDH1A1-negative cells could not generate ALDH1A1-positive cells. In an in vivo orthotopic mouse model of ovarian cancer, ALDH1A1 silencing using nanoliposomal siRNA sensitized both taxane- and platinum-resistant cell lines to chemotherapy, significantly reducing tumor growth in mice compared to chemotherapy alone (a 74–90% reduction, p<0.015). These data demonstrate that the ALDH1A1 subpopulation is associated with chemoresistance and outcome in ovarian cancer patients, and targeting ALDH1A1 sensitizes resistant cells to chemotherapy. ALDH1A1-positive cells have enhanced, but not absolute, tumorigenicity, but do have differentiation capacity lacking in ALDH1A1-negative cells. This enzyme may be important for identification and targeting of chemoresistant cell populations in ovarian cancer. PMID:20889728

  6. Ovarian Cancer, Stem Cells, and Bioreactors

    DTIC Science & Technology

    2009-10-01

    produced by the tumor cells and released in the blood stream. CEA serum level is a clinical screening test for colon cancer, but some types of ovarian...Development of a hybrid liver support system: a review. Int J Artif Organs 19, 645-654 (1996). 12. Kusumbe, A.P., Mali, A.M. & Bapat, S.A. CD133-Expressing

  7. Role of the Microenvironment in Ovarian Cancer Stem Cell Maintenance

    PubMed Central

    Pasquier, Jennifer; Rafii, Arash

    2013-01-01

    Despite recent progresses in cancer therapy and increased knowledge in cancer biology, ovarian cancer remains a challenging condition. Among the latest concepts developed in cancer biology, cancer stem cells and the role of microenvironment in tumor progression seem to be related. Indeed, cancer stem cells have been described in several solid tumors including ovarian cancers. These particular cells have the ability to self-renew and reconstitute a heterogeneous tumor. They are characterized by specific surface markers and display resistance to therapeutic regimens. During development, specific molecular cues from the tumor microenvironment can play a role in maintaining and expanding stemness of cancer cells. The tumor stroma contains several compartments: cellular component, cytokine network, and extracellular matrix. These different compartments interact to form a permissive niche for the cancer stem cells. Understanding the molecular cues underlying this crosstalk will allow the design of new therapeutic regimens targeting the niche. In this paper, we will discuss the mechanisms implicated in the interaction between ovarian cancer stem cells and their microenvironment. PMID:23484135

  8. Cellular immunotherapy in ovarian cancer: Targeting the stem of recurrence.

    PubMed

    Wefers, Christina; Lambert, Laurens J; Torensma, Ruurd; Hato, Stanleyson V

    2015-05-01

    Ovarian cancer is a devastating disease with a high relapse rate. Due to a mostly asymptomatic early stage and lack of early diagnostic tools, the disease is usually diagnosed in a late stage. Surgery and chemotherapy with taxanes and platinum compounds are very effective in reducing tumor burden. However, relapses occur frequently and there is a lack of credible second-line options. Therefore, new treatment modalities are eagerly awaited. The presence and influx of immune cells in the ovarian cancer tumor microenvironment are correlated with survival. High numbers of infiltrating T cells correlate with improved progression free and overall survival, while the presence of regulatory T cells and expression of T cell inhibitory molecules is correlated with a poor prognosis. These data indicate that immunotherapy, especially cell-based immunotherapy could be a promising novel addition to the treatment of ovarian cancer. Here, we review the available data on the immune contexture surrounding ovarian cancer and discuss novel strategies and targets for immunotherapy in ovarian cancer. In the end the addition of immunotherapy to existing therapeutic options could lead to a great improvement in the outcome of ovarian cancer, especially when targeting cancer stem cells.

  9. Differential Cytotoxic Potential of Silver Nanoparticles in Human Ovarian Cancer Cells and Ovarian Cancer Stem Cells.

    PubMed

    Choi, Yun-Jung; Park, Jung-Hyun; Han, Jae Woong; Kim, Eunsu; Jae-Wook, Oh; Lee, Seung Yoon; Kim, Jin-Hoi; Gurunathan, Sangiliyandi

    2016-12-12

    The cancer stem cell (CSC) hypothesis postulates that cancer cells are composed of hierarchically-organized subpopulations of cells with distinct phenotypes and tumorigenic capacities. As a result, CSCs have been suggested as a source of disease recurrence. Recently, silver nanoparticles (AgNPs) have been used as antimicrobial, disinfectant, and antitumor agents. However, there is no study reporting the effects of AgNPs on ovarian cancer stem cells (OvCSCs). In this study, we investigated the cytotoxic effects of AgNPs and their mechanism of causing cell death in A2780 (human ovarian cancer cells) and OvCSCs derived from A2780. In order to examine these effects, OvCSCs were isolated and characterized using positive CSC markers including aldehyde dehydrogenase (ALDH) and CD133 by fluorescence-activated cell sorting (FACS). The anticancer properties of the AgNPs were evaluated by assessing cell viability, leakage of lactate dehydrogenase (LDH), reactive oxygen species (ROS), and mitochondrial membrane potential (mt-MP). The inhibitory effect of AgNPs on the growth of ovarian cancer cells and OvCSCs was evaluated using a clonogenic assay. Following 1-2 weeks of incubation with the AgNPs, the numbers of A2780 (bulk cells) and ALDH⁺/CD133⁺ colonies were significantly reduced. The expression of apoptotic and anti-apoptotic genes was measured by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Our observations showed that treatment with AgNPs resulted in severe cytotoxicity in both ovarian cancer cells and OvCSCs. In particular, AgNPs showed significant cytotoxic potential in ALDH⁺/CD133⁺ subpopulations of cells compared with other subpopulation of cells and also human ovarian cancer cells (bulk cells). These findings suggest that AgNPs can be utilized in the development of novel nanotherapeutic molecules for the treatment of ovarian cancers by specific targeting of the ALDH⁺/CD133⁺ subpopulation of cells.

  10. Differential Cytotoxic Potential of Silver Nanoparticles in Human Ovarian Cancer Cells and Ovarian Cancer Stem Cells

    PubMed Central

    Choi, Yun-Jung; Park, Jung-Hyun; Han, Jae Woong; Kim, Eunsu; Jae-Wook, Oh; Lee, Seung Yoon; Kim, Jin-Hoi; Gurunathan, Sangiliyandi

    2016-01-01

    The cancer stem cell (CSC) hypothesis postulates that cancer cells are composed of hierarchically-organized subpopulations of cells with distinct phenotypes and tumorigenic capacities. As a result, CSCs have been suggested as a source of disease recurrence. Recently, silver nanoparticles (AgNPs) have been used as antimicrobial, disinfectant, and antitumor agents. However, there is no study reporting the effects of AgNPs on ovarian cancer stem cells (OvCSCs). In this study, we investigated the cytotoxic effects of AgNPs and their mechanism of causing cell death in A2780 (human ovarian cancer cells) and OvCSCs derived from A2780. In order to examine these effects, OvCSCs were isolated and characterized using positive CSC markers including aldehyde dehydrogenase (ALDH) and CD133 by fluorescence-activated cell sorting (FACS). The anticancer properties of the AgNPs were evaluated by assessing cell viability, leakage of lactate dehydrogenase (LDH), reactive oxygen species (ROS), and mitochondrial membrane potential (mt-MP). The inhibitory effect of AgNPs on the growth of ovarian cancer cells and OvCSCs was evaluated using a clonogenic assay. Following 1–2 weeks of incubation with the AgNPs, the numbers of A2780 (bulk cells) and ALDH+/CD133+ colonies were significantly reduced. The expression of apoptotic and anti-apoptotic genes was measured by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Our observations showed that treatment with AgNPs resulted in severe cytotoxicity in both ovarian cancer cells and OvCSCs. In particular, AgNPs showed significant cytotoxic potential in ALDH+/CD133+ subpopulations of cells compared with other subpopulation of cells and also human ovarian cancer cells (bulk cells). These findings suggest that AgNPs can be utilized in the development of novel nanotherapeutic molecules for the treatment of ovarian cancers by specific targeting of the ALDH+/CD133+ subpopulation of cells. PMID:27973444

  11. S100B Mediates Stemness of Ovarian Cancer Stem-Like Cells Through Inhibiting p53.

    PubMed

    Yang, Tao; Cheng, Jianan; Yang, Yang; Qi, Wei; Zhao, Yuetao; Long, Haixia; Xie, Rongkai; Zhu, Bo

    2017-02-01

    S100B is one of the members of the S100 protein family and is involved in the progression of a variety of cancers. Ovarian cancer is driven by cancer stem-like cells (CSLCs) that are involved in tumorigenesis, metastasis, chemo-resistance and relapse. We then hypothesized that S100B might exert pro-tumor effects by regulating ovarian CSLCs stemness, a key characteristic of CSLCs. First, we observed the high expression of S100B in ovarian cancer specimens when compared to that in normal ovary. The S100B upregulation associated with more advanced tumor stages, poorer differentiation and poorer survival. In addition, elevated S100B expression correlated with increased expression of stem cell markers including CD133, Nanog and Oct4. Then, we found that S100B was preferentially expressed in CD133(+) ovarian CSLCs derived from both ovarian cancer cell lines and primary tumors of patients. More importantly, we revealed that S100B knockdown suppressed the in vitro self-renewal and in vivo tumorigenicity of ovarian CSLCs and decreased their expression of stem cell markers. S100B ectopic expression endowed non-CSLCs with stemness, which has been demonstrated with both in vitro and in vivo experiments. Mechanically, we demonstrated that the underlying mechanism of S100B-mediated effects on CSLCs stemness was not dependent on its binding with a receptor for advanced glycation end products (RAGE), but might be through intracellular regulation, through the inhibition of p53 expression and phosphorylation. In conclusion, our results elucidate the importance of S100B in maintenance of ovarian CSLCs stemness, which might provide a promising therapeutic target for ovarian cancer. Stem Cells 2017;35:325-336.

  12. Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Stage III Ovarian Cancer

    ClinicalTrials.gov

    2016-03-17

    Malignant Ovarian Mixed Epithelial Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Primary Peritoneal Carcinoma; Stage III Ovarian Cancer; Undifferentiated Ovarian Carcinoma

  13. Ovarian cancer

    MedlinePlus

    ... cancer, CT scan Ovarian cancer dangers Ovarian growth worries Uterus Ovarian cancer Ovarian cancer metastasis References Coleman ... Duplication for commercial use must be authorized in writing by ADAM Health Solutions. About MedlinePlus Site Map ...

  14. DDX4 (DEAD box polypeptide 4) colocalizes with cancer stem cell marker CD133 in ovarian cancers

    SciTech Connect

    Kim, Ki Hyung; Kang, Yun-Jeong; Jo, Jin-Ok; Ock, Mee Sun; Moon, Soo Hyun; Suh, Dong Soo; Yoon, Man Soo; Park, Eun-Sil; Jeong, Namkung; Eo, Wan-Kyu; Kim, Heung Yeol; Cha, Hee-Jae

    2014-05-02

    Highlights: • Germ cell marker DDX4 was significantly increased in ovarian cancer. • Ovarian cancer stem cell marker CD133 was significantly increased in ovarian cancer. • DDX4 and CD133 were mostly colocalized in various types of ovarian cancer tissues. • CD133 positive ovarian cancer cells also express DDX4 whereas CD133-negative cells did not possess DDX4. • Germ cell marker DDX4 has the potential of ovarian cancer stem cell marker. - Abstract: DDX4 (DEAD box polypeptide 4), characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), is an RNA helicase which is implicated in various cellular processes involving the alteration of RNA secondary structure, such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. DDX4 is known to be a germ cell-specific protein and is used as a sorting marker of germline stem cells for the production of oocytes. A recent report about DDX4 in ovarian cancer showed that DDX4 is overexpressed in epithelial ovarian cancer and disrupts a DNA damage-induced G2 checkpoint. We investigated the relationship between DDX4 and ovarian cancer stem cells by analyzing the expression patterns of DDX4 and the cancer stem cell marker CD133 in ovarian cancers via tissue microarray. Both DDX4 and CD133 were significantly increased in ovarian cancer compared to benign tumors, and showed similar patterns of expression. In addition, DDX4 and CD133 were mostly colocalized in various types of ovarian cancer tissues. Furthermore, almost all CD133 positive ovarian cancer cells also express DDX4 whereas CD133-negative cells did not possess DDX4, suggesting a strong possibility that DDX4 plays an important role in cancer stem cells, and/or can be used as an ovarian cancer stem cell marker.

  15. Ovarian Cancer

    MedlinePlus

    ... deaths than other female reproductive cancers. The sooner ovarian cancer is found and treated, the better your chance for recovery. But ovarian cancer is hard to detect early. Women with ovarian ...

  16. Investigating Molecular Profiles of Ovarian Cancer: An Update on Cancer Stem Cells

    PubMed Central

    Tomao, Federica; Papa, Anselmo; Strudel, Martina; Rossi, Luigi; Lo Russo, Giuseppe; Benedetti Panici, Pierluigi; Ciabatta, Francesca Romana; Tomao, Silverio

    2014-01-01

    Currently we are more and more improving our knowledge about the characteristics and the role of cancer stem cells in human cancer. Particularly we have realized that self-renewing ovarian cancer stem cells (CSCs) or ovarian cancer-initiating cells, and mesenchymal stem cells (SCs) too, are probably implicated in the etiopathogenesis of epithelial ovarian cancer (EOC). There is clear evidence that these cells are also involved in its intra- and extra-peritoneal diffusion and in the occurrence of chemo-resistance. In assessing the molecular characteristics of ovarian CSCs, we have to take note that these cellular populations are rare and the absence of specific cell surface markers represents a challenge to isolate and identify pure SC populations. In our review, we focused our attention on the molecular characteristics of epithelial ovarian CSCs and on the methods to detect them starting from their biological features. The study of ovarian CSCs is taking on an increasingly important strategic role, mostly for the potential therapeutic application in the next future. PMID:24723972

  17. Salinomycin reduces stemness and induces apoptosis on human ovarian cancer stem cell

    PubMed Central

    Lee, Hyun-Gyo; Shin, So-Jin; Cha, Soon-Do

    2017-01-01

    Objective Cancer stem cells (CSCs) represent a subpopulation of undifferentiated tumorigenic cells thought to be responsible for tumor initiation, maintenance, drug resistance, and metastasis. The role of CSCs in drug resistance and relapse of cancers could significantly affect outcomes of ovarian cancer patient. Therefore, therapies that target CSCs could be a promising approach for ovarian cancer treatment. The antibiotic salinomycin has recently been shown to deplete CSCs. In this study, we evaluated the effect of salinomycin on ovarian cancer stem cells (OCSCs), both alone and in combination with paclitaxel (PTX). Methods The CD44+CD117+CSCs were obtained from the ascitic fluid of patients with epithelial ovarian cancer by using an immune magnetic-activated cell sorting system. OCSCs were treated with PTX and salinomycin either singly or in combination. Cell viability and apoptosis assays were performed and spheroid-forming ability was measured. The expression of sex determining region Y-box 2 (SOX2) and octamer-binding transcription factor 3/4 (OCT3/4) mRNA was determined using reverse transcription polymerase chain reaction, and protein expression was observed using western blot analysis. Results Treatment with salinomycin alone reduced the stemness marker expression and spheroid-forming ability of OCSCs. Treatment with PTX alone did not decrease the viability of OCSCs. Treatment with a combination of salinomycin decreased the viability of OCSCs and promoted cell apoptosis. The enhancement of combination treatment was achieved through the apoptosis as determined by annexin V/propidium iodide (PI) staining, caspase-3 activity, and DNA fragmentation assay. Conclusion Based on our findings, combining salinomycin with other anti-cancer therapeutic agents holds promise as an ovarian cancer treatment approach that can target OCSCs. PMID:27894167

  18. Ovarian Cancer

    MedlinePlus

    OVARIAN CANCER Get the Facts About Gynecologic Cancer There are five main types of cancer that affect a ... rare fallopian tube cancer.) This fact sheet about ovarian cancer is part of the Centers for Disease Control ...

  19. Syngeneic murine ovarian cancer model reveals that ascites enriches for ovarian cancer stem-like cells expressing membrane GRP78

    PubMed Central

    Mo, Lihong; Bachelder, Robin E.; Kennedy, Margaret; Chen, Po-Han; Chi, Jen-Tsan; Berchuck, Andrew; Cianciolo, George; Pizzo, Salvatore V.

    2016-01-01

    Ovarian cancer patients are generally diagnosed at FIGO (International Federation of Gynecology and Obstetrics) stage III/IV, when ascites is common. The volume of ascites correlates positively with the extent of metastasis and negatively with prognosis. Membrane GRP78, a stress-inducible endoplasmic reticulum chaperone that is also expressed on the plasma membrane (memGRP78) of aggressive cancer cells, plays a crucial role in the embryonic stem cell maintenance. We studied ascites effects on ovarian cancer stem-like cells using a syngeneic mouse model. Our study demonstrates that ascites-derived tumor cells from mice injected intraperitoneally with murine ovarian cancer cells (ID8) express increased memGRP78 levels compared to ID8 cells from normal culture. We hypothesized that these ascites associated memGRP78+ cells are cancer stem-like cells (CSC). Supporting this hypothesis, we show that memGRP78+ cells isolated from murine ascites exhibit increased sphere forming and tumor initiating abilities compared to memGRP78− cells. When the tumor microenvironment is recapitulated by adding ascites fluid to cell culture, ID8 cells express more memGRP78 and increased self-renewing ability compared to those cultured in medium alone. Moreover, compared to their counterparts cultured in normal medium, ID8 cells cultured in ascites, or isolated from ascites, show increased stem cell marker expression. Antibodies directed against the carboxy-terminal domain of GRP78: 1) reduce self-renewing ability of murine and human ovarian cancer cells pre-incubated with ascites and 2) suppress a GSK3α-AKT/SNAI1 signaling axis in these cells. Based on these data, we suggest that memGRP78 is a logical therapeutic target for late stage ovarian cancer. PMID:25589495

  20. Identification of a distinct population of CD133+CXCR4+ cancer stem cells in ovarian cancer

    PubMed Central

    Cioffi, Michele; D’Alterio, Crescenzo; Camerlingo, Rosalba; Tirino, Virginia; Consales, Claudia; Riccio, Anna; Ieranò, Caterina; Cecere, Sabrina Chiara; Losito, Nunzia Simona; Greggi, Stefano; Pignata, Sandro; Pirozzi, Giuseppe; Scala, Stefania

    2015-01-01

    CD133 and CXCR4 were evaluated in the NCI-60 cell lines to identify cancer stem cell rich populations. Screening revealed that, ovarian OVCAR-3, -4 and -5 and colon cancer HT-29, HCT-116 and SW620 over expressed both proteins. We aimed to isolate cells with stem cell features sorting the cells expressing CXCR4+CD133+ within ovarian cancer cell lines. The sorted population CD133+CXCR4+ demonstrated the highest efficiency in sphere formation in OVCAR-3, OVCAR-4 and OVCAR-5 cells. Moreover OCT4, SOX2, KLF4 and NANOG were highly expressed in CD133+CXCR4+ sorted OVCAR-5 cells. Most strikingly CXCR4+CD133+ sorted OVCAR-5 and -4 cells formed the highest number of tumors when inoculated in nude mice compared to CD133−CXCR4−, CD133+CXCR4−, CD133−CXCR4+ cells. CXCR4+CD133+ OVCAR-5 cells were resistant to cisplatin, overexpressed the ABCG2 surface drug transporter and migrated toward the CXCR4 ligand, CXCL12. Moreover, when human ovarian cancer cells were isolated from 37 primary ovarian cancer, an extremely variable level of CXCR4 and CD133 expression was detected. Thus, in human ovarian cancer cells CXCR4 and CD133 expression identified a discrete population with stem cell properties that regulated tumor development and chemo resistance. This cell population represents a potential therapeutic target. PMID:26020117

  1. Identification of a distinct population of CD133(+)CXCR4(+) cancer stem cells in ovarian cancer.

    PubMed

    Cioffi, Michele; D'Alterio, Crescenzo; Camerlingo, Rosalba; Tirino, Virginia; Consales, Claudia; Riccio, Anna; Ieranò, Caterina; Cecere, Sabrina Chiara; Losito, Nunzia Simona; Greggi, Stefano; Pignata, Sandro; Pirozzi, Giuseppe; Scala, Stefania

    2015-05-28

    CD133 and CXCR4 were evaluated in the NCI-60 cell lines to identify cancer stem cell rich populations. Screening revealed that, ovarian OVCAR-3, -4 and -5 and colon cancer HT-29, HCT-116 and SW620 over expressed both proteins. We aimed to isolate cells with stem cell features sorting the cells expressing CXCR4(+)CD133(+) within ovarian cancer cell lines. The sorted population CD133(+)CXCR4(+) demonstrated the highest efficiency in sphere formation in OVCAR-3, OVCAR-4 and OVCAR-5 cells. Moreover OCT4, SOX2, KLF4 and NANOG were highly expressed in CD133(+)CXCR4(+) sorted OVCAR-5 cells. Most strikingly CXCR4(+)CD133(+) sorted OVCAR-5 and -4 cells formed the highest number of tumors when inoculated in nude mice compared to CD133(-)CXCR4(-), CD133(+)CXCR4(-), CD133(-)CXCR4(+) cells. CXCR4(+)CD133(+) OVCAR-5 cells were resistant to cisplatin, overexpressed the ABCG2 surface drug transporter and migrated toward the CXCR4 ligand, CXCL12. Moreover, when human ovarian cancer cells were isolated from 37 primary ovarian cancer, an extremely variable level of CXCR4 and CD133 expression was detected. Thus, in human ovarian cancer cells CXCR4 and CD133 expression identified a discrete population with stem cell properties that regulated tumor development and chemo resistance. This cell population represents a potential therapeutic target.

  2. Ovarian cancer stem cells express ROR1, which can be targeted for anti-cancer-stem-cell therapy.

    PubMed

    Zhang, Suping; Cui, Bing; Lai, Hsien; Liu, Grace; Ghia, Emanuela M; Widhopf, George F; Zhang, Zhuhong; Wu, Christina C N; Chen, Liguang; Wu, Rongrong; Schwab, Richard; Carson, Dennis A; Kipps, Thomas J

    2014-12-02

    Although initially responsive to chemotherapy, many patients with ovarian cancer subsequently develop relapsed and potentially fatal metastatic disease, which is thought to develop from cancer stem cells (CSCs) that are relatively resistant to conventional therapy. Here, we show that CSCs express a type I receptor tyrosine kinase-like orphan receptor (ROR1), which is expressed during embryogenesis and by many different cancers, but not normal postpartum tissues. Ovarian cancers with high levels of ROR1 had stem cell-like gene-expression signatures. Furthermore, patients with ovarian cancers with high levels of ROR1 had higher rates of relapse and a shorter median survival than patients with ovarian cancers that expressed low-to-negligible amounts of ROR1. We found that ROR1-positive (ROR1(+)) cells isolated from primary tumor-derived xenografts (PDXs) also expressed aldehyde dehydrogenase 1 (ALDH1) and had a greater capacity to form spheroids and to engraft immune-deficient mice than did ROR1-negative (ROR1(Neg)) ovarian cancer cells isolated from the same tumor population. Treatment with UC-961, an anti-ROR1 mAb, or shRNA silencing of ROR1 inhibited expression of the polycomb ring-finger oncogene, Bmi-1, and other genes associated with the epithelial-mesenchymal transition. Moreover, shRNA silencing of ROR1, depletion of ROR1(+) cells, or treatment with UC-961 impaired the capacity of ovarian cancer cells to form spheroids or tumor xenografts. More importantly, treatment with anti-ROR1 affected the capacity of the xenograft to reseed a virgin mouse, indicating that targeting ROR1 may affect CSC self-renewal. Collectively, these studies indicate that ovarian CSCs express ROR1, which contributes to their capacity to form tumors, making ROR1 a potential target for the therapy of patients with ovarian cancer.

  3. Bruton's tyrosine kinase (Btk) inhibitor ibrutinib suppresses stem-like traits in ovarian cancer.

    PubMed

    Zucha, Muhammad Ary; Wu, Alexander T H; Lee, Wei-Hwa; Wang, Liang-Shun; Lin, Wan-Wan; Yuan, Chiou-Chung; Yeh, Chi-Tai

    2015-05-30

    According to a Prognoscan database, upregulation of Bruton's tyrosine kinase (Btk) is associated with low overall survival in ovarian cancer patients. We found that spheroids-forming ovarian cancer cell, which highly expressed cancer stem-like cell (CSC) markers and Btk, were cisplatin resistant. We next treated CSCs and non-CSCs by a combination of ibrutinib and cisplatin. We found that chemoresistance was dependent on Btk and JAK2/STAT3, which maintained CSC by inducing Sox-2 and prosurvival genes. We suggest that addition of ibrutinib to cisplatin may improve treatment outcome in ovarian cancer.

  4. Identification of a potential ovarian cancer stem cell gene expression profile from advanced stage papillary serous ovarian cancer.

    PubMed

    Vathipadiekal, Vinod; Saxena, Deepa; Mok, Samuel C; Hauschka, Peter V; Ozbun, Laurent; Birrer, Michael J

    2012-01-01

    Identification of gene expression profiles of cancer stem cells may have significant implications in the understanding of tumor biology and for the design of novel treatments targeted toward these cells. Here we report a potential ovarian cancer stem cell gene expression profile from isolated side population of fresh ascites obtained from women with high-grade advanced stage papillary serous ovarian adenocarcinoma. Affymetrix U133 Plus 2.0 microarrays were used to interrogate the differentially expressed genes between side population (SP) and main population (MP), and the results were analyzed by paired T-test using BRB-ArrayTools. We identified 138 up-regulated and 302 down-regulated genes that were differentially expressed between all 10 SP/MP pairs. Microarray data was validated using qRT-PCR and17/19 (89.5%) genes showed robust correlations between microarray and qRT-PCR expression data. The Pathway Studio analysis identified several genes involved in cell survival, differentiation, proliferation, and apoptosis which are unique to SP cells and a mechanism for the activation of Notch signaling is identified. To validate these findings, we have identified and isolated SP cells enriched for cancer stem cells from human ovarian cancer cell lines. The SP populations were having a higher colony forming efficiency in comparison to its MP counterpart and also capable of sustained expansion and differentiation in to SP and MP phenotypes. 50,000 SP cells produced tumor in nude mice whereas the same number of MP cells failed to give any tumor at 8 weeks after injection. The SP cells demonstrated a dose dependent sensitivity to specific γ-secretase inhibitors implicating the role of Notch signaling pathway in SP cell survival. Further the generated SP gene list was found to be enriched in recurrent ovarian cancer tumors.

  5. Targeting Ovarian Carcinoma Stem Cells

    DTIC Science & Technology

    2012-05-01

    expertise with expertise in gynecologic oncology /ovarian carcinoma and in animal models of cancer this proposal will: 1) Identify, isolate, and...more numerous differentiated progeny characterizing the malignancy . Although the clinical significance of these cancer stem cells (CSC) has been...the dramatic initial response rates in ovarian carcinoma represent therapeutic effectiveness against the differentiated cancer cells making up the

  6. Cancer stem cell marker CD90 inhibits ovarian cancer formation via β3 integrin

    PubMed Central

    Chen, Wei-Ching; Hsu, Hui-Ping; Li, Chung-Yen; Yang, Ya-Ju; Hung, Yu-Hsuan; Cho, Chien-Yu; Wang, Chih-Yang; Weng, Tzu-Yang; Lai, Ming-Derg

    2016-01-01

    Cancer stem cell (CSC) markers have been identified for CSC isolation and proposed as therapeutic targets in various types of cancers. CD90, one of the characterized markers in liver and gastric cancer, is shown to promote cancer formation. However, the underexpression level of CD90 in ovarian cancer cells and the evidence supporting the cellular mechanism have not been investigated. In the present study, we found that the DNA copy number of CD90 is correlated with mRNA expression in ovarian cancer tissue and the ovarian cancer patients with higher CD90 have good prognosis compared to the patients with lower CD90. Although the expression of CD90 in human ovarian cancer SKOV3 cells enhances the cell proliferation by MTT and anchorage-dependent growth assay, CD90 inhibits the anchorage-independent growth ability in vitro and tumor formation in vivo. CD90 overexpression suppresses the sphere-forming ability and ALDH activity and enhances the cell apoptosis, indicating that CD90 may reduce the cell growth by the properties of CSC and anoikis. Furthermore, CD90 reduces the expression of other CSC markers, including CD133 and CD24. The inhibition of CD133 is attenuated by the mutant CD90, which is replaced with RLE domain into RLD domain. Importantly, the CD90-regulated inhibition of CD133 expression, anchorage-independent growth and signal transduction of mTOR and AMPK are restored by the β3 integrin shRNA. Our results provide evidence that CD90 mediates the antitumor formation by interacting with β3 integrin, which provides new insight that can potentially be applied in the development of therapeutic strategies in ovarian cancer. PMID:27633757

  7. Regulation of Ovarian Cancer Stem Cells or Tumor-Initiating Cells

    PubMed Central

    Kwon, Mi Jeong; Shin, Young Kee

    2013-01-01

    Cancer stem cells or tumor-initiating cells (CSC/TICs), which can undergo self-renewal and differentiation, are thought to play critical roles in tumorigenesis, therapy resistance, tumor recurrence and metastasis. Tumor recurrence and chemoresistance are major causes of poor survival rates of ovarian cancer patients, which may be due in part to the existence of CSC/TICs. Therefore, elucidating the molecular mechanisms responsible for the ovarian CSC/TICs is required to develop a cure for this malignancy. Recent studies have indicated that the properties of CSC/TICs can be regulated by microRNAs, genes and signaling pathways which also function in normal stem cells. Moreover, emerging evidence suggests that the tumor microenvironments surrounding CSC/TICs are crucial for the maintenance of these cells. Similarly, efforts are now being made to unravel the mechanism involved in the regulation of ovarian CSC/TICs, although much work is still needed. This review considers recent advances in identifying the genes and pathways involved in the regulation of ovarian CSC/TICs. Furthermore, current approaches targeting ovarian CSC/TICs are described. Targeting both CSC/TICs and bulk tumor cells is suggested as a more effective approach to eliminating ovarian tumors. Better understanding of the regulation of ovarian CSC/TICs might facilitate the development of improved therapeutic strategies for recurrent ovarian cancer. PMID:23528891

  8. NF-κB Participates in the Stem Cell Phenotype of Ovarian Cancer Cells.

    PubMed

    Gonzalez-Torres, Carolina; Gaytan-Cervantes, Javier; Vazquez-Santillan, Karla; Mandujano-Tinoco, Edna Ayerim; Ceballos-Cancino, Gisela; Garcia-Venzor, Alfredo; Zampedri, Cecilia; Sanchez-Maldonado, Paulina; Mojica-Espinosa, Raul; Jimenez-Hernandez, Luis Enrique; Maldonado, Vilma

    2017-09-05

    NF-κB is a transcription factor involved in cancer stem cells maintenance of many tumors. Little is known about the specific stem-associated upstream regulators of this pathway in ovarian cancer. The Aim of the study was to analyze the role of the canonical and non-canonical NF-κB pathways in stem cells of ovarian cancer cell lines. Stem cells were isolated using sorting cytometry. Western blot and RT-PCR were used to quantify protein and messenger RNA levels. Loss and gain of function assays were performed using siRNAs and dominant-negative proteins, respectively. NF-κB binding activity was measured with a reporter gene assay. The stem phenotype was estimated with clonogenic assays using soft agar, colony formation, ovospheres formation and in vivo tumorigenicity assays. The CD44+ subpopulation of SKOV3 ovarian cancer cell line presented higher mRNA levels of key stemness genes, an increased tumorigenic capacity and higher expression of the RelA, RelB and IKKα. When the canonical pathway was inhibited by means of a dominant-negative version of IkBα, the stem cell population was reduced, as shown by a reduced CD44+ subpopulation, a decrease in the expression of the stemness genes and a reduction of the stem phenotype. In addition, IKKα, the main upstream non-canonical kinase, was highly expressed in the CSC population. Accordingly, when IKKα was inhibited using shRNAs, the expression of the stemness genes was reduced. This report is the first to show the importance of several elements of both NF-κB pathway in maintaining the ovarian cancer stem cell population. Copyright © 2017. Published by Elsevier Inc.

  9. FOXP1 functions as an oncogene in promoting cancer stem cell-like characteristics in ovarian cancer cells.

    PubMed

    Choi, Eun Jung; Seo, Eun Jin; Kim, Dae Kyoung; Lee, Su In; Kwon, Yang Woo; Jang, Il Ho; Kim, Ki-Hyung; Suh, Dong-Soo; Kim, Jae Ho

    2016-01-19

    Ovarian cancer has the highest mortality rate of all gynecological cancers with a high recurrence rate. It is important to understand the nature of recurring cancer cells to terminally eliminate ovarian cancer. The winged helix transcription factor Forkhead box P1 (FOXP1) has been reported to function as either oncogene or tumor-suppressor in various cancers. In the current study, we show that FOXP1 promotes cancer stem cell-like characteristics in ovarian cancer cells. Knockdown of FOXP1 expression in A2780 or SKOV3 ovarian cancer cells decreased spheroid formation, expression of stemness-related genes and epithelial to mesenchymal transition-related genes, cell migration, and resistance to Paclitaxel or Cisplatin treatment, whereas overexpression of FOXP1 in A2780 or SKOV3 ovarian cancer cells increased spheroid formation, expression of stemness-related genes and epithelial to mesenchymal transition-related genes, cell migration, and resistance to Paclitaxel or Cisplatin treatment. In addition, overexpression of FOXP1 increased promoter activity of ABCG2, OCT4, NANOG, and SOX2, among which the increases in ABCG2, OCT4, and SOX2 promoter activity were dependent on the presence of FOXP1-binding site. In xenotransplantation of A2780 ovarian cancer cells into nude mice, knockdown of FOXP1 expression significantly decreased tumor size. These results strongly suggest FOXP1 functions as an oncogene by promoting cancer stem cell-like characteristics in ovarian cancer cells. Targeting FOXP1 may provide a novel therapeutic opportunity for developing a relapse-free treatment for ovarian cancer patients.

  10. Identification of inhibitors of ovarian cancer stem-like cells by high-throughput screening

    PubMed Central

    2012-01-01

    Background Ovarian cancer stem cells are characterized by self-renewal capacity, ability to differentiate into distinct lineages, as well as higher invasiveness and resistance to many anticancer agents. Since they may be responsible for the recurrence of ovarian cancer after initial response to chemotherapy, development of new therapies targeting this special cellular subpopulation embedded within bulk ovarian cancers is warranted. Methods A high-throughput screening (HTS) campaign was performed with 825 compounds from the Mechanistic Set chemical library [Developmental Therapeutics Program (DTP)/National Cancer Institute (NCI)] against ovarian cancer stem-like cells (CSC) using a resazurin-based cell cytotoxicity assay. Identified sets of active compounds were projected onto self-organizing maps to identify their putative cellular response groups. Results From 793 screening compounds with evaluable data, 158 were found to have significant inhibitory effects on ovarian CSC. Computational analysis indicates that the majority of these compounds are associated with mitotic cellular responses. Conclusions Our HTS has uncovered a number of candidate compounds that may, after further testing, prove effective in targeting both ovarian CSC and their more differentiated progeny. PMID:23078816

  11. Characterization of aldehyde dehydrogenase 1 high ovarian cancer cells: Towards targeted stem cell therapy.

    PubMed

    Sharrow, Allison C; Perkins, Brandy; Collector, Michael I; Yu, Wayne; Simons, Brian W; Jones, Richard J

    2016-08-01

    The cancer stem cell (CSC) paradigm hypothesizes that successful clinical eradication of CSCs may lead to durable remission for patients with ovarian cancer. Despite mounting evidence in support of ovarian CSCs, their phenotype and clinical relevance remain unclear. We and others have found high aldehyde dehydrogenase 1 (ALDH(high)) expression in a variety of normal and malignant stem cells, and sought to better characterize ALDH(high) cells in ovarian cancer. We compared ALDH(high) to ALDH(low) cells in two ovarian cancer models representing distinct subtypes: FNAR-C1 cells, derived from a spontaneous rat endometrioid carcinoma, and the human SKOV3 cell line (described as both serous and clear cell subtypes). We assessed these populations for stem cell features then analyzed expression by microarray and qPCR. ALDH(high) cells displayed CSC properties, including: smaller size, quiescence, regenerating the phenotypic diversity of the cell lines in vitro, lack of contact inhibition, nonadherent growth, multi-drug resistance, and in vivo tumorigenicity. Microarray and qPCR analysis of the expression of markers reported by others to enrich for ovarian CSCs revealed that ALDH(high) cells of both models showed downregulation of CD24, but inconsistent expression of CD44, KIT and CD133. However, the following druggable targets were consistently expressed in the ALDH(high) cells from both models: mTOR signaling, her-2/neu, CD47 and FGF18/FGFR3. Based on functional characterization, ALDH(high) ovarian cancer cells represent an ovarian CSC population. Differential gene expression identified druggable targets that have the potential for therapeutic efficacy against ovarian CSCs from multiple subtypes. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Epigenetics changes caused by the fusion of human embryonic stem cell and ovarian cancer cells

    PubMed Central

    He, Ke; Qu, Hu; Xu, Li-Nan; Gao, Jun; Cheng, Fu-Yi; Xiang, Peng; Zhou, Can-Quan

    2016-01-01

    To observe the effect of gene expression and tumorigenicity in hybrid cells of human embryonic stem cells (hESCs) and ovarian cancer cells in vitro and in vivo using a mouse model, and to determine its feasibility in reprogramming tumour cells growth and apoptosis, for a potential exploration of the role of hESCs and tumour cells fusion in the management of ovarian cancer. Stable transgenic hESCs (H1) and ovarian cancer cell line OVCAR-3 were established before fusion, and cell fusion system was established to analyse the related indicators. PTEN expression in HO-H1 cells was higher than those in the parental stem cells and lower than those in parental tumour cells; the growth of OV-H1 (RFP+GFP) hybrid cells with double fluorescence expressions were obviously slower than that of human embryonic stem cells and OVCAR-3 ovarian cancer cells. The apoptosis signal of the OV-H1 hybrid cells was significantly higher than that of the hESCs and OVCAR-3 ovarian cancer cells. In vivo results showed that compared with 7 days, 28 days and 35 days after inoculation of OV-H1 hybrid cells; also, apoptotic cell detection indicated that much stronger apoptotic signal was found in OV-H1 hybrid cells inoculated mouse. The hESCs can inhibit the growth of OVCAR-3 cells in vitro by suppressing p53 and PTEN expression to suppress the growth of tumour that may be achieved by inducing apoptosis of OVCAR-3 cells. The change of epigenetics after fusion of ovarian cancer cells and hESCs may become a novel direction for treatment of ovarian cancer. PMID:27377320

  13. Lysine-specific demethylase KDM3A regulates ovarian cancer stemness and chemoresistance

    PubMed Central

    Ramadoss, S; Sen, S; Ramachandran, I; Roy, S; Chaudhuri, G; Farias-Eisner, R

    2017-01-01

    Ovarian cancer is the leading cause of death among all gynecological malignancies due to the development of acquired chemoresistance and disease relapse. Although the role of cancer stem cells (CSCs), a subset of tumor cells with the self-renewal and differentiation capabilities, in therapeutic resistance is beginning to be better understood, the significance of epigenetic regulatory mechanisms responsible for integrating the stemness with drug resistance remain poorly understood. Here we identified that lysine demethylase KDM3A as a critical regulator of ovarian cancer stemness and cisplatin resistance by inducing the expressions of pluripotent molecules Sox2 and Nanog and anti-apoptotic B-cell lymphoma 2 (Bcl-2), respectively. In addition, KDM3A induces ovarian cancer growth while antagonizing cellular senescence by repressing the expression of cyclin-dependent kinase inhibitor, p21Waf1/Cip1. The underlying mechanism of the noted biological processes include KDM3A-mediated stimulation of Sox2 expression, and demethylating p53 protein and consequently, modulating its target genes such as Bcl-2 and p21Waf1/Cip1 expression. Consistently, KDM3A depletion inhibited the growth of subcutaneously implanted cisplatin-resistant human ovarian cancer cells in athymic nude mice. Moreover, KDM3A is abundantly expressed and positively correlated with Sox2 expression in human ovarian cancer tissues. In brief, our findings reveal a novel mechanism by which KDM3A promotes ovarian CSCs, proliferation and chemoresistance and thus, highlights the significance of KDM3A as a novel therapeutic target for resistant ovarian cancer. PMID:27694900

  14. Lipid Desaturation Is a Metabolic Marker and Therapeutic Target of Ovarian Cancer Stem Cells.

    PubMed

    Li, Junjie; Condello, Salvatore; Thomes-Pepin, Jessica; Ma, Xiaoxiao; Xia, Yu; Hurley, Thomas D; Matei, Daniela; Cheng, Ji-Xin

    2017-03-02

    Lack of sensitive single-cell analysis tools has limited the characterization of metabolic activity in cancer stem cells. By hyperspectral-stimulated Raman scattering imaging of single living cells and mass spectrometry analysis of extracted lipids, we report here significantly increased levels of unsaturated lipids in ovarian cancer stem cells (CSCs) as compared to non-CSCs. Higher lipid unsaturation levels were also detected in CSC-enriched spheroids compared to monolayer cultures of ovarian cancer cell lines or primary cells. Inhibition of lipid desaturases effectively eliminated CSCs, suppressed sphere formation in vitro, and blocked tumor initiation capacity in vivo. Mechanistically, we demonstrate that nuclear factor κB (NF-κB) directly regulates the expression levels of lipid desaturases, and inhibition of desaturases blocks NF-κB signaling. Collectively, our findings reveal that increased lipid unsaturation is a metabolic marker for ovarian CSCs and a target for CSC-specific therapy.

  15. Adipose-derived mesenchymal stem cells promote cell proliferation and invasion of epithelial ovarian cancer

    SciTech Connect

    Chu, Yijing; Tang, Huijuan; Guo, Yan; Guo, Jing; Huang, Bangxing; Fang, Fang; Cai, Jing Wang, Zehua

    2015-09-10

    Adipose-derived mesenchymal stem cell (ADSC) is an important component of tumor microenvironment. However, whether ADSCs have a hand in ovarian cancer progression remains unclear. In this study, we investigated the impact of human ADSCs derived from the omentum of normal donors on human epithelial ovarian cancer (EOC) cells in vitro and in vivo. Direct and indirect co-culture models including ADSCs and human EOC cell lines were established and the effects of ADSCs on EOC cell proliferation were evaluated by EdU incorporation and flow cytometry. Transwell migration assays and detection of MMPs were performed to assess the invasion activity of EOC cells in vitro. Mouse models were established by intraperitoneal injection of EOC cells with or without concomitant ADSCs to investigate the role of ADSCs in tumor progression in vivo. We found that ADSCs significantly promoted proliferation and invasion of EOC cells in both direct and indirect co-culture assays. In addition, after co-culture with ADSCs, EOC cells secreted higher levels of matrix metalloproteinases (MMPs), and inhibition of MMP2 and MMP9 partially relieved the tumor-promoting effects of ADSCs in vitro. In mouse xenograft models, we confirmed that ADSCs promoted EOC growth and metastasis and elevated the expression of MMP2 and MMP9. Our findings indicate that omental ADSCs play a promotive role during ovarian cancer progression. - Highlights: • Omental adipose derived stem cells enhanced growth and invasion properties of ovarian cancer cells. • Adipose derived stem cells promoted the growth and metastasis of ovarian cancer in mice models. • Adipose derived stem cells promoted MMPs expression and secretion of ovarian cancer cells. • Elevated MMPs mediated the tumor promoting effects of ADSCs.

  16. Protein tyrosine phosphatase PTPN3 promotes drug resistance and stem cell-like characteristics in ovarian cancer

    PubMed Central

    Li, Shuqin; Cao, Jian; Zhang, Wei; Zhang, Fan; Ni, Guantai; Luo, Qian; Wang, Man; Tao, Xiang; Xia, Hongping

    2016-01-01

    The current standard treatment for ovarian cancer is aggressive surgery followed by platinum-based combination chemotherapy. Recurrence and chemotherapeutic drug resistance are the two main factors that account for the high mortality of most ovarian cancers. Liposomal doxorubicin is primarily used for the treatment of ovarian cancer when the disease has progressed after platinum-based chemotherapy. However, relatively little is known about the genomic changes that contribute to both cisplatin and doxorubicin resistance in high-grade serous ovarian cancer (HGSC) under the selective pressure of chemotherapy. Here, we found that protein tyrosine phosphatase PTPN3 gene expression was substantially increased in both cisplatin and doxorubicin-resistant ovarian cancer cells. Silencing of PTPN3 restored sensitivity to cisplatin and doxorubicin in resistant ovarian cancer cells. Down-regulation of PTPN3 also inhibited cell cycle progression, migration, stemness in vitro and the tumorigenicity of resistant ovarian cancer cells in vivo. Meanwhile, the expression of PTPN3 was found to be regulated by miR-199 in resistant ovarian cancer cells. These findings suggest that PTPN3 promotes tumorigenicity, stemness and drug resistance in ovarian cancer, and thus is a potential therapeutic target for the treatment of ovarian cancer. PMID:27833130

  17. The effect of salinomycin on ovarian cancer stem-like cells

    PubMed Central

    Chung, Hyewon; Kim, Yu-Hwan; Kwon, Myoung; Shin, So-Jin; Kwon, Sang-Hoon; Cha, Soon-Do

    2016-01-01

    Objective The identification of cancer stem-like cells is a recent development in ovarian cancer. Compared to other cancer cells, cancer stem-like cells present more chemo-resistance and more aggressive characteristics. They play an important role in the recurrence and drug resistance of cancer. Therefore, the target therapy of cancer stem-like cell may become a promising and effective approach for ovarian cancer treatment. It may also help to provide novel diagnostic and therapeutic strategies. Methods The OVCAR3 cell line was cultured under serum-free conditions to produce floating spheres. The CD44+CD117+ cell line was isolated from the human ovarian cancer cell line OVCAR3 by using immune magnetic-activated cell sorting system. The expression of stemness genes such as OCT3/4, NANOG and SOX2 mRNA were determined by reverse transcription polymerase chain reaction. OVCAR3 parental and OVCAR3 CD44+CD117+ cells were grown in different doses of paclitaxel and salinomycin to evaluate the effect of salinomycin. And growth inhibition of OVCAR3 CD44+CD117+ cells by paclitaxel combined with salinomycin was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Results Tumor spheroids generated from the OVCAR3 cell line are shown to have highly enriched CD44 and CD117 expression. Treatment with a combination of paclitaxel and salinomycin demonstrated growth inhibition of OVCAR3 CD44+CD117+ cells. Conclusion The present study is a detailed investigation on the expression of CD44 and CD117 in cancer stem cells and evaluates their specific tumorigenic characteristics in ovarian cancer. This study also demonstrates significant growth inhibition of cancer stem-like cells by paclitaxel combined with salinomycin. Identification of these cancer stem-like cell markers and growth inhibition effect of salinomycin may be the next step to the development of novel target therapy in ovarian cancer. PMID:27462592

  18. Ovarian Cancer

    MedlinePlus

    ... and getting enough rest can help combat the stress and fatigue of cancer. There's no sure way to prevent ovarian cancer. But certain factors are associated with lower risk: Use of oral contraceptives, especially for more than 10 years Previous ...

  19. Novel population of small tumour-initiating stem cells in the ovaries of women with borderline ovarian cancer

    PubMed Central

    Virant-Klun, Irma; Stimpfel, Martin

    2016-01-01

    Small stem cells with diameters of up to 5 μm previously isolated from adult human ovaries indicated pluripotency and germinal lineage, especially primordial germ cells, and developed into primitive oocyte-like cells in vitro. Here, we show that a comparable population of small stem cells can be found in the ovarian tissue of women with borderline ovarian cancer, which, in contrast to small stem cells in “healthy” ovaries, formed spontaneous tumour-like structures and expressed some markers related to pluripotency and germinal lineage. The gene expression profile of these small putative cancer stem cells differed from similar cells sorted from “healthy” ovaries by 132 upregulated and 97 downregulated genes, including some important forkhead box and homeobox genes related to transcription regulation, developmental processes, embryogenesis, and ovarian cancer. These putative cancer stem cells are suggested to be a novel population of ovarian tumour-initiating cells in humans. PMID:27703207

  20. The Crosstalk between Ovarian Cancer Stem Cell Niche and the Tumor Microenvironment

    PubMed Central

    2017-01-01

    Ovarian cancer is one of the most important causes of cancer-related death among women in the world. Despite advances in ovarian cancer treatment, 70–80% of women who initially respond to therapy eventually relapse and die. There is evidence that a small population of cells within the tumors called cancer stem cells (CSCs) could be responsible for treatment failure due to their enhanced chemoresistance and tumorigenicity. These cells reside in a niche that maintains the principal properties of CSCs. These properties are associated with the capacity of CSCs to interact with different cells of the tumor microenvironment including mesenchymal stem cells, endothelial cells, immune cells, and fibroblasts, promoting cancer progression. This interaction can be mediated by cytokines, growth factors, lipids, and/or extracellular vesicles released in the CSC niche. In this review, we will discuss how the interaction between ovarian CSCs and the tumor microenvironment can contribute to the maintenance of the CSC niche and consequently to tumor progression in ovarian cancer. PMID:28819364

  1. The Crosstalk between Ovarian Cancer Stem Cell Niche and the Tumor Microenvironment.

    PubMed

    Varas-Godoy, Manuel; Rice, Gregory; Illanes, Sebastián E

    2017-01-01

    Ovarian cancer is one of the most important causes of cancer-related death among women in the world. Despite advances in ovarian cancer treatment, 70-80% of women who initially respond to therapy eventually relapse and die. There is evidence that a small population of cells within the tumors called cancer stem cells (CSCs) could be responsible for treatment failure due to their enhanced chemoresistance and tumorigenicity. These cells reside in a niche that maintains the principal properties of CSCs. These properties are associated with the capacity of CSCs to interact with different cells of the tumor microenvironment including mesenchymal stem cells, endothelial cells, immune cells, and fibroblasts, promoting cancer progression. This interaction can be mediated by cytokines, growth factors, lipids, and/or extracellular vesicles released in the CSC niche. In this review, we will discuss how the interaction between ovarian CSCs and the tumor microenvironment can contribute to the maintenance of the CSC niche and consequently to tumor progression in ovarian cancer.

  2. Autotaxin Regulates Maintenance of Ovarian Cancer Stem Cells through Lysophosphatidic Acid-Mediated Autocrine Mechanism.

    PubMed

    Seo, Eun Jin; Kwon, Yang Woo; Jang, Il Ho; Kim, Dae Kyoung; Lee, Soo In; Choi, Eun Jung; Kim, Ki-Hyung; Suh, Dong-Soo; Lee, Jeong Hee; Choi, Kyung Un; Lee, Jae Won; Mok, Hyuck Jun; Kim, Kwang Pyo; Matsumoto, Hirotaka; Aoki, Junken; Kim, Jae Ho

    2016-03-01

    Ovarian cancer shows high mortality due to development of resistance to chemotherapy and relapse. Cancer stem cells (CSCs) have been suggested to be a major contributor in developing drug resistance and relapse in ovarian cancer. In this study, we isolated CSCs through sphere culture of A2780, SKOV3, OVCAR3 epithelial ovarian cancer cells and primary ovarian cancer cells from patients. We identified heat-stable factors secreted from ovarian CSCs stimulated migration and proliferation of CSCs. Mass spectrometry and ELISA analysis revealed that lysophosphatidic acid (LPA) was significantly elevated in CSC culture media compared with non-CSC culture media. Treatment of CSCs with LPA resulted in augmented CSC characteristics such as sphere-forming ability, resistance to anticancer drugs, tumorigenic potential in xenograft transplantation, and high expression of CSC-associated genes, including OCT4, SOX2, and aldehyde dehydrogenase 1. Treatment of CSCs with LPA receptor 1-specific inhibitors or silencing of LPA receptor 1 expression abrogated the LPA-stimulated CSC properties. Autotaxin, an LPA-producing enzyme, is highly secreted from ovarian CSCs, and pharmacological inhibition or knockdown of autotaxin markedly attenuated the LPA-producing, tumorigenic, and drug resistance potentials of CSCs. Clinicopathological analysis showed a significant survival disadvantage of patients with positive staining of autotaxin. In addition, we further identified that AKT1 activity was upregulated in ovarian CSCs through an LPA-dependent mechanism and silencing of AKT1 expression led to suppression of CSC characteristics. These results suggest that autotaxin-LPA-LPA receptor 1-AKT1 signaling axis is critical for maintaining CSC characteristics through an autocrine loop and provide a novel therapeutic target for ovarian CSCs. © 2016 AlphaMed Press.

  3. Hypoxia-NOTCH1-SOX2 signaling is important for maintaining cancer stem cells in ovarian cancer

    PubMed Central

    Jang, Il Ho; Choi, Eun Jung; Shin, Sang Hun; Lee, Su In; Kwon, Sang-Mo; Kim, Ki-Hyung; Suh, Dong-Soo; Kim, Jae Ho

    2016-01-01

    Hypoxia and NOTCH signaling have been reported to be associated with the self-renewal and drug resistance of cancer stem cells (CSCs). However, the molecular mechanisms by which hypoxia and NOTCH signaling stimulate the self-renewal and drug resistance of ovarian CSCs are poorly understood. In the present study, we identified SOX2 as a key transcription factor for CSC-like characteristics in the downstream of hypoxia-induced NOTCH signaling in epithelial ovarian cancer cells. Hypoxic treatment or overexpression of intracellular domain of NOTCH1 (NICD1) in ovarian cancer cells increased sphere formation, drug resistance, and expression of CSC-associated genes such as SOX2, ALDH, and ABC transporters. Hypoxic treatment increased the expression of NICD1, and hypoxic treatment or NICD1 overexpression increased SOX2 promoter activity, which was inhibited by deletion of HIF-1 or CSL binding sites. Furthermore, DAPT treatment decreased the effect of hypoxic treatment, and SOX2 knockdown decreased the effect of hypoxic treatment and NICD overexpression on sphere formation and drug resistance in established ovarian cancer cell lines and primary ovarian cancer cells. These results suggest that hypoxia-NOTCH1-SOX2 signaling axis is important for activation of ovarian CSCs, which may provide a novel opportunity for developing therapeutics to eradicate CSCs in ovarian cancer patients. PMID:27489349

  4. Cancer stem cells, epithelial-mesenchymal transition, and drug resistance in high-grade ovarian serous carcinoma.

    PubMed

    Chen, Xiaoxiang; Zhang, Jing; Zhang, Zhihong; Li, Hongxia; Cheng, Wenjun; Liu, Jinsong

    2013-11-01

    Although epithelial ovarian cancer cells are eliminated by debulking surgery and chemotherapy during initial treatment, it is believed that only a subset of cancer cells, that is, cancer stem cells, may be an important source of tumor recurrence and drug resistance. This review highlights our current understanding of high-grade serous carcinoma, ovarian cancer stem cells, common methods for enrichment of ovarian cancer stem cells, mechanisms involved in drug resistance, and potential strategies for overcoming drug resistance, with associated potential controversies and pitfalls. We also review the potential relationship between epithelial-to-mesenchymal transition and cancer stem cells and how we can induce cancer cells to differentiate into benign stromal fibroblasts in response to certain chemotherapy drugs.

  5. Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche.

    PubMed

    Flesken-Nikitin, Andrea; Hwang, Chang-Il; Cheng, Chieh-Yang; Michurina, Tatyana V; Enikolopov, Grigori; Nikitin, Alexander Yu

    2013-03-14

    Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer deaths among women in the United States, but its pathogenesis is poorly understood. Some epithelial cancers are known to occur in transitional zones between two types of epithelium, whereas others have been shown to originate in epithelial tissue stem cells. The stem cell niche of the ovarian surface epithelium (OSE), which is ruptured and regenerates during ovulation, has not yet been defined unequivocally. Here we identify the hilum region of the mouse ovary, the transitional (or junction) area between the OSE, mesothelium and tubal (oviductal) epithelium, as a previously unrecognized stem cell niche of the OSE. We find that cells of the hilum OSE are cycling slowly and express stem and/or progenitor cell markers ALDH1, LGR5, LEF1, CD133 and CK6B. These cells display long-term stem cell properties ex vivo and in vivo, as shown by our serial sphere generation and long-term lineage-tracing assays. Importantly, the hilum cells show increased transformation potential after inactivation of tumour suppressor genes Trp53 and Rb1, whose pathways are altered frequently in the most aggressive and common type of human EOC, high-grade serous adenocarcinoma. Our study supports experimentally the idea that susceptibility of transitional zones to malignant transformation may be explained by the presence of stem cell niches in those areas. Identification of a stem cell niche for the OSE may have important implications for understanding EOC pathogenesis.

  6. Autocrine interleukin-23 promotes self-renewal of CD133+ ovarian cancer stem-like cells

    PubMed Central

    Lin, Kailong; Yin, Pin; Jiang, Lupin; Liang, Zhiqing; Zhu, Bo

    2016-01-01

    Cancer stem cells (CSCs) are a group of cells which possess the ability of self-renewing and unlimited proliferation. And these CSCs are thought to be the cause of metastasis, recurrence and resistance. Recent study has found that pro-inflammatory cytokine and chemotactic factor mediate the self-renewing and differentiation of most of CSCs. Thus we speculate that ovarian cancer stem cells (OCSCs) can also maintain the ability of self-renewing and differentiation by releasing inflammatory factor. This report we discuss the biological characteristics and the specific molecular mechanism mediated by interleukin-23 (IL-23) and its receptor on the self-renewing of OCSCs. We found that OCSCs had high expression of IL-23 and IL-23R. IL-23 could promote the self-renewal ability of OCSCs and played a very important role to maintain the stable expression of stem cell markers in vitro. Moreover, we verified that IL-23 could maintain the potential tumorigenic of OCSCs in vivo and mediate the self-renewal ability and the formation of tumor in OCSCs by activating the signal pathways of STAT3 and NF-κB. In addition, human low differentiation tissues showed overexpression of IL-23. And IL-23 positively correlated to the expression level of CD133, Nanog and Oct4. In conclusion, Our discoveries demonstrate that autocrine IL-23 contribute to ovarian cancer malignancy through promoting the self-renewal of CD133+ ovarian cancer stem-like cells, and this suggests that IL-23 and its signaling pathway might serve as therapeutic targets for the treatment of ovarian cancer. PMID:27738346

  7. A2780 human ovarian cancer cells with acquired paclitaxel resistance display cancer stem cell properties.

    PubMed

    Han, Xiaofeng; DU, Fangfang; Jiang, Li; Zhu, Yifei; Chen, Zhen; Liu, Yanjun; Hong, Tingting; Wang, Teng; Mao, Yong; Wu, Xiaohong; Bruce, Iain C; Jin, Jian; Ma, Xin; Hua, Dong

    2013-11-01

    The use of chemotherapy to treat cancer is effective, but chemoresistance reduces this efficacy. Chemotherapy resistance involves several mechanisms, including the cancer stem cell (CSC) concept. The aim of the present study was to assess whether paclitaxel-resistant epithelial ovarian carcinoma is capable of generating cells with CSC-like properties. Using the paclitaxel-resistant A2780/PTX cell line, it was demonstrated that high aldehyde dehydrogenase 1 (ALDH1) activity identifies CSCs from diverse sources. Furthermore, the A2780/PTX cells had a strong ability to form colonies in soft agar assays. Notably, it was demonstrated that the inhibition of the PI3K signaling pathway abolished colony formation. These data suggest that there is a link between paclitaxel resistance and CSC enrichment. It is possible that therapeutic benefits, such as the restoration of chemosensitivity or the suppression of tumorigenicity, may be enabled by gaining further insights into the mechanisms underlying chemoresistance and the generation of CSCs.

  8. Ovarian cancer stem cell like side populations are enriched following chemotherapy and overexpress EZH2

    PubMed Central

    Rizzo, Siân; Hersey, Jenny M.; Mellor, Paul; Dai, Wei; Santos-Silva, Alessandra; Liber, Daniel; Luk, Louisa; Titley, Ian; Carden, Craig P; Box, Garry; Hudson, David L.; Kaye, Stanley B.; Brown, Robert

    2010-01-01

    Platinum-based chemotherapy, with cytoreductive surgery, is the cornerstone of treatment of advanced ovarian cancer, however acquired drug resistance is a major clinical obstacle. It has been proposed that subpopulations of tumour cells with stem-cell like properties, such as so-called side populations (SP) which over-express ABC drug-transporters, can sustain the growth of drug resistant tumour cells, leading to tumour recurrence following chemotherapy. The histone methyltransferase EZH2 is a key component of the Polycomb Repressive Complex 2 (PRC2) required for maintenance of a stem cell state and overexpression has been implicated in drug resistance and shorter survival of ovarian cancer patients. We observe higher percentage SP in ascites from patients that have relapsed following chemotherapy compared to chemonaive patients, consistent with selection for this subpopulation during platinum-based chemotherapy. Furthermore, ABCB1 (P-glycoprotein) and EZH2 are consistently over-expressed in SP compared to non-SP from patients’ tumour cells. SiRNA knockdown of EZH2 leads to loss of SP in ovarian tumour models, reduced anchorage-independent growth and reduced tumour growth in vivo. Together these data support a key role for EZH2 in the maintenance of a drug-resistant tumour-sustaining subpopulation of cells in ovarian cancers undergoing chemotherapy. As such, EZH2 is an important target for anticancer drug development. PMID:21216927

  9. STROBE-compliant integrin through focal adhesion involve in cancer stem cell and multidrug resistance of ovarian cancer

    PubMed Central

    Wei, Luwei; Yin, Fuqiang; Zhang, Wei; Li, Li

    2017-01-01

    Abstract Cancer stem cells (CSCs) are considered to be the root of carcinoma relapse and drug resistance in ovarian cancer. Hunting for the potential CSC genes and explain their functions would be a feasible strategy to meet the challenge of the drug resistance in ovarian cancer. In this study, we performed bioinformatic approaches such as biochip data extraction and pathway enrichment analyses to elucidate the mechanism of the CSC genes in regulation of drug resistance. Potential key genes, integrins, were identified to be related to CSC in addition to their associations with drug resistance and prognosis in ovarian cancer. A total of 36 ovarian CSC genes involved in regulation of drug resistance were summarized, and potential drug resistance-related CSC genes were identified based on 3 independent microarrays retrieved from the Gene Expression Omnibus (GEO) Profiles. Pathway enrichment of CSC genes associated with drug resistance in ovarian cancer indicated that focal adhesion signaling might play important roles in CSC genes-mediated drug resistance. Integrins are members of the adhesion molecules family, and integrin subunit alpha 1, integrin subunit alpha 5, and integrin subunit alpha 6 (ITGA6) were identified as central CSC genes and their expression in side population cells, cisplatin-resistant SKOV3 (SKOV3/DDP2) cells, and cisplatin-resistant A2780 (A2780/DDP) cells were dysregulated as measured by real-time quantitative polymerase chain reaction. The high expression of ITGA6 in 287 ovarian cancer patients of TCGA cohort was significantly associated with poorer progression-free survival. This study provide the basis for further understanding of CSC genes in regulation of drug resistance in ovarian cancer, and integrins could be a potential biomarker for prognosis of ovarian cancer. PMID:28328815

  10. Characteristics of Human Amniotic Fluid Mesenchymal Stem Cells and Their Tropism to Human Ovarian Cancer

    PubMed Central

    Li, Liru; Wang, Dejun; Zhou, Jun; Cheng, Yan; Liang, Tian; Zhang, Guangmei

    2015-01-01

    The mesenchymal stem cells (MSCs) derived from amniotic fluid (AF) have become an attractive stem cells source for cell-based therapy because they can be harvested at low cost and avoid ethical disputes. In human research, stem cells derived from AF gradually became a hot research direction for disease treatment, specifically for their plasticity, their reduced immunogenicity and their tumor tropism regardless of the tumor size, location and source. Our work aimed to obtain and characterize human amniotic fluid mesenchymal stem cells (AFMSCs) and detect their ovarian cancer tropsim in nude mice model. Ten milliliters of twenty independent amniotic fluid samples were collected from 16-20 week pregnant women who underwent amniocentesis for fetal genetic determination in routine prenatal diagnosis in the first affiliated hospital of Harbin medical university. We successfully isolated the AFMSCs from thirteen of twenty amniotic fluid samples. AFMSCs presented a fibroblastic-like morphology during the culture. Flow cytometry analyses showed that the cells were positive for specific stem cell markers CD73,CD90, CD105, CD166 and HLA-ABC (MHC class I), but negative for CD 45,CD40, CD34, CD14 and HLA-DR (MHC class II). RT-PCR results showed that the AFMSCs expressed stem cell marker OCT4. AFMSCs could differentiate into bone cells, fat cells and chondrocytes under certain conditions. AFMSCs had the high motility to migrate to ovarian cancer site but didn’t have the tumorigenicity. This study enhances the possibility of AFMSCs as drug carrier in human cell-based therapy. Meanwhile, the research emphasis in the future can also put in targeting therapy of ovarian cancer. PMID:25880317

  11. Characteristics of human amniotic fluid mesenchymal stem cells and their tropism to human ovarian cancer.

    PubMed

    Li, Liru; Wang, Dejun; Zhou, Jun; Cheng, Yan; Liang, Tian; Zhang, Guangmei

    2015-01-01

    The mesenchymal stem cells (MSCs) derived from amniotic fluid (AF) have become an attractive stem cells source for cell-based therapy because they can be harvested at low cost and avoid ethical disputes. In human research, stem cells derived from AF gradually became a hot research direction for disease treatment, specifically for their plasticity, their reduced immunogenicity and their tumor tropism regardless of the tumor size, location and source. Our work aimed to obtain and characterize human amniotic fluid mesenchymal stem cells (AFMSCs) and detect their ovarian cancer tropsim in nude mice model. Ten milliliters of twenty independent amniotic fluid samples were collected from 16-20 week pregnant women who underwent amniocentesis for fetal genetic determination in routine prenatal diagnosis in the first affiliated hospital of Harbin medical university. We successfully isolated the AFMSCs from thirteen of twenty amniotic fluid samples. AFMSCs presented a fibroblastic-like morphology during the culture. Flow cytometry analyses showed that the cells were positive for specific stem cell markers CD73,CD90, CD105, CD166 and HLA-ABC (MHC class I), but negative for CD 45,CD40, CD34, CD14 and HLA-DR (MHC class II). RT-PCR results showed that the AFMSCs expressed stem cell marker OCT4. AFMSCs could differentiate into bone cells, fat cells and chondrocytes under certain conditions. AFMSCs had the high motility to migrate to ovarian cancer site but didn't have the tumorigenicity. This study enhances the possibility of AFMSCs as drug carrier in human cell-based therapy. Meanwhile, the research emphasis in the future can also put in targeting therapy of ovarian cancer.

  12. Small putative NANOG, SOX2, and SSEA-4-positive stem cells resembling very small embryonic-like stem cells in sections of ovarian tissue in patients with ovarian cancer.

    PubMed

    Virant-Klun, Irma; Kenda-Suster, Natasa; Smrkolj, Spela

    2016-03-03

    In previous studies it has been found that in cell cultures of human adult ovaries there is a population of small stem cells with diameters of 2-4 μm, which are present mainly in the ovarian surface epithelium and are comparable to very small embryonic-like stem cells (VSELs) from bone marrow. These cells are not observed by histopathologists in the ovarian tissue due to their small size and unknown clinical significance. Because these cells express a degree of pluripotency, they might be involved in the manifestation of ovarian cancer. Therefore we studied the ovarian tissue sections in women with borderline ovarian cancer and serous ovarian carcinoma to perhaps identify the small putative stem cells in situ. In 27 women with borderline ovarian cancer and 20 women with high-grade serous ovarian carcinoma the ovarian tissue sections were stained, per standard practice, with eosin and hematoxylin staining and on NANOG, SSEA-4 and SOX2 markers, related to pluripotency, using immunohistochemistry. We focused on the presence and localization of small putative stem cells with diameters of up to 5 μm and with the nuclei spread over nearly the full cell volume. In ovarian sections of both borderline ovarian cancer and serous ovarian carcinoma patients we were able to identify the presence of small round cells complying with the above criteria. Some of these small cells were NANOG-positive, were located among epithelial cells in the ovarian surface epithelium and as a single cell or groups of cells/clusters in typical "chambers", were found only in the presence of ovarian cancer and not in healthy ovaries and are comparable to those in fetal ovaries. We envision that these small cells could be related to NANOG-positive tumor-like structures and oocyte-like cells in similar "chambers" found in sections of cancerous ovaries, which could support their stemness and pluripotency. Further immunohistochemistry revealed a similar population of SSEA-4 and SOX2-positive cells. We

  13. TARGETING THE MITOCHONDRIA ACTIVATES TWO INDEPENDENT CELL DEATH PATHWAYS IN THE OVARIAN CANCER STEM CELLS

    PubMed Central

    Alvero, Ayesha B.; Montagna, Michele K.; Holmberg, Jennie C.; Craveiro, Vinicius; Brown, David; Mor, Gil

    2013-01-01

    Cancer stem cells are responsible for tumor initiation and chemo-resistance. In ovarian cancer, the CD44+/MyD88+ ovarian cancer stem cells (OCSCs) are also able to repair the tumor and serve as tumor vascular progenitors. Targeting these cells is therefore necessary to improve treatment outcome and patient survival. The previous demonstration that the OCSCs are resistant to apoptotic cell death induced by conventional chemotherapy agents suggests that other forms of targeted therapy should be explored. We show in this study that targeting mitochondrial bioenergetics is a potent stimulus to induce caspase-independent cell death in a panel of OCSCs. Treatment of these cells with the novel isoflavone derivative, NV-128, significantly depressed mitochondrial function exhibited by decrease in ATP, Cox-I, and Cox-IV levels, and increase in mitochondrial superoxide and hydrogen peroxide. This promotes a state of “cellular starvation” that activates two independent pathways: 1) AMPKα1 pathway leading to mTOR inhibition; and 2) mitochondrial MEK/ERK pathway leading to loss of mitochondrial membrane potential. The demonstration that a compound can specifically target the mitochondria to induce cell death in this otherwise chemo-resistant cell population opens a new venue for treating ovarian cancer patients. PMID:21677151

  14. TWIST and ovarian cancer stem cells: implications for chemoresistance and metastasis

    PubMed Central

    Nuti, Sudhakar V.; Mor, Gil; Li, Peiyao; Yin, Gang

    2014-01-01

    The transcription factor TWIST1 is a highly evolutionally conserved basic Helix-Loop-Helix (bHLH) transcription factor that functions as a master regulator of gastrulation and mesodermal development. Although TWIST1 was initially associated with embryo development, an increasing number of studies have shown TWIST1 role in the regulation of tissue homeostasis, primarily as a regulator of inflammation. More recently, TWIST1 has been found to be involved in the process of tumor metastasis through the regulation of Epithelial Mesenchymal Transition (EMT). The objective of this review is to examine the normal functions of TWIST1 and its role in tumor development, with a particular focus on ovarian cancer. We discuss the potential role of TWIST1 in the context of ovarian cancer stem cells and its influence in the process of tumor formation. PMID:25238494

  15. CD133+ ovarian cancer stem-like cells promote non-stem cancer cell metastasis via CCL5 induced epithelial-mesenchymal transition

    PubMed Central

    Qi, Wei; Huang, Jiani; Chen, Junying; He, Luhang; Liang, Zhiqing; Guo, Bo; Li, Yongsheng; Xie, Rongkai; Zhu, Bo

    2015-01-01

    Cancer stem cells (CSCs, also called cancer stem-like cells, CSLCs) can function as “seed cells” for tumor recurrence and metastasis. Here, we report that, in the presence of CD133+ ovarian CSLCs, CD133− non-CSLCs can undergo an epithelial-mesenchymal transition (EMT)-like process and display enhanced metastatic capacity in vitro and in vivo. Highly elevated expression of chemokine (C-C motif) ligand 5 (CCL5) and its receptors chemokine (C-C motif) receptor (CCR) 1/3/5 are observed in clinical and murine metastatic tumor tissues from epithelial ovarian carcinomas. Mechanistically, paracrine CCL5 from ovarian CSLCs activates the NF-κB signaling pathway in ovarian non-CSLCs via binding CCR1/3/5, thereby inducing EMT and tumor invasion. Taken together, our results redefine the metastatic potential of non-stem cancer cells and provide evidence that targeting the CCL5:CCR1/3/5-NF-κB pathway could be an effective strategy to prevent ovarian cancer metastasis. PMID:25788271

  16. The hypoxic microenvironment upgrades stem-like properties of ovarian cancer cells

    PubMed Central

    2012-01-01

    Background To study whether hypoxia influences the stem-like properties of ovarian cancer cells and their biological behavior under hypoxia. Method Ovarian cancer cell lines ES-2 and OVCAR-3 were cultivated in different oxygen tensions for proliferation, cell cycling and invasion analyses. The clonogenic potential of cells was examined by colony formation and sphere formation assays. Stem cell surface markers, SP and CD44bright and CD44dim cells were analyzed by flow cytometry. Protein expression of HIF-1α, HIF-2α, Ot3/4 and Sox2 were investigated by Western blotting. Results Both cell lines cultivated at hypoxic condition grew relatively slowly with extended G0/G1 phase. However, if the cells were pre-treated under 1% O2 for 48 hrs before brought back to normoxia, the cells showed significantly higher proliferation rate with higher infiltration capability, and significant more colonies and spheres, in comparison to the cells always cultivated under normoxia. CD44bright cells expressed significantly higher levels of Oct3/4 and Sox2 than the CD44dim cells and formed significantly more clones and spheres examined in vitro. Hypoxic treatment of the cells resulted in stronger CD44 expression in both cell lines, and stronger CD133 expression in the OVCAR-3 cell line. In parallel with these findings, significantly increased number of side population (SP) cells and up-regulated expression of Oct3/4 and Sox2 in both ES-2 and OVCAR-3 cell lines were observed. Conclusion We conclude that ovarian cancer cells survive hypoxia by upgrading their stem-like properties through up-regulation of stemness-related factors and behave more aggressively when brought back to higher oxygen environment. PMID:22642602

  17. The side population of ovarian cancer cells defines a heterogeneous compartment exhibiting stem cell characteristics.

    PubMed

    Boesch, Maximilian; Zeimet, Alain G; Reimer, Daniel; Schmidt, Stefan; Gastl, Guenther; Parson, Walther; Spoeck, Franziska; Hatina, Jiri; Wolf, Dominik; Sopper, Sieghart

    2014-08-30

    Cancer stem cells (CSC) are believed to be involved in tumor evasion of classical antitumor therapies and have thus become an attractive target for further improvement of anticancer strategies. However, the existence and identity of CSC are still a matter of controversy. In a systematic screen of 13 ovarian cancer cell lines we show that cells with stem cell properties are reliably detectable as a minor population, characterized by ABC transporter expression resulting in the side population (SP) phenotype. In different cell lines, either ABCG2 or ABCB1 was found to be responsible for this effect. Purified SP cells featured virtually all characteristics of bona fide CSC, including clonogenicity, asymmetric division and high tumorigenicity in vivo. Using in-depth phenotyping by multicolor flow cytometry, we found that among the investigated ovarian cancer cell lines the SP compartment exhibits tremendous heterogeneity and is composed of multiple phenotypically distinct subpopulations. Thus, our study confirms previous results showing that CSC are contained within the SP. However, the exact identity of the CSC is still disguised by the high complexity of the CSC-containing compartment. Further functional studies are needed to determine whether a single cellular subset can unambiguously be defined as CSC or whether multiple stem cell-like cells with different properties coexist. Moreover, the observed heterogeneity may reflect a high level of plasticity and likely influences tumor progression, escape from immune-surveillance and development of resistance to anticancer therapies and should therefore be considered in the development of new treatment strategies.

  18. The side population of ovarian cancer cells defines a heterogeneous compartment exhibiting stem cell characteristics

    PubMed Central

    Boesch, Maximilian; Zeimet, Alain G.; Reimer, Daniel; Schmidt, Stefan; Gastl, Guenther; Parson, Walther; Spoeck, Franziska; Hatina, Jiri

    2014-01-01

    Cancer stem cells (CSC) are believed to be involved in tumor evasion of classical antitumor therapies and have thus become an attractive target for further improvement of anticancer strategies. However, the existence and identity of CSC are still a matter of controversy. In a systematic screen of 13 ovarian cancer cell lines we show that cells with stem cell properties are reliably detectable as a minor population, characterized by ABC transporter expression resulting in the side population (SP) phenotype. In different cell lines, either ABCG2 or ABCB1 was found to be responsible for this effect. Purified SP cells featured virtually all characteristics of bona fide CSC, including clonogenicity, asymmetric division and high tumorigenicity in vivo. Using in-depth phenotyping by multicolor flow cytometry, we found that among the investigated ovarian cancer cell lines the SP compartment exhibits tremendous heterogeneity and is composed of multiple phenotypically distinct subpopulations. Thus, our study confirms previous results showing that CSC are contained within the SP. However, the exact identity of the CSC is still disguised by the high complexity of the CSC-containing compartment. Further functional studies are needed to determine whether a single cellular subset can unambiguously be defined as CSC or whether multiple stem cell-like cells with different properties coexist. Moreover, the observed heterogeneity may reflect a high level of plasticity and likely influences tumor progression, escape from immune-surveillance and development of resistance to anticancer therapies and should therefore be considered in the development of new treatment strategies. PMID:25216521

  19. Systemic mesenchymal stem cells reduce growth rate of cisplatin-resistant ovarian cancer

    PubMed Central

    Zhu, Pengfei; Chen, Mo; Wang, Li; Ning, Yanxia; Liang, Jie; Zhang, Hao; Xu, Congjian; Chen, Sifeng; Yao, Liangqing

    2013-01-01

    Epithelial ovarian cancer is one of the most malignant cancers in women and resistant to chemotherapy is the major obstacle for the five-year survival rate. Cisplatin is one of the effective anticancer drug used in the ovarian cancer. To find a good strategy to cure the tumors which is resistant to cisplatin, the cisplatin-resistant 3SKOV3 cells were selected from SKOV-3 ovarian cancer cells. Furthermore, the isolated mesenchymal stem cells were infused systemically to try to cure the transplanted tumor induced by 3SKOV3 cells in nude mice. The morphology and cell membrane CD44 expression were investigated by microscope and flow cytometry. The biological behaviors of resistant 3SKOV3 and its parental SKOV3 cells, including proliferation, adhesion, and cell cycle were determined by CCK8, absorbance assay and FCM methods. The transplanted tumors were set up in nude mice with 3SKOV3 cells injection. The growth rate of transplanted tumors was detected following with MSCs injection. The 3SKOV3 cells have different morphologic manifestation and expressed high level of CD44 molecule. At the same time, 3SKOV3 cells have less adhesion ability and less S-phase ratio. The isolated MSCs from bone marrow could inhibit the growth of transplanted tumor via systemic injection. The cisplatin-resistant 3SKOV3 cells have the different biological behaviors as its parental SKOV3 cells. The present study indicated that systemic MSCs have the therapeutic role on ovarian cancer. However, further investigations are in progress to elucidate the underlying mechanism. PMID:24228113

  20. Systemic mesenchymal stem cells reduce growth rate of cisplatin-resistant ovarian cancer.

    PubMed

    Zhu, Pengfei; Chen, Mo; Wang, Li; Ning, Yanxia; Liang, Jie; Zhang, Hao; Xu, Congjian; Chen, Sifeng; Yao, Liangqing

    2013-01-01

    Epithelial ovarian cancer is one of the most malignant cancers in women and resistant to chemotherapy is the major obstacle for the five-year survival rate. Cisplatin is one of the effective anticancer drug used in the ovarian cancer. To find a good strategy to cure the tumors which is resistant to cisplatin, the cisplatin-resistant 3SKOV3 cells were selected from SKOV-3 ovarian cancer cells. Furthermore, the isolated mesenchymal stem cells were infused systemically to try to cure the transplanted tumor induced by 3SKOV3 cells in nude mice. The morphology and cell membrane CD44 expression were investigated by microscope and flow cytometry. The biological behaviors of resistant 3SKOV3 and its parental SKOV3 cells, including proliferation, adhesion, and cell cycle were determined by CCK8, absorbance assay and FCM methods. The transplanted tumors were set up in nude mice with 3SKOV3 cells injection. The growth rate of transplanted tumors was detected following with MSCs injection. The 3SKOV3 cells have different morphologic manifestation and expressed high level of CD44 molecule. At the same time, 3SKOV3 cells have less adhesion ability and less S-phase ratio. The isolated MSCs from bone marrow could inhibit the growth of transplanted tumor via systemic injection. The cisplatin-resistant 3SKOV3 cells have the different biological behaviors as its parental SKOV3 cells. The present study indicated that systemic MSCs have the therapeutic role on ovarian cancer. However, further investigations are in progress to elucidate the underlying mechanism.

  1. Eradication of chemotherapy-resistant CD44+ human ovarian cancer stem cells in mice by intraperitoneal administration of Clostridium perfringens enterotoxin.

    PubMed

    Casagrande, Francesca; Cocco, Emiliano; Bellone, Stefania; Richter, Christine E; Bellone, Marta; Todeschini, Paola; Siegel, Eric; Varughese, Joyce; Arin-Silasi, Dan; Azodi, Masoud; Rutherford, Thomas J; Pecorelli, Sergio; Schwartz, Peter E; Santin, Alessandro D

    2011-12-15

    Emerging evidence has suggested that the capability to sustain tumor formation, growth, and chemotherapy resistance in ovarian as well as other human malignancies exclusively resides in a small proportion of tumor cells termed cancer stem cells. During the characterization of CD44(+) ovarian cancer stem cells, we found a high expression of the genes encoding for claudin-4. Because this tight junction protein is the natural high-affinity receptor for Clostridium perfringens enterotoxin (CPE), we have extensively investigated the sensitivity of ovarian cancer stem cells to CPE treatment in vitro and in vivo. Real-time polymerase chain reaction and flow cytometry were used to evaluate claudin-3/-4 expression in ovarian cancer stem cells. Small interfering RNA knockdown experiments and MTS assays were used to evaluate CPE-induced cytotoxicity against ovarian cancer stem cell lines in vitro. C.B-17/SCID mice harboring ovarian cancer stem cell xenografts were used to evaluate CPE therapeutic activity in vivo. CD44(+) ovarian cancer stem cells expressed claudin-4 gene at significantly higher levels than matched autologous CD44(-) ovarian cancer cells, and regardless of their higher resistance to chemotherapeutic agents died within 1 hour after exposure to 1.0 μg/mL of CPE in vitro. Conversely, small-interfering RNA-mediated knockdown of claudin-3/-4 expression in CD44(+) cancer stem cells significantly protected cancer stem cells from CPE-induced cytotoxicity. Importantly, multiple intraperitoneal administrations of sublethal doses of CPE in mice harboring xenografts of chemotherapy-resistant CD44(+) ovarian cancer stem cells had a significant inhibitory effect on tumor progression leading to the cure and/or long-term survival of all treated animals (ie, 100% reduction in tumor burden in 50% of treated mice; P < .0001). CPE may represent an unconventional, potentially highly effective strategy to eradicate chemotherapy-resistant cancer stem cells. Copyright © 2011

  2. [Expression Level of Membrane-associated Proteins Numb in Epithelial Ovarian Carcinoma and Its Relationship with Ovarian Cancer Stem Cell Markers CD117, CD133, ALDH1.

    PubMed

    Jing, Hong; Liu, Xiao-Yu; Chen, Ya-Li; Bai, Li-Ping; Zheng, Ai

    2016-11-01

    To explore the expression level of membrane-associated protein Numb in epithelial ovarian carcinoma and its relationship with ovarian cancer stem cell markers CD117,CD133,acetaldehyde dehydrogenase 1(ALDH1). A total of 136 patients who had ovarian tumors and 22 patients who had not ovarian tumors in Department of Gynaecology and Obstetrics,West China Second University Hospital,Sichuan University were chosen as the study subjects.According to the histopathologic examination results,they were divided into epithelial ovarian carcinoma group (n=92),ovarian borderline tumor group (n=23),ovarian benign tumor group (n=21) and normal ovary group (n=22).Expression levels of Numb protein,CD117,CD133 and ALDH1 in ovarian tissue were detected by immunohistochemical SP method and these several kinds of protein expression differences and correlation statistical analysis were performend. 1 The positive expression rate of Numb protein in epithelial ovarian carcinoma group was higher than that in benign tumor or normal ovary group,also Numb protein positive expression rate in ovarian borderline tumor group was higher than that in normal ovary group,and the differences were statistically significant (P<0.05).2 Numb protein positive expression rate in ovarian tissue in patients with epithelial ovarian carcinoma FIGO stage1-2 was lower than that in stage 3-4,also the same in no lymph nodes metastasis compared with lymph nodes invasion,and the differences of positive expression rate were statistically significant (P<0.05).While there were no significant differences among different age,histopathological types,pathological grades and residual tumor size (P>0.05).3 There was no correlation between Numb protein and CD117 and CD133 positive expression rate in epithelial ovarian carcinoma tissue [correlation coefficient (r)=0.116,P=0.261; r=0.083,P=0.425].However,the positive expression rate of Numb protein and ALDH1 was positively correlated (r=0.296,P=0.261). The expression of Numb protein

  3. Epithelial ovarian cancer stem cells: underlying complexity of a simple paradigm.

    PubMed

    Garson, Kenneth; Vanderhyden, Barbara C

    2015-02-01

    The lack of significant progress in the treatment of epithelial ovarian cancer (EOC) underscores the need to gain a better understanding of the processes that lead to chemoresistance and recurrence. The cancer stem cell (CSC) hypothesis offers an attractive explanation of how a subpopulation of cells within a patient's tumour might remain refractory to treatment and subsequently form the basis of recurrent chemoresistant disease. This review examines the literature defining somatic stem cells of the ovary and fallopian tube, two tissues that give rise to EOC. In addition, considerable research has been reviewed, that has identified subpopulations of EOC cells, based on marker expression (CD133, CD44, CD117, CD24, epithelial cell adhesion molecule, LY6A, ALDH1 and side population (SP)), which are enriched for tumour initiating cells (TICs). While many studies identified either CD133 or CD44 as markers useful for enriching for TICs, there is little consensus. This suggests that EOC cells may have a phenotypic plasticity that may preclude the identification of universal markers defining a CSC. The assay that forms the basis of quantifying TICs is the xenograft assay. Considerable controversy surrounds the xenograft assay and it is essential that some of the potential limitations be examined in this review. Highlighting such limitations or weaknesses is required to properly evaluate data and broaden our interpretation of potential mechanisms that might be contributing to the pathogenesis of ovarian cancer.

  4. CD24 and Nanog identify stem cells signature of ovarian epithelium and cysts that may develop to ovarian cancer.

    PubMed

    Schreiber, Letizia; Raanan, Calanit; Amsterdam, Abraham

    2014-03-01

    Ovarian cancer is the most lethal gynecological cancer. There is a general debate whether ovarian cancer is an intrinsic or an imported disease. We investigated whether in normal morphological appearance and in early stages of ovarian tumorgenesis typical cancer cell markers such as CD24 and Nanog are expressed. In 25% of normal appearing ovaries of post-menopausal women there was co-localization of CD24 and Nanog in the walls of the ovarian cysts, leaving the epithelial cells on the surface of these ovaries free of Nanog or CD24 expression. In benign ovarian tumors 37% of specimens were positive to CD24 and Nanog labeling while 26% of them were localized in the cyst walls. In contrast, in serous borderline tumors 79% specimens were labeled with CD24, 42% of them were localized in cysts and in 32% of them showed co-localization with CD24 and Nanog was evident: the rest were labeled in the ovarian epithelial cells. In serous ovarian carcinomas 81% specimens were labeled with CD24 antibodies. In 45% of them co-localization with Nanog was evident in the bulk of the cancerous tissue. In mucinous carcinomas no labeling with CD24 or Nanog was evident. In view of the synergistic effect of CD24 and Nanog expressed in malignant cancer development in other systems, it is suggested that such an analysis can be valuable for early detection of ovarian cancer. Moreover, the abundance of these markers in cysts in the development of ovarian cancer may suggest that they present an intrinsic source of the development of the highly malignant disease. Finally, since CD24 is exposed on the surface of the cancer cells, it may be highly beneficial to target these cells with antibodies to CD24 conjugated to cytotoxic drugs for more efficient treatment of this malignant disease.

  5. DOXIL when combined with Withaferin A (WFA) targets ALDH1 positive cancer stem cells in ovarian cancer.

    PubMed

    Kakar, Sham S; Worth, Christopher A; Wang, Zhenglong; Carter, Kelsey; Ratajczak, Mariusz; Gunjal, Pranesh

    Ovarian cancer is a highly aggressive and deadly disease. Currently, the treatment for ovarian cancer entails cytoreductive surgery followed by chemotherapy, mainly cisplatin or carboplatin combined with paclitaxel. Although this regimen is initially effective in a high percentage of cases, unfortunately, after few months of initial treatment, tumor relapse occurs due to platinum-resistance. DOXIL (liposomal preparation of doxorubicin) is a choice of drug for recurrent ovarian cancer. However, its response rate is very low and is accompanied by myocardial toxicity. Resistance to chemotherapy and recurrence of cancer is primarily attributed to the presence of cancer stem cells (CSCs), a small population of cells present in cancer. Effect of DOXIL and withaferin A (WFA), both alone and in combination, was investigated on cell proliferation of ovarian cancer cell line A2780 and tumor growth in SCID mice bearing i.p. ovarian tumors. ALDH1 cells were isolated from A2780 using cell sorter, and effect of DOXIL and WFA both alone and in combination on tumorigenic function of ALDH1 was studied using spheroids formation assays in vitro. Western blots were performed to examine the expression of ALDH1 and Notch 1 genes. In our studies, we showed, for the first time, that DOXIL when combined with withaferin A (WFA) elicits synergistic effect on inhibition of cell proliferation of ovarian cancer cells and inhibits the expression of ALDH1 protein, a marker for ALDH1 positive cancer stem cells (CSCs), and Notch1, a signaling pathway gene required for self-renewal of CSCs. Inhibition of expression of both ALDH1 and Notch1 genes by WFA was found to be dose dependent, whereas DOXIL (200 nM) was found to be ineffective. SCID mice, bearing i.p. ovarian tumors, were treated with a small dose of DOXIL (2 mg/kg) in combination with a sub-optimal dose of WFA (2 mg/kg) which resulted in a highly significant (60% to 70%) reduction in tumor growth, and complete inhibition of metastasis

  6. Developing ovarian cancer stem cell models: laying the pipeline from discovery to clinical intervention.

    PubMed

    Ffrench, Brendan; Gasch, Claudia; O'Leary, John J; Gallagher, Michael F

    2014-12-11

    Despite decades of research, ovarian cancer is still associated with unacceptably high mortality rates, which must be addressed by novel therapeutic approaches. One avenue through which this may be achieved is targeting of tumor-initiating 'Cancer Stem Cells' (CSCs). CSCs are sufficient to generate primary and recurrent disease through extensive rounds of asymmetric division, which maintain the CSC pool while producing the tissues that form the bulk of the tumor. CSCs thrive in the harsh tumor niche, are generally refractory to therapeutic intervention and closely-linked to the Epithelial-Mesenchymal Transition process, which facilitates invasion and metastasis. While it is well-accepted that CSC-targeting must be assessed as a novel therapeutic avenue, few ovarian CSC models have been developed due to perceived and actual difficulties associated with the process of 'CSC Discovery'. In this article we review contemporary approaches to CSC Discovery and argue that this process should start with an understanding of the specific challenges associated with clinical intervention, laying the pipeline backwards towards CSC Discovery. Such an approach would expedite the bridging of the gap between laboratory isolation and clinical targeting of ovarian CSCs.

  7. Biomechanical profile of cancer stem-like/tumor-initiating cells derived from a progressive ovarian cancer model.

    PubMed

    Babahosseini, Hesam; Ketene, Alperen N; Schmelz, Eva M; Roberts, Paul C; Agah, Masoud

    2014-07-01

    We herein report, for the first time, the mechanical properties of ovarian cancer stem-like/tumor-initiating cells (CSC/TICs). The represented model is a spontaneously transformed murine ovarian surface epithelial (MOSE) cell line that mimics the progression of ovarian cancer from early/non-tumorigenic to late/highly aggressive cancer stages. Elastic modulus measurements via atomic force microscopy (AFM) illustrate that the enriched CSC/TICs population (0.32±0.12kPa) are 46%, 61%, and 72% softer (P<0.0001) than their aggressive late-stage, intermediate, and non-malignant early-stage cancer cells, respectively. Exposure to sphingosine, an anti-cancer agent, induced an increase in the elastic moduli of CSC/TICs by more than 46% (0.47±0.14kPa, P<0.0001). Altogether, our data demonstrate that the elastic modulus profile of CSC/TICs is unique and responsive to anti-cancer treatment strategies that impact the cytoskeleton architecture of cells. These findings increase the chance for obtaining distinctive cell biomechanical profiles with the intent of providing a means for effective cancer detection and treatment control. This novel study utilized atomic force microscopy to demonstrate that the elastic modulus profile of cancer stem cell-like tumor initiating cells is unique and responsive to anti-cancer treatment strategies that impact the cytoskeleton of these cells. These findings pave the way to the development of unique means for effective cancer detection and treatment control. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells.

    PubMed

    You, Yanan; Li, Yiying; Li, Ming; Mi, Lei; Wu, Mengyao; Qu, Ying; Yuan, Yan; Chen, Tong; Jiang, Hua

    2017-09-04

    Emerging evidence indicates a link between the increased proportion of regulatory T cells (Tregs) and reduced survival in patients who have been diagnosed with cancer. Cancer stem cells (CSCs) have been indicated to play a vital role in tumour initiation, drug resistance and recurrence. However, the relationship between Tregs and CSCs remains largely unknown. Here, we sorted out ovarian cancer stem-like side population (SP) cells and CD133(+) cells to investigate the influence of ovarian CSCs on Tregs. Among the various immune-related molecules that we assessed, C-C motif chemokine ligand 5 (CCL5) was the most elevated in ovarian CSCs relative to that in the non-CSCs. The expression of its receptor, C-C motif chemokine receptor 5 (CCR5), was also increased on the surface of Tregs in ovarian cancer patients. This receptor-ligand expression profile indicated that ovarian CSCs recruit Tregs via CCL5-CCR5 interactions. We further assessed the expression of interleukin-10 (IL-10) in Tregs cultured with different cancer cells. Tregs cultured in conditioned medium (CM) from ovarian CD133(+) cells expressed a higher level of IL-10 than Tregs cultured in CM from CD133(-) cells, indicating that Tregs exert pronounced immune-inhibitory functions in CSC-rich environments. Furthermore, co-culture with ovarian cancer cell lines induced the expression of matrix metalloproteinase-9 (MMP9) in Tregs, which in turn enhanced the degradation of the extracellular matrix and enabled the invasion of tumour cells, thereby facilitating tumour metastasis. For the first time here, our findings describe the relationship between ovarian CSCs and Tregs, and demonstrated that these two cell populations cooperate to promote tumour immune tolerance and enhance tumour progression. This article is protected by copyright. All rights reserved. © 2017 British Society for Immunology.

  9. What Is Ovarian Cancer?

    MedlinePlus

    ... to be similar to widespread ovarian cancer. Fallopian tube cancer This is another rare cancer that is ... to epithelial ovarian cancer. It begins in the tube that carries an egg from the ovary to ...

  10. Niche-Dependent Gene Expression Profile of Intratumoral Heterogeneous Ovarian Cancer Stem Cell Populations

    PubMed Central

    Abelson, Sagi; Shamai, Yeela; Berger, Liron; Skorecki, Karl; Tzukerman, Maty

    2013-01-01

    Intratumoral heterogeneity challenges existing paradigms for anti-cancer therapy. We have previously demonstrated that the human embryonic stem cells (hESC)-derived cellular microenvironment in immunocompromised mice, enables functional distinction of heterogeneous tumor cells, including cells which do not grow into a tumor in a conventional direct tumor xenograft platform. We have identified and characterized six cancer cell subpopulations each clonally expanded from a single cell, derived from human ovarian clear cell carcinoma of a single tumor, to demonstrate striking intratumoral phenotypic heterogeneity that is dynamically dependent on the tumor growth microenvironment. These cancer cell subpopulations, characterized as cancer stem cell subpopulations, faithfully recapitulate the full spectrum of histological phenotypic heterogeneity known for human ovarian clear cell carcinoma. Each of the six subpopulations displays a different level of morphologic and tumorigenic differentiation wherein growth in the hESC-derived microenvironment favors growth of CD44+/aldehyde dehydrogenase positive pockets of self-renewing cells that sustain tumor growth through a process of tumorigenic differentiation into CD44-/aldehyde dehydrogenase negative derivatives. Strikingly, these derivative cells display microenvironment-dependent plasticity with the capacity to restore self-renewal markers and CD44 expression. In the current study, we delineate the distinct gene expression and epigenetic profiles of two such subpopulations, representing extremes of phenotypic heterogeneity in terms of niche-dependent self-renewal and tumorigenic differentiation. By combining Gene Set Enrichment, Gene Ontology and Pathway-focused array analyses with methylation status, we propose a suite of robust differences in tumor self-renewal and differentiation pathways that underlie the striking intratumoral phenotypic heterogeneity which characterize this and other solid tumor malignancies. PMID

  11. Human carcinoma-associated mesenchymal stem cells promote ovarian cancer chemotherapy resistance via a BMP4/HH signaling loop.

    PubMed

    Coffman, Lan G; Choi, Yun-Jung; McLean, Karen; Allen, Benjamin L; di Magliano, Marina Pasca; Buckanovich, Ronald J

    2016-02-09

    The tumor microenvironment is critical to cancer growth and therapy resistance. We previously characterized human ovarian carcinoma-associated mesenchymal stem cells (CA-MSCs). CA-MSCs are multi-potent cells that can differentiate into tumor microenvironment components including fibroblasts, myofibroblasts and adipocytes. We previously reported CA-MSCs, compared to normal MSCs, express high levels of BMP proteins and promote tumor growth by increasing numbers of cancer stem-like cells (CSCs). We demonstrate here that ovarian tumor cell-secreted Hedgehog (HH) induces CA-MSC BMP4 expression. CA-MSC-derived BMP4 reciprocally increases ovarian tumor cell HH expression indicating a positive feedback loop. Interruption of this loop with a HH pathway inhibitor or BMP4 blocking antibody decreases CA-MSC-derived BMP4 and tumor-derived HH preventing enrichment of CSCs and reversing chemotherapy resistance. The impact of HH inhibition was only seen in CA-MSC-containing tumors, indicating the importance of a humanized stroma. These results are reciprocal to findings in pancreatic and bladder cancer, suggesting HH signaling effects are tumor tissue specific warranting careful investigation in each tumor type. Collectively, we define a critical positive feedback loop between CA-MSC-derived BMP4 and ovarian tumor cell-secreted HH and present evidence for the further investigation of HH as a clinical target in ovarian cancer.

  12. Human carcinoma-associated mesenchymal stem cells promote ovarian cancer chemotherapy resistance via a BMP4/HH signaling loop

    PubMed Central

    Coffman, Lan G.; Choi, Yun-Jung; McLean, Karen; Allen, Benjamin L.; di Magliano, Marina Pasca; Buckanovich, Ronald J.

    2016-01-01

    The tumor microenvironment is critical to cancer growth and therapy resistance. We previously characterized human ovarian carcinoma-associated mesenchymal stem cells (CA-MSCs). CA-MSCs are multi-potent cells that can differentiate into tumor microenvironment components including fibroblasts, myofibroblasts and adipocytes. We previously reported CA-MSCs, compared to normal MSCs, express high levels of BMP proteins and promote tumor growth by increasing numbers of cancer stem-like cells (CSCs). We demonstrate here that ovarian tumor cell-secreted Hedgehog (HH) induces CA-MSC BMP4 expression. CA-MSC-derived BMP4 reciprocally increases ovarian tumor cell HH expression indicating a positive feedback loop. Interruption of this loop with a HH pathway inhibitor or BMP4 blocking antibody decreases CA-MSC-derived BMP4 and tumor-derived HH preventing enrichment of CSCs and reversing chemotherapy resistance. The impact of HH inhibition was only seen in CA-MSC-containing tumors, indicating the importance of a humanized stroma. These results are reciprocal to findings in pancreatic and bladder cancer, suggesting HH signaling effects are tumor tissue specific warranting careful investigation in each tumor type. Collectively, we define a critical positive feedback loop between CA-MSC-derived BMP4 and ovarian tumor cell-secreted HH and present evidence for the further investigation of HH as a clinical target in ovarian cancer. PMID:26755648

  13. Suppression of cancer stemness p21-regulating mRNA and microRNA signatures in recurrent ovarian cancer patient samples

    PubMed Central

    2012-01-01

    Background Malignant ovarian disease is characterised by high rates of mortality due to high rates of recurrent chemoresistant disease. Anecdotal evidence indicates this may be due to chemoresistant properties of cancer stem cells (CSCs). However, our understanding of the role of CSCs in recurrent ovarian disease remains sparse. In this study we used gene microarrays and meta-analysis of our previously published microRNA (miRNA) data to assess the involvement of cancer stemness signatures in recurrent ovarian disease. Methods Microarray analysis was used to characterise early regulation events in an embryonal carcinoma (EC) model of cancer stemness. This was then compared to our previously published microarray data from a study of primary versus recurrent ovarian disease. In parallel, meta-analysis was used to identify cancer stemness miRNA signatures in tumor patient samples. Results Microarray analysis demonstrated a 90% difference between gene expression events involved in early regulation of differentiation in murine EC (mEC) and embryonic stem (mES) cells. This contrasts the known parallels between mEC and mES cells in the undifferentiated and well-differentiated states. Genelist comparisons identified a cancer stemness signature set of genes in primary versus recurrent data, a subset of which are known p53-p21 regulators. This signature is present in primary and recurrent or in primary alone but essentially never in recurrent tumors specifically. Meta-analysis of miRNA expression showed a much stronger cancer stemness signature within tumor samples. This miRNA signature again related to p53-p21 regulation and was expressed prominently in recurrent tumors. Our data indicate that the regulation of p53-p21 in ovarian cancer involves, at least partially, a cancer stemness component. Conclusion We present a p53-p21 cancer stemness signature model for ovarian cancer. We propose that this may, at least partially, differentially regulate the p53-p21 mechanism in

  14. MiR-1207 overexpression promotes cancer stem cell-like traits in ovarian cancer by activating the Wnt/β-catenin signaling pathway.

    PubMed

    Wu, Geyan; Liu, Aibin; Zhu, Jinrong; Lei, Fangyong; Wu, Shu; Zhang, Xin; Ye, Liping; Cao, Lixue; He, Shanyang

    2015-10-06

    Wnt/β-catenin signaling pathway is strictly controlled by multiple negative regulators. However, how tumor cells override the negative regulatory effects to maintain constitutive activation of Wnt/β-catenin signaling, which is commonly observed in various cancers, remains puzzling. In current study, we reported that overexpression of miR-1207 in ovarian cancer activated Wnt/β-catenin signaling by directly targeting and suppressing secreted Frizzled-related protein 1 (SFRP1), AXIN2 and inhibitor of β-catenin and TCF-4 (ICAT), which are vital negative regulators of the Wnt/β-catenin pathway. We found that the expression of miR-1207 was ubiquitously upregulated in both ovarian cancer tissues and cells, which inversely correlated with patient overall survival. Furthermore, overexpression of miR-1207 enhanced, while silencing miR-1207 reduced, stem cell-like traits of ovarian cancer cells in vitro and in vivo, including tumor sphere formation capability and proportion of SP+ and CD133+ cells. Importantly, upregulating miR-1207 promoted, while silencing miR-1207 inhibited, the tumorigenicity of ovarian cancer cells. Hence, our results suggest that miR-1207 plays a vital role in promoting the cancer stem cell-like phenotype in ovarian cancer and might represent a potential target for anti-ovarian cancer therapy.

  15. MV-NIS Infected Mesenchymal Stem Cells in Treating Patients With Recurrent Ovarian Cancer

    ClinicalTrials.gov

    2017-03-14

    Malignant Ovarian Brenner Tumor; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Ovarian Carcinoma

  16. Adenovirus-mediated truncated Bid overexpression induced by the Cre/LoxP system promotes the cell apoptosis of CD133+ ovarian cancer stem cells.

    PubMed

    Long, Qifang; Yang, Ru; Lu, Weixian; Zhu, Weipei; Zhou, Jundong; Zheng, Cui; Zhou, Dongmei; Yu, Ling; Wu, Jinchang

    2017-01-01

    Cancer stem cells are a small subset of cancer cells that contribute to cancer progression, metastasis, chemoresistance and recurrence. CD133-positive (CD133+) ovarian cancer cells have been identified as ovarian cancer stem cells. Adenovirus-mediated gene therapy is an innovative therapeutic method for cancer treatment. In the present study, we aimed to develop a new gene therapy to specifically eliminate CD133+ ovarian cancer stem cells by targeting CD133. We used the Cre/LoxP system to augment the selective expression of the truncated Bid (tBid) gene as suicide gene therapy in CD133+ ovarian cancer stem cells. The adenovirus (Ad)-CD133-Cre expressing Cre recombinase under the control of the CD133 promoter and Ad-CMV-LoxP-Neo-LoxP-tBid expressing tBid under the control of the CMV promoter were successfully constructed using the Cre/LoxP switching system. The co-infection of Ad-CMV-LoxP-Neo-LoxP-tBid and Ad-CD133-Cre selectively induced tBid overexpression, which inhibited cell growth and triggered the cell apoptosis of CD133+ ovarian cancer stem cells. The Cre/LoxP system-mediated tBid overexpression activated the pro-apoptotic signaling pathway and augmented the cytotoxic effect of cisplatin in CD133+ ovarian cancer stem cells. Furthermore, in xenograft experiments, co-infection with the two recombinant adenoviruses markedly suppressed tumor growth in vivo and promoted cell apoptosis in tumor tissues. Taken together, the present study provides evidence that the adenovirus-mediated tBid overexpression induced by the Cre/LoxP system can effectively eliminate CD133+ ovarian cancer stem cells, representing a novel therapeutic strategy for the treatment of ovarian cancer.

  17. Ovarian Cancer and Reproductive System Biology: A Harvard Stem Cell Institution Consortium

    DTIC Science & Technology

    2010-12-01

    involving Lin28A /B and the tumor suppressor microRNA let-7 for roles in ovarian and germ cell tumor initiation and maintenance; and 6) performing...Cancer - The Lin28A /let-7 pathway in ovarian and reproductive system cancers It was also agreed that Stephen Cannistra would serve as a scientific...murine models of ovarian and germ cell cancers; 5) testing a novel genetic pathway involving Lin28A /B and the tumor suppressor microRNA let-7 for roles

  18. Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy.

    PubMed

    McAuliffe, Shannon M; Morgan, Stefanie L; Wyant, Gregory A; Tran, Lieu T; Muto, Katherine W; Chen, Yu Sarah; Chin, Kenneth T; Partridge, Justin C; Poole, Barish B; Cheng, Kuang-Hung; Daggett, John; Cullen, Kristen; Kantoff, Emily; Hasselbatt, Kathleen; Berkowitz, Julia; Muto, Michael G; Berkowitz, Ross S; Aster, Jon C; Matulonis, Ursula A; Dinulescu, Daniela M

    2012-10-23

    Chemoresistance to platinum therapy is a major obstacle that needs to be overcome in the treatment of ovarian cancer patients. The high rates and patterns of therapeutic failure seen in patients are consistent with a steady accumulation of drug-resistant cancer stem cells (CSCs). This study demonstrates that the Notch signaling pathway and Notch3 in particular are critical for the regulation of CSCs and tumor resistance to platinum. We show that Notch3 overexpression in tumor cells results in expansion of CSCs and increased platinum chemoresistance. In contrast, γ-secretase inhibitor (GSI), a Notch pathway inhibitor, depletes CSCs and increases tumor sensitivity to platinum. Similarly, a Notch3 siRNA knockdown increases the response to platinum therapy, further demonstrating that modulation of tumor chemosensitivity by GSI is Notch specific. Most importantly, the cisplatin/GSI combination is the only treatment that effectively eliminates both CSCs and the bulk of tumor cells, indicating that a dual combination targeting both populations is needed for tumor eradication. In addition, we found that the cisplatin/GSI combination therapy has a synergistic cytotoxic effect in Notch-dependent tumor cells by enhancing the DNA-damage response, G(2)/M cell-cycle arrest, and apoptosis. Based on these results, we conclude that targeting the Notch pathway could significantly increase tumor sensitivity to platinum therapy. Our study suggests important clinical applications for targeting Notch as part of novel treatment strategies upon diagnosis of ovarian cancer and at recurrence. Both platinum-resistant and platinum-sensitive relapses may benefit from such an approach as clinical data suggest that all relapses after platinum therapy are increasingly platinum resistant.

  19. Interleukin-6 from Ovarian Mesenchymal Stem Cells Promotes Proliferation, Sphere and Colony Formation and Tumorigenesis of an Ovarian Cancer Cell Line SKOV3

    PubMed Central

    Ding, Dah-Ching; Liu, Hwan-Wun; Chu, Tang-Yuan

    2016-01-01

    The origin of the majority of epithelial ovarian cancers (EOC) is regarded as extraovarian, with the ovary being the secondary site. The aim of this study was to explore the possible role of ovarian mesenchymal stem cells (OvMSCs) and secreted IL-6 in the development of EOC. OvMSCs were derived from normal ovarian stroma. Cell surface markers and differentiation capability were determined. The effects of IL-6 and conditioned medium of OvMSCs on the malignant phenotype of SKOV3 ovarian cancer cells were tested, and the status of STAT3 and ERK phosphorylation was investigated. OvMSCs had similar surface marker profiles as bone marrow mesenchymal stem cells, i.e., CD44 (+), CD90 (+) and CD45 (-), and was readily inducible to osteogenic, adipogenic and chondrogenic differentiation. OvMSCs secreted an extremely high level (>2500 pg/ml) of IL-6. Treatment of SKOV3 cells with conditioned media from OvMSCs increased cell proliferation, tumor sphere formation and anchorage independent growth, and resulted in activation of STAT3 but not ERK. Coinjection of OvMSCs with SKOV3 cell enhanced tumorigenesis in NOD-SCID mice. All of these behaviors were blocked by IL-6 receptor blocking antibody administered in vitro or in vivo. The OvMSCs alone injected into mice had no tumor growth after 3 months. By secreting high levels of IL-6, OvMSCs enhance the proliferation, sphere and colony formation and tumorigenesis of SKOV3 cells. PMID:27698921

  20. Human endometrial mesenchymal stem cells exhibit intrinsic anti-tumor properties on human epithelial ovarian cancer cells

    PubMed Central

    Bu, Shixia; Wang, Qian; Zhang, Qiuwan; Sun, Junyan; He, Biwei; Xiang, Charlie; Liu, Zhiwei; Lai, Dongmei

    2016-01-01

    Epithelial ovarian cancer (EOC) is the most lethal tumor of all gynecologic tumors. There is no curative therapy for EOC thus far. The tumor-homing ability of adult mesenchymal stem cells (MSCs) provide the promising potential to use them as vehicles to transport therapeutic agents to the site of tumor. Meanwhile, studies have showed the intrinsic anti-tumor properties of MSCs against various kinds of cancer, including epithelial ovarian cancer. Human endometrial mesenchymal stem cells (EnSCs) derived from menstrual blood are a novel source for adult MSCs and exert restorative function in some diseases. Whether EnSCs endow innate anti-tumor properties on EOC cells has never been reported. By using tumor-bearing animal model and ex vivo experiments, we found that EnSCs attenuated tumor growth by inducing cell cycle arrest, promoting apoptosis, disturbing mitochondria membrane potential and decreasing pro-angiogenic ability in EOC cells in vitro and/or in vivo. Furthermore, EnSCs decreased AKT phosphorylation and promoted nuclear translocation of Forkhead box O-3a (FoxO3a) in EOC cells. Collectively, our findings elucidated the potential intrinsic anti-tumor properties of EnSCs on EOC cells in vivo and in vitro. This research provides a potential strategy for EnSC-based anti-cancer therapy against epithelial ovarian cancer. PMID:27845405

  1. Effect of the WWOX gene on the regulation of the cell cycle and apoptosis in human ovarian cancer stem cells.

    PubMed

    Yan, Hongchao; Tong, Jianye; Lin, Xiaoman; Han, Qiuyu; Huang, Hongxiang

    2015-08-01

    In order to examine new ideas for gene therapy in ovarian cancer, the specific mechanism underlying the effects of the WW domain containing oxidoreductase (WWOX) gene on cell cycle regulation and apoptosis in human ovarian cancer stem cells was investigated. Ovarian cancer stem cells were transfected with a eukaryotic expression vector carrying the WWOX gene in vitro (recombinant plasmid) and cells transfected with the empty plasmid (empty plasmid) or untransfected cells were used as controls. Stably transfected cells were screened and amplified in culture and the WWOX protein was detected by western blot analysis in the three groups of cells. Western blot analysis was performed to detect the expression of cell cycle regulatory proteins cyclin E, cyclin-dependent kinase (CDK) 2, cyclin D1, CDK4 and apoptosis-related protein Wnt-5α and c-Jun N-terminal kinase (JNK), while polymerase chain reaction (PCR) was used to detect alterations in the mRNA expression levels of caspase-3. The results demonstrated that the WWOX protein was stably expressed in cells of the recombinant plasmid group, but was not detected in cells of the empty plasmid group and the control group. Cell proliferation at each time point decreased significantly in the recombinant plasmid group compared with the empty plasmid group and the control group. Flow cytometric analysis demonstrated that the proportion of cells in the G0/G1 phase in the recombinant plasmid group was significantly higher than that of cells in the empty plasmid group and the control group. The rate of apoptosis in the recombinant plasmid group was significantly higher than that of cells in the empty plasmid group and the control group. Western blot analysis demonstrated that the expression levels of cyclin E, CDK2, cyclin D1 and CDK4 in the recombinant plasmid group were significantly lower than those in the empty plasmid group and the control group; however, the expression levels of Wnt-5α and JNK were significantly higher

  2. Leptin stimulates migration and invasion and maintains cancer stem-like properties in ovarian cancer cells: an explanation for poor outcomes in obese women.

    PubMed

    Kato, Sumie; Abarzua-Catalan, Lorena; Trigo, César; Delpiano, Ana; Sanhueza, Cristobal; García, Karen; Ibañez, Carolina; Hormazábal, Katherine; Diaz, Daniela; Brañes, Jorge; Castellón, Enrique; Bravo, Erasmo; Owen, Gareth; Cuello, Mauricio A

    2015-08-28

    The evidence linking obesity with ovarian cancer remains controversial. Leptin is expressed at higher levels in obese women and stimulates cell migration in other epithelial cancers. Here, we explored the clinical impact of overweight/obesity on patient prognosis and leptin's effects on the metastatic potential of ovarian cancer cells. We assessed clinical outcomes in 70 ovarian cancer patients (33 healthy weight and 37 overweight) that were validated with an external cohort from The Cancer Genome Atlas (TCGA) database. Progression-free and overall survival rates were significantly decreased in overweight patients. Similarly, a worse overall survival rate was found in TCGA patients expressing higher leptin/OB-Rb levels. We explored serum and ascites leptin levels and OB-Rb expression in our cohort. Serum and ascites leptin levels were higher in overweight patients experiencing worse survival. OB-Rb was more highly expressed in ascites and metastases than in primary tumors. Leptin exposure increased cancer cell migration/invasion through leptin-mediated activation of JAK/STAT3, PI3/AKT and RhoA/ROCK and promoted new lamellipodial, stress-fiber and focal adhesion formation. Leptin also contributed to the maintenance of stemness and the mesenchymal phenotype in ovarian cancer cells. Our findings demonstrate that leptin stimulated ovarian cancer cell migration and invasion, offering a potential explanation for the poor prognosis among obese women.

  3. Leptin stimulates migration and invasion and maintains cancer stem-like properties in ovarian cancer cells: an explanation for poor outcomes in obese women

    PubMed Central

    Kato, Sumie; Abarzua-Catalan, Lorena; Trigo, César; Delpiano, Ana; Sanhueza, Cristobal; García, Karen; Ibañez, Carolina; Hormazábal, Katherine; Diaz, Daniela; Brañes, Jorge; Castellón, Enrique; Bravo, Erasmo; Owen, Gareth; Cuello, Mauricio

    2015-01-01

    The evidence linking obesity with ovarian cancer remains controversial. Leptin is expressed at higher levels in obese women and stimulates cell migration in other epithelial cancers. Here, we explored the clinical impact of overweight/obesity on patient prognosis and leptin's effects on the metastatic potential of ovarian cancer cells. We assessed clinical outcomes in 70 ovarian cancer patients (33 healthy weight and 37 overweight) that were validated with an external cohort from The Cancer Genome Atlas (TCGA) database. Progression-free and overall survival rates were significantly decreased in overweight patients. Similarly, a worse overall survival rate was found in TCGA patients expressing higher leptin/OB-Rb levels. We explored serum and ascites leptin levels and OB-Rb expression in our cohort. Serum and ascites leptin levels were higher in overweight patients experiencing worse survival. OB-Rb was more highly expressed in ascites and metastases than in primary tumors. Leptin exposure increased cancer cell migration/invasion through leptin-mediated activation of JAK/STAT3, PI3/AKT and RhoA/ROCK and promoted new lamellipodial, stress-fiber and focal adhesion formation. Leptin also contributed to the maintenance of stemness and the mesenchymal phenotype in ovarian cancer cells. Our findings demonstrate that leptin stimulated ovarian cancer cell migration and invasion, offering a potential explanation for the poor prognosis among obese women. PMID:26053184

  4. NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer through inactivating Gadd45 pathway.

    PubMed

    Jinawath, N; Vasoontara, C; Yap, K-L; Thiaville, M M; Nakayama, K; Wang, T-L; Shih, I-M

    2009-05-07

    Nucleus accumbens-1 (Nac1 or NAC-1) belongs to the BTB/POZ (Pox virus and Zinc finger/Bric-a-brac Tramtrack Broad complex) transcription factor family and is a novel protein that potentially participates in self-renewal and pluripotency in embryonic stem cells. In human cancer, NAC-1 is upregulated in several types of neoplasms, but particularly in recurrent chemoresistant ovarian carcinomas, suggesting a biological role for NAC-1 in the development of drug resistance in ovarian cancer. We have assessed this possibility and shown a correlation between NAC-1 expression and ex vivo paclitaxel resistance in ovarian serous carcinoma tissues and cell lines. We found that expression of Gadd45-gamma-interacting protein 1 (Gadd45gip1), a downstream target negatively regulated by NAC-1, was reduced in paclitaxel-resistant cells. Ectopic expression of NAC-1 or knockdown of Gadd45gip1 conferred paclitaxel resistance, whereas NAC-1 knockdown or ectopic expression of Gadd45gip1 increased paclitaxel sensitivity. Furthermore, silencing NAC-1 expression or disrupting NAC-1 homodimerization by a dominant negative NAC-1 protein that contained only the BTB/POZ domain induced the expression of Gadd45gamma, which interacted with Gadd45gip1. Reducing Gadd45gamma expression by small hairpin RNAs partially enhanced paclitaxel resistance. Thus, this study provides new evidence that NAC-1 upregulation and homodimerization contribute to tumor recurrence by equipping ovarian cancer cells with the paclitaxel-resistant phenotype through negative regulation of the Gadd45 pathway.

  5. Inhibition of Aurora-A kinase induces cell cycle arrest in epithelial ovarian cancer stem cells by affecting NFĸB pathway.

    PubMed

    Chefetz, Ilana; Holmberg, Jennie C; Alvero, Ayesha B; Visintin, Irene; Mor, Gil

    2011-07-01

    Recurrent ovarian cancer is resistant to conventional chemotherapy. A sub-population of ovarian cancer cells, the epithelial ovarian cancer stem cells (EOC stem cells) have stemness properties, constitutive NFκB activity, and represent the chemoresistant population. Currently, there is no effective treatment that targets these cells. Aurora-A kinase (Aurora-A) is associated with tumor initiation and progression and is overexpressed in numerous malignancies. The aim of this study is to determine the effect of Aurora-A inhibition in EOC stem cells. EOC stem cells were treated with the Aurora-A inhibitor, MK-5108. Cell growth was monitored by Incucyte real-time imaging system, cell viability was measured using the Celltiter 96 assay and cytokine levels were quantified using xMAP technology. The intracellular changes associated with MK-5108 treatment are: (1) polyploidy and cell cycle arrest; (2) inhibition of NFκB activity; (3) decreased cytokine production; and (4) nuclear accumulation of IκBα. Thus, inhibition of Aurora-A decreases cell proliferation in the EOC stem cells by inducing cell cycle arrest and affecting the NFκB pathway. As EOC stem cells represent a source of recurrence and chemoresistance, these results suggest that Aurora-A inhibition may effectively target the cancer stem cell population in ovarian cancer.

  6. Familial ovarian cancer.

    PubMed Central

    Elit, L.

    2001-01-01

    OBJECTIVE: To assist family physicians in evaluating patients' risk for hereditary ovarian cancer and to review strategies for preventing ovarian cancer. QUALITY OF EVIDENCE: The MEDLINE, EMBASE, CANCERLIT, and CINAHL databases were searched from 1970 to 1999 using key words related to hereditary ovarian cancer, screening, oral contraceptives, prophylactic oophorectomy, cancer worriers, satisfaction, and perceived risk. Recommendations in this paper are based on evidence from case-control and cohort studies and, where appropriate, consensus conferences. MAIN MESSAGE: Of all women who present with ovarian cancer, 20% have a family history of ovarian cancer and 8% carry a BRCA 1 or BRCA 2 mutation. Women who carry a BRCA 1 mutation have a 63% lifetime risk of developing ovarian cancer, and women who carry a BRCA 2 mutation have a 27% lifetime risk of developing ovarian cancer. Preventive strategies include screening (level 3 evidence for postmenopausal women and level 5 evidence for women with a family history of ovarian cancer), use of oral contraceptives (level 3 evidence for the general population and for mutation carriers), and prophylactic oophorectomy (level 3 evidence in first-degree relatives of patients with breast or ovarian cancer). CONCLUSION: Women who have a family history of ovarian cancer should be offered genetic counseling and discussion of various preventive strategies for minimizing their risk. PMID:11340759

  7. Ovarian cancer stem-like cells differentiate into endothelial cells and participate in tumor angiogenesis through autocrine CCL5 signaling.

    PubMed

    Tang, Shu; Xiang, Tong; Huang, Shuo; Zhou, Jie; Wang, Zhongyu; Xie, Rongkai; Long, Haixia; Zhu, Bo

    2016-06-28

    Cancer stem cells (CSCs) are well known for their self-regeneration and tumorigenesis potential. In addition, the multi-differentiation potential of CSCs has become a popular issue and continues to attract increased research attention. Recent studies demonstrated that CSCs are able to differentiate into functional endothelial cells and participate in tumor angiogenesis. In this study, we found that ovarian cancer stem-like cells (CSLCs) activate the NF-κB and STAT3 signal pathways through autocrine CCL5 signaling and mediate their own differentiation into endothelial cells (ECs). Our data demonstrate that CSLCs differentiate into ECs morphologically and functionally. Anti-CCL5 antibodies and CCL5-shRNA lead to markedly inhibit EC differentiation and the tube formation of CSLCs, both in vitro and in vivo. Recombinant human-CCL5 significantly promotes ovarian CSLCs that differentiate into ECs and form microtube network. The CCL5-mediated EC differentiation of CSLCs depends on binding to receptors, such as CCR1, CCR3, and CCR5. The results demonstrated that CCL5-CCR1/CCR3/CCR5 activates the NF-κB and STAT3 signal pathways, subsequently mediating the differentiation of CSLCs into ECs. Therefore, this study was conducted based on the theory that CSCs improve tumor angiogenesis and provides a novel strategy for anti-angiogenesis in ovarian cancer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  8. Co-expression of the Follicle Stimulating Hormone Receptor and Stem Cell Markers: A Novel Approach to Target Ovarian Cancer Stem Cells

    DTIC Science & Technology

    2013-09-01

    cautiously as a functional end point characteristic of ovarian cancer stem cells (Appendix I). 7 Year 2 1. Our veterinary staff has since...WTA system ® to amplify the RNA into a double stranded cDNA product. Real- time PCR using intron-spanning primers was carried out using a BioRad...mince, and digest in enzyme-free cell dissociation buffer (Gibco). This material has worked well for us with cultured cell expressing the FSHR and

  9. The impact of different extracellular matrices on melatonin effect in proliferation and stemness properties of ovarian cancer cells.

    PubMed

    Akbarzadeh, Maryam; Rahbarghazi, Reza; Nabat, Elahe; Movassaghpour, Ali Akbar; Shanehbandi, Daruish; Faramarzian Azimi Maragheh, Behnaz; Matluobi, Danial; Barazvan, Balal; Kazemi, Masoume; Samadi, Nasser; Nouri, Mohammad

    2017-03-01

    Endogenous melatonin has numerous physiological roles on modulating the function of different organs. Recent studies revealed oncostatic and protective effects of this molecule on tumor development. In this study, we examined the impact of melatonin and key underlying mechanisms on stemness, morphology, invasiveness and viability of SKOV3 ovarian cancer cells in different types of extracellular matrix. Cell viability was evaluated by MTT Assay. Colony-forming assay was performed by seeding 4×10(3) cells on different matrices in six well-plate. The percentage of cancer stem like cells was determined by flow cytometric assay after applying antibodies against stemness markers, CD133 and CD44. Different types of extracellular matrix including fibronectin, gelatin, collagen and matrigel were applied to incubate the cells in the presence of melatonin. Downstream gene expressions including VEGF and E-cadherin were determined by Real-time PCR. Melatonin (0.1mM) decreased the percentage of viable cells up to 61.79±8.2% (p<0.05). Colony formation assay revealed the significant impact of melatonin in inhibition of colony formation in these cells. The maximum effect was shown in the cells incubated with melatonin on gelatin (p<0.05). Identification of stemness markers showed that applying matrigel caused significant increase in the percentage of cancer stem like cells compared to other types of extracellular matrix (p<0.05). However melatonin slightly diminished the number of stem cell like cells in all incubated matrices. Our results from gene expression assays revealed that melatonin induced a marked increase in E-cadherin along with decrease in VEGF expression levels (p<0.05). Our results suggest that interaction between ovarian cancer cells and neighboring matrices determines the subsequent anti invasive activities of melatonin. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  10. Fusion-derived epithelial cancer cells express hematopoietic markers and contribute to stem cell and migratory phenotype in ovarian carcinoma.

    PubMed

    Ramakrishnan, Mallika; Mathur, Sandeep R; Mukhopadhyay, Asok

    2013-09-01

    For a long time, the external milieu of cancer cells was considered to be of secondary importance when compared with its intrinsic properties. That has changed now as the microenvironment is considered to be a major contributing factor toward the progression of tumor. In this study, we show that in human and mouse epithelial ovarian carcinoma and mouse lung carcinoma, the interaction between tumor-infiltrating hematopoietic cells and epithelial cancer cells results in their fusion. Intriguingly, even after the fusion event, cancer cells retain the expression of the pan-hematopoietic marker (CD45) and various markers of hematopoietic lineage, including those of hematopoietic stem cells, indicating that the hematopoietic genome is not completely reprogrammed. This observation may have implications on the bone marrow contribution to the cancer stem cell population. Interestingly, it was seen that in both cancer models, the expression of chemokine receptor CXCR4 was largely contributed to by the fused compartment of cancer cells. We hypothesize that the superior migratory potential gained by the cancer cells due to the fusion helps in its dissemination to various secondary organs upon activation of the CXCR4/CXCL12 axis. We are the first to report the presence of a hemato-epithelial cancer compartment, which contributes to stem cell markers and CXCR4 in epithelial carcinoma. This finding has repercussions on CXCR4-based therapeutics and opens new avenues in discovering novel molecular targets against fusion and metastasis.

  11. Mesenchymal stem cells enhance ovarian cancer cell infiltration through IL6 secretion in an amniochorionic membrane based 3D model.

    PubMed

    Touboul, Cyril; Lis, Raphael; Al Farsi, Halema; Raynaud, Christophe M; Warfa, Mohamed; Althawadi, Hamda; Mery, Eliane; Mirshahi, Massoud; Rafii, Arash

    2013-01-31

    The early peritoneal invasion of epithelial ovarian cancer (EOC) by tumoral aggregates presents in ascites is a major concern. The role of the microenvironment seems to be important in this process but the lack of adequate models to study cellular interactions between cancer cells and stromal cells does not allow to uncover the molecular pathways involved. Our goal was to study the interactions between ovarian cancer cells (OCC) and mesenchymal stem cells (MSC) using a 3D model. We used millimetric pieces of amniochorionic membrane - referred to as amniotic membrane scaffold (AMS) - to create 3D peritoneal nodules mimicking EOC early invasion. We were able to measure the distribution and the depth of infiltration using confocal microsopy. We extracted MSC from the amniochorionic membrane using the markers CD34-, CD45-, CD73+, CD90+, CD105+ and CD29+ at the Fluorescence Activated Cell Sorting (FACS) analysis. We used transwell and wound healing tests to test OCC migration and invasion in vitro. Here we show that OCC tumors were located in regions rich in MSC (70%). The tumors infiltrated deeper within AMS in regions rich in MSC (p<0.001). In vitro tests revealed that higher IL6 secretion in a context of MSC-OCC co-culture could enhance migration and invasion of OCC. After IL6 receptor antagonism, OCC infiltration was significantly decreased, mostly in regions rich in MSCs, indicating that recruitment and tridimensional invasion of OCC was dependent of IL6 secretion. The use of tridimensional models using AMS could be a useful tool to decipher early molecular events in ovarian cancer metastasis. Cytokine inhibitors interrupting the cross-talk between OCCs and MSCs such as IL6 should be investigated as a new therapeutic approach in ovarian cancer.

  12. The impact of novel retinoids in combination with platinum chemotherapy on ovarian cancer stem cells.

    PubMed

    Whitworth, Jenny M; Londoño-Joshi, Angelina I; Sellers, Jeffrey C; Oliver, Patsy J; Muccio, Donald D; Atigadda, Venkatram R; Straughn, J Michael; Buchsbaum, Donald J

    2012-04-01

    Retinoids are important modulators of cell growth, differentiation, and proliferation. 9cUAB30, 9cUAB124, and 9cUAB130 are three novel retinoid compounds that show cytotoxic effects in other malignancies. We evaluated these novel retinoids in combination with chemotherapy against ovarian cancer stem cells (CSCs) in vitro and in an ex vivo model. A2780 cells were plated in 96-well plates and treated with retinoid, carboplatin, or combination therapy. Cell viability was evaluated using ATPLite assay. The A2780 cell line was also analyzed for CSCs by evaluating ALDH activity using flow cytometry. A2780 cells treated ex vivo with retinoids and chemotherapy were injected into the flank of athymic nude mice in order to evaluate subsequent tumor initiating capacity. A2780 cells were sensitive to treatment with retinoids and carboplatin. The best treatment resulted from the combination of retinoid 9cUAB130 and carboplatin. Untreated A2780 cells demonstrated ALDH activity in 3.3% of the cell population. Carboplatin treatment enriched ALDH activity to 27.3%, while 9cUAB130±carboplatin maintained the ALDH positive levels similar to untreated controls (2.3% and 6.7%, respectively). Similar results were found in tumorsphere-forming conditions. Flank injections of ex vivo treated A2780 cells resulted in 4/4 mice developing tumors at 40 days in the untreated group, while 0/4 tumors developed in the 9cUAB130 and carboplatin treated group. Combination treatment with carboplatin and retinoids reduced cell-viability, reduced CSC marker expression, and inhibited tumorigenicity, making it a more effective treatment when compared with carboplatin alone. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Vitamin D3 stimulates embryonic stem cells but inhibits migration and growth of ovarian cancer and teratocarcinoma cell lines.

    PubMed

    Abdelbaset-Ismail, Ahmed; Pedziwiatr, Daniel; Suszyńska, Ewa; Sluczanowska-Glabowska, Sylwia; Schneider, Gabriela; Kakar, Sham S; Ratajczak, Mariusz Z

    2016-04-18

    Deficiency in Vitamin D3 (cholecalciferol) may predispose to some malignancies, including gonadal tumors and in experimental models vitamin D3 has been proven to inhibit the growth of cancer cells. To learn more about the potential role of vitamin D3 in cancerogenesis, we evaluated the expression and functionality of the vitamin D receptor (VDR) and its role in metastasis of ovarian cancer cells and of murine and human teratocarcinoma cell lines. In our studies we employed murine embrynic stem cells (ESD3), murine (P19) and human (NTERA-2) teratocarcimona cells lines, human ovarian cancer cells (A2780) as well as purified murine and human purified very small embryonic like stem cells (VSELs). We evaluated expression of Vitamin D3 receptor (VDR) in these cells as well as effect of vitamin D3 exposure on cell proliferation and migration. We here provide also more evidence for the role of vitamin D3 in germline-derived malignancies, and this evidence supports the proposal that vitamin D3 treatment inhibits growth and metastatic potential of several germline-derived malignancies. We also found that the ESD3 murine immortalized embryonic stem cell line and normal, pluripotent, germline-marker-positive very small embryonic-like stem cells (VSELs) isolated from adult tissues are stimulated by vitamin D3, which suggests that vitamin D3 affects the earliest stages of embryogenesis. We found that however all normal and malignant germ-line derived cells express functional VDR, Vitamin D3 differently affects their proliferation and migration. We postulate that while Vitamin D3 as anticancer drug inhibits proliferation of malignant cells, it may protect normal stem cells that play an important role in development and tissue/organ regeneration.

  14. Mesenchymal stem cell carriers protect oncolytic measles viruses from antibody neutralization in an orthotopic ovarian cancer therapy model

    PubMed Central

    Mader, Emily K; Maeyama, Yoshihiro; Lin, Yi; Butler, Greg W; Russell, Holly M; Galanis, Evanthia; Russell, Stephen J; Dietz, Allan B; Peng, Kah-Whye

    2009-01-01

    Purpose Pre-existing antiviral antibodies in cancer patients can quickly neutralize oncolytic measles virus (MV) and decrease its anti-tumor potency. In contrast to `naked' viruses, cell-associated viruses are protected from antibody neutralization. Hence, we hypothesized that measles virotherapy of ovarian cancer in measles immune mice might be superior if MV infected mesenchymal stem cell (MSC) carriers are used. Experimental Design Antimeasles antibodies titers in ovarian cancer patients were determined. The protection of MV by MSC from antimeasles antibodies, the in vivo biodistribution profiles and tumor infiltration capability of MSC were determined. Measles naïve or immune tumor-bearing mice were treated with naked virus or MSC-associated virus and mice survivals were compared. Results MSC transferred MV infection to target cells via cell-to-cell heterofusion and induced syncytia formation in the presence of high titers of antimeasles antibody; at levels which completely inactivated naked virus. Athymic mice bearing intraperitoneal human SKOV3ip.1 ovarian tumor xenografts passively immunized with measles immune human serum were treated with saline, naked MV or MV infected MSC. Bioluminescent and fluorescent imaging data indicated that intraperitoneally administered MSC localized to peritoneal tumors, infiltrated into the tumor parenchyma and transferred virus infection to tumors in measles naïve and passively immunized mice. Survival of the measles immune mice was significantly enhanced by treatment with MV-infected MSC. In contrast, survivals of passively immunized mice were not prolonged by treatment with naked virus or uninfected MSC. Conclusions MSC should be used as carriers of MV for intraperitoneal virotherapy in measles-immune ovarian cancer patients. PMID:19934299

  15. MEK1-independent activation of MAPK and MEK1-dependent activation of p70 S6 kinase by stem cell factor (SCF) in ovarian cancer cells

    SciTech Connect

    Liu, Lian; Zhang, Xin; Du, Chao; Zhang, Xiaoning; Hou, Nan; Zhao, Di; Sun, Jianzhi; Li, Li; Wang, Xiuwen; Ma, Chunhong

    2009-05-01

    We discovered a stem cell factor (SCF)-triggered, MEK1-independent, and PI3K-dependent MAPK activation pathway in the Kit-expressing ovarian cancer cell line HEY. When we knocked down MEK1 with RNA interference (RNAi) to study the function of MEK1 on the proliferation and survival of ovarian cancer cells, we found that impaired cell growth still occurred after MEK1 expression had been suppressed, although MAPK activation remained intact. This suggests that there is MEK1-independent activation of MAPK in the SCF-induced ovarian cancer cell growth process, and that MEK1 still plays a crucial role in maintaining the malignant properties of ovarian cancer cells even when it fails to activate MAPK as expected.

  16. Ovarian Cancer Stage II

    MedlinePlus

    ... hyphen, e.g. -historical Searches are case-insensitive Ovarian Cancer Stage II Add to My Pictures View /Download : ... 1650x675 View Download Large: 3300x1350 View Download Title: Ovarian Cancer Stage II Description: Three-panel drawing of stage ...

  17. Ovarian Cancer Stage I

    MedlinePlus

    ... hyphen, e.g. -historical Searches are case-insensitive Ovarian Cancer Stage I Add to My Pictures View /Download : ... 1650x675 View Download Large: 3300x1350 View Download Title: Ovarian Cancer Stage I Description: Three-panel drawing of stage ...

  18. Ovarian Cancer Stage IV

    MedlinePlus

    ... hyphen, e.g. -historical Searches are case-insensitive Ovarian Cancer Stage IV Add to My Pictures View /Download : ... 1200x1335 View Download Large: 2400x2670 View Download Title: Ovarian Cancer Stage IV Description: Drawing of stage IV shows ...

  19. Ovarian Cancer Stage IIIC

    MedlinePlus

    ... hyphen, e.g. -historical Searches are case-insensitive Ovarian Cancer Stage IIIC Add to My Pictures View /Download : ... 1530x1350 View Download Large: 3060x2700 View Download Title: Ovarian Cancer Stage IIIC Description: Drawing of stage IIIC shows ...

  20. ALDH1A1 Maintains Ovarian Cancer Stem Cell-Like Properties by Altered Regulation of Cell Cycle Checkpoint and DNA Repair Network Signaling

    PubMed Central

    Meng, Erhong; Mitra, Aparna; Tripathi, Kaushlendra; Finan, Michael A.; Scalici, Jennifer; McClellan, Steve; da Silva, Luciana Madeira; Reed, Eddie; Shevde, Lalita A.; Palle, Komaraiah; Rocconi, Rodney P.

    2014-01-01

    Objective Aldehyde dehydrogenase (ALDH) expressing cells have been characterized as possessing stem cell-like properties. We evaluated ALDH+ ovarian cancer stem cell-like properties and their role in platinum resistance. Methods Isogenic ovarian cancer cell lines for platinum sensitivity (A2780) and platinum resistant (A2780/CP70) as well as ascites from ovarian cancer patients were analyzed for ALDH+ by flow cytometry to determine its association to platinum resistance, recurrence and survival. A stable shRNA knockdown model for ALDH1A1 was utilized to determine its effect on cancer stem cell-like properties, cell cycle checkpoints, and DNA repair mediators. Results ALDH status directly correlated to platinum resistance in primary ovarian cancer samples obtained from ascites. Patients with ALDHHIGH displayed significantly lower progression free survival than the patients with ALDHLOW cells (9 vs. 3 months, respectively p<0.01). ALDH1A1-knockdown significantly attenuated clonogenic potential, PARP-1 protein levels, and reversed inherent platinum resistance. ALDH1A1-knockdown resulted in dramatic decrease of KLF4 and p21 protein levels thereby leading to S and G2 phase accumulation of cells. Increases in S and G2 cells demonstrated increased expression of replication stress associated Fanconi Anemia DNA repair proteins (FANCD2, FANCJ) and replication checkpoint (pS317 Chk1) were affected. ALDH1A1-knockdown induced DNA damage, evidenced by robust induction of γ-H2AX and BAX mediated apoptosis, with significant increases in BRCA1 expression, suggesting ALDH1A1-dependent regulation of cell cycle checkpoints and DNA repair networks in ovarian cancer stem-like cells. Conclusion This data suggests that ovarian cancer cells expressing ALDH1A1 may maintain platinum resistance by altered regulation of cell cycle checkpoint and DNA repair network signaling. PMID:25216266

  1. Nintedanib in ovarian cancer.

    PubMed

    Khalique, Saira; Banerjee, Susana

    2017-09-01

    Advanced ovarian cancer remains an unmet clinical need. Angiogenesis is considered a therapeutic target in ovarian cancer, with bevacizumab, a monoclonal antibody against VEGF, being the first drug to show a progression-free survival benefit. Nintedanib is an oral tyrosine kinase inhibitor targeting VEGF receptor 1-3, FGFR 1-3 and PDGFR α and β, which has entered phase III trial development in ovarian cancer. Areas covered: This article reviews the preclinical and clinical efficacy of nintedanib in ovarian cancer, its pharmacokinetic and pharmacodynamics profile, safety issues, together with an overview of clinical trials carried out so far. A literature search was made in PubMed for nintedanib, ovarian cancer, angiogenesis, and on ClinicalTrials.gov site for clinical trials with nintedanib. Expert opinion: An ongoing phase III trial investigating nintedanib combined with first-line chemotherapy in ovarian cancer has shown a statistically significant progression free survival benefit, although there were toxicity issues. The true clinical benefit of nintedanib in ovarian cancer including its optimal treatment setting and dosage still need to be addressed.

  2. The role of cancer vaccines following autologous stem cell rescue in breast and ovarian cancer patients: experience with the STn-KLH vaccine (Theratope).

    PubMed

    Holmberg, Leona A; Oparin, Dimitri V; Gooley, Ted; Sandmaier, Brenda M

    2003-02-01

    The success of high-dose chemotherapy followed by autologous stem-cell rescue as treatment for breast and ovarian cancer is limited by a high incidence of relapse. After autologous transplantation, patients are likely to have a low tumor burden and thus would be more likely to respond immunologically to a cancer vaccine. Sialyl-Tn (STn) is a carbohydrate associated with the MUC1 mucin on breast and ovarian cancer and is an ideal candidate for vaccine immunotherapy. Sialyl-Tn-keyhole limpet hemocyanin (STn-KLH) vaccine (Theratope) incorporates a synthetic STn antigen that mimics the unique tumor-associated STn carbohydrate and is designed to stimulate tumor antigen-specific immune responses in patients with mucin-expressing tumors. Between 1995 and 2000, 70 patients (16 with stage II/III breast cancer, 17 with stage III/IV ovarian cancer, and 37 with stage IV breast cancer) were treated with 2 different formulations of STn-KLH. Toxicity, outcome, and immune response data are reported. STn-KLH was well-tolerated with minimal toxicity. The most common side effects were indurations and erythema at the sites of injections. Humoral and cellular responses were elicited in the majority of patients. Overall, these data indicate that post-autologous transplant patients are able to mount an effective immune response to vaccine immunotherapy with minimal side effects, and that vaccine immunotherapy may be a useful addition to high-dose chemotherapy regimens.

  3. Ferritin heavy chain is a negative regulator of ovarian cancer stem cell expansion and epithelial to mesenchymal transition

    PubMed Central

    Pisanu, Maria Elena; Faniello, Maria Concetta; Jakopin, Žiga; Chiarella, Emanuela; Giovannone, Emilia Dora; Mancini, Rita; Ciliberto, Gennaro

    2016-01-01

    Objectives Ferritin is the major intracellular iron storage protein essential for maintaining the cellular redox status. In recent years ferritin heavy chain (FHC) has been shown to be involved also in the control of cancer cell growth. Analysis of public microarray databases in ovarian cancer revealed a correlation between low FHC expression levels and shorter survival. To better understand the role of FHC in cancer, we have silenced the FHC gene in SKOV3 cells. Results FHC-KO significantly enhanced cell viability and induced a more aggressive behaviour. FHC-silenced cells showed increased ability to form 3D spheroids and enhanced expression of NANOG, OCT4, ALDH and Vimentin. These features were accompanied by augmented expression of SCD1, a major lipid metabolism enzyme. FHC apparently orchestrates part of these changes by regulating a network of miRNAs. Methods FHC-silenced and control shScr SKOV3 cells were monitored for changes in proliferation, migration, ability to propagate as 3D spheroids and for the expression of stem cell and epithelial-to-mesenchymal-transition (EMT) markers. The expression of three miRNAs relevant to spheroid formation or EMT was assessed by q-PCR. Conclusions In this paper we uncover a new function of FHC in the control of cancer stem cells. PMID:27566559

  4. Identification of Small Molecule Inhibitors of microRNA Involved in Chemoresistance and Cancer Stem Cells for Ovarian Cancer Intervention

    DTIC Science & Technology

    2012-03-01

    characteristics and prostate cancer resistance to androgen dep- rivation. Oncogene 30, 3833–3845 16. Leis, O., Eguiara, A., Lopez -Arribillaga, E., Alberdi...Yang, K., Bai, S., Cabrera , L., Keller, E., McCauley, L., Cho, K. R., and Buckanovich, R. J. (2011) Human ovarian carcinoma-associated mesenchymal

  5. Ovarian Cancer: Nutrition

    MedlinePlus

    ... and phytochemicals. High fiber intakes may have a positive benefit by altering hormonal actions of ovarian and other hormonal-dependent cancers. Daily fiber intake should be 25-35 grams of insoluble and soluble fiber. Important Plant Sources ...

  6. Genetic Modifiers of Ovarian Cancer

    DTIC Science & Technology

    2013-06-01

    cancer suggesting the presence of genetic modifiers of ovarian cancer in this population. A genome wide association study ( GWAS ) for ovarian cancer...cancer and 1,000 age-matched unaffected BRCA1 carriers. As outlined in detail in our previous annual report, we recently conducted a GWAS of BRCA1...between ovarian cancer risk and SNPs implicated in Aim 1 by genotyping 1,500 BRCA1 ovarian cancer cases and 1,500 unaffected BRCA1 carriers. GWAS

  7. Effects and mechanism of RhoC downregulation in suppressing ovarian cancer stem cell proliferation, drug resistance, invasion and metastasis.

    PubMed

    Sang, Xiu-Bo; Sun, Kai-Xuan; Wang, Li-Li; Chen, Shuo; Wu, Dan-Dan; Zong, Zhi-Hong; Zhao, Yang

    2016-12-01

    Cancer stem cells are considered to be the root cause of tumor initiation, metastasis, recurrence and therapeutic resistance. Recent studies have reported that RhoC plays a critical role in regulating cancer stem cells; however, its function in ovarian cancer stem cells (OCSCs) remains unknown. The ovarian cancer cell line A2780, and the paclitaxel-resistant A2780 cell line (A2780-PTX) were obtained. A2780 cells were used to isolate and identify the highly invasive A2780-PM cells, and A2780-PTX cells were used to isolate and identify the highly drug-resistant and highly invasive A2780-PTX-PM cells by Transwell assay. MTT, Transwell and wound healing assays were used to compare the differences in cell proliferation, invasion and migration ability among the four cell lines. Immunofluorescence was used to detect the expression of stem cell markers CD117 and CD133. OCSCs were sorted by flow cytometry. Following si-RhoC transfection of the OCSCs, cell proliferation, drug resistance, invasion and migration ability and RhoC, CD117 and CD133 expression levels were assayed. RT-PCR was used to assess RhoC, CD117, CD133 and matrix metalloproteinase 9 (MMP9) mRNA expression levels. A2780-PM and A2780‑PTX-PM cells exhibited higher cell proliferation, drug resistance, and invasion and migration ability than the A2780 and A2780-PTX cell lines. Furthermore, CD133 and CD117 expression levels were higher in the A2780-PM and A2780‑PTX-PM cells than levels in the A2780 and A2780-PTX cells. Transfection of si-RhoC in OCSCs suppressed the proliferation, drug resistance, invasion, migration and CD117 and CD133 expression levels. Furthermore, the expression levels of RhoC, CD117, CD133, MDR1, and MMP9 mRNA were downregulated in the transfected population. Taken together, our results demonstrated that RhoC downregulation may inhibit the proliferation, drug resistance, invasion and migration of OCSCs, and RhoC may play an important role in the formation of OCSCs.

  8. Re-purposing of curcumin as an anti-metastatic agent for the treatment of epithelial ovarian cancer: in vitro model using cancer stem cell enriched ovarian cancer spheroids

    PubMed Central

    He, Misi; Wang, Dong; Zou, Dongling; Wang, Chen; Lopes-Bastos, Bruno; Jiang, Wen G.; Chester, John; Zhou, Qi; Cai, Jun

    2016-01-01

    Malignant epithelial ovarian cancer (EOC) spheroids high frequently are detected in the malignant ascites of the patients with the extensive peritoneal metastasis of ovarian cancer, which represent a significant obstacle to efficacious treatment. Clinical data also suggested that EOC spheroids play a putative role in the development of chemoresistance. Since standard surgery and conventional chemotherapy is the only available treatment, there is an urgent need to identify a more effective therapeutic strategy. Recent studies demonstrated that curcumin exerts an anticancer effect in a variety of human cancers including ovarian cancer. This study evaluates anti-peritoneal metastasis and chemoresistance of curcumin related to the EOC spheroids. In this study, we confirm that the high invasive EOC cells forming the spheroids express a high level of a cancer stem cell (CSC) marker, aldehyde dehydrogenase 1 family member A1 (ALDH1A1), which was significantly down-regulated by curcumin treatment. Curcumin treatment markedly enhances the sensitivity of EOC spheroids to cisplatin in a dose-dependent manner. Our experiments provided evidence that curcumin could abolish the sphere-forming capacity of EOC cells in a dose-dependent manner. Moreover, curcumin substantially suppressed the growth of the pre-existed EOC spheroids, inhibited the adhesion of EOC spheroids to ECM as well as the invasion of EOC spheroids to the mesothelial monolayers. We propose to re-purpose curcumin as anti-metastatic and chemoresistant agent for EOC management in combination with conventional regimen. Further preclinical studies are necessary to validate the anti-cancer effect of curcumin in patients with EOC. PMID:27863439

  9. Hereditary ovarian cancer.

    PubMed

    Russo, Antonio; Calò, Valentina; Bruno, Loredana; Rizzo, Sergio; Bazan, Viviana; Di Fede, Gaetana

    2009-01-01

    At least 10% of ovarian tumors are hereditary and associated with highly penetrant, autosomal, dominant genetic predisposition. Three clinical manifestations of hereditary ovarian cancer have been identified: site-specific ovarian cancer, hereditary breast and/or ovarian cancer (HBOC) and hereditary non-polyposis colorectal cancer (HNPCC) syndromes. BRCA germline mutations account for more than 90% of all hereditary epithelial ovarian tumors whereas most of the remaining 10% are caused by MLH1 and MSH2 mutations, which are susceptibility genes of HNPCC. Genetic testing is available for each of the three hereditary syndromes above mentioned. The recommendations for OC surveillance in high-risk women having a strong family history or BRCA mutation carriers include transvaginal pelvic ultrasound with color Doppler and serum CA125 every 6 months. Bilateral salpingo-oophorectomy appears to be effective to reduce the risk of ovarian cancer in BRCA mutation carriers. Hysterosalpingo-oophorectomy should be considered in HNPCC women who undergo surgery for colorectal carcinoma.

  10. MicroRNA-136 inhibits cancer stem cell activity and enhances the anti-tumor effect of paclitaxel against chemoresistant ovarian cancer cells by targeting Notch3.

    PubMed

    Jeong, Ju-Yeon; Kang, Haeyoun; Kim, Tae Hoen; Kim, Gwangil; Heo, Jin-Hyung; Kwon, Ah-Young; Kim, Sewha; Jung, Sang-Geun; An, Hee-Jung

    2017-02-01

    To identify microRNAs (miRNAs) regulating Notch3 expression in association with paclitaxel resistance, candidate miRNAs targeting Notch3 were predicted using TargetScan. We found that miR-136 directly targets Notch3, and miR-136 was significantly downregulated in OSC tissues relative to normal control tissues, and low expression of miR-136 correlated with poor overall in ovarian cancer patients. Artificial miR-136 overexpression significantly reduced cell viability, proliferation, Cancer stem cell (CSC) spheroid formation, and angiogenesis, and increased apoptosis in paclitaxel-resistant SKpac cells compared with the effects of paclitaxel alone. miR-136 overexpression downregulated cell survival- (survivin, DNA-PK, pS6, S6) and cell cycle- (Cyclin D1, NF-κB) related proteins, and anti-apoptotic proteins (BCL2, and BCL-XL), and upregulated pro-apoptotic proteins (Bim, Bid, and Bax). Taken together, miR-136 targets the Notch3 oncogene and functions as a tumor suppressor. miR-136 overexpression resensitized paclitaxel-resistant ovarian cancer cells and reduced CSC activities, suggesting a promising new target for the treatment of chemoresistant ovarian cancers. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Withaferin A Alone and in Combination with Cisplatin Suppresses Growth and Metastasis of Ovarian Cancer by Targeting Putative Cancer Stem Cells

    PubMed Central

    Kakar, Sham S.; Ratajczak, Mariusz Z.; Powell, Karen S.; Moghadamfalahi, Mana; Miller, Donald M.; Batra, Surinder K.; Singh, Sanjay K.

    2014-01-01

    Currently, the treatment for ovarian cancer entails cytoreductive surgery followed by chemotherapy, mainly, carboplatin combined with paclitaxel. Although this regimen is initially effective in a high percentage of cases, unfortunately within few months of initial treatment, tumor relapse occurs because of platinum-resistance. This is attributed to chemo-resistance of cancer stem cells (CSCs). Herein we show for the first time that withaferin A (WFA), a bioactive compound isolated from the plant Withania somnifera, when used alone or in combination with cisplatin (CIS) targets putative CSCs. Treatment of nude mice bearing orthotopic ovarian tumors generated by injecting human ovarian epithelial cancer cell line (A2780) with WFA and cisplatin (WFA) alone or in combination resulted in a 70 to 80% reduction in tumor growth and complete inhibition of metastasis to other organs compared to untreated controls. Histochemical and Western blot analysis of the tumors revealed that inclusion of WFA (2 mg/kg) resulted in a highly significant elimination of cells expressing CSC markers - CD44, CD24, CD34, CD117 and Oct4 and downregulation of Notch1, Hes1 and Hey1 genes. In contrast treatment of mice with CIS alone (6 mg/kg) had opposite effect on those cells. Increase in cells expressing CSC markers and Notch1 signaling pathway in tumors exposed to CIS may explain recurrence of cancer in patients treated with carboplatin and paclitaxel. Since, WFA alone or in combination with CIS eliminates putative CSCs, we conclude that WFA in combination with CIS may present more efficacious therapy for ovarian cancer. PMID:25264898

  12. Ixabepilone and Liposomal Doxorubicin in Advanced Ovarian Cancer

    ClinicalTrials.gov

    2016-02-11

    Fallopian Tube Cancer; Female Reproductive Cancer; Recurrent Breast Cancer; Recurrent Ovarian Epithelial Cancer; Stage III Ovarian Epithelial Cancer; Stage IV Breast Cancer; Stage IV Ovarian Epithelial Cancer

  13. Symptoms of Ovarian Cancer

    MedlinePlus

    ... Statistics Rates by Race and Ethnicity Rates by State Trends Related Links Ovarian Cancer Basic Information What Are the Risk Factors? What Can ... Statistics Rates by Race and Ethnicity Rates by State Trends Related Links Uterine Cancer Basic Information What Are the Risk Factors? What Can ...

  14. Cell of Origin: Exploring an Alternative Contributor to Ovarian Cancer

    DTIC Science & Technology

    2014-09-01

    Our studies to date have determined that human oogonial stem cells , while far less stable than their murine counterparts, can be successfully expanded...DNA signature of the oogonial stem cell -derived tumors to that of primary human ovarian cancer. We have also successfully introduced in human...oogonial stem cells genetic alterations commonly detected in ovarian cancer. We are now generating tumors from these altered oogonial stem cells and will

  15. Screening for ovarian cancer.

    PubMed

    Menon, Usha; Jacobs, Ian

    2002-08-01

    There has been considerable interest in the prospect of early detection of ovarian cancer through screening asymptomatic women, in both the general and 'high-risk' populations. Over the last decade screening strategies using the serum marker CA126 and transvaginal ultrasound have been refined and encouraging data have emerged on the impact of screening on ovarian cancer survival rates. Two randomized controlled trials are now underway in the general population to establish the impact of screening on ovarian cancer mortality while comprehensively tackling the issues of compliance, health economics and physical and psychological morbidity. In addition, trials in the high-risk population aimed at optimizing the current strategy have commenced in both the USA and the UK.

  16. Effect of targeted ovarian cancer therapy using amniotic fluid mesenchymal stem cells transfected with enhanced green fluorescent protein-human interleukin-2 in vivo

    PubMed Central

    YOU, QI; YAO, YUAN; ZHANG, YUANLONG; FU, SONGBIN; DU, MEI; ZHANG, GUANGMEI

    2015-01-01

    The aim of the present study was to investigate the effect of using amniotic fluid mesenchymal stem cells (AF-MSCs) in targeted ovarian cancer therapy in vivo. AF-MSCs were isolated from human second trimester AF and a plasmid, enhanced green fluorescent protein-human interleukin-2 (pEGFP-hIL-2) was formed. The plasmid was stably transfected into the AF-MSCs and the cells were intravenously injected into ovarian cancer nude mice models. Following stable transfection of the vector, tumor formation, and the expression and activity of hIL-2 were investigated, and microscopic pathological examinations of the tumor were performed. It was found that AF-MSCs exhibited high motility during migration in vivo, and the vector, pEGFP-hIL-2 can be stably transfected into AF-MSCs. Following stable transfection, this type of stem cell is able to successfully transport the therapeutic gene, IL-2, migrate to the ovarian cancer tumor site to secrete the functional IL-2 and treat the tumor. Thus, AF-MSCs may serve as transporters for therapeutic genes targeting ovarian tumor sites and, therefore, be involved in the treatment of tumors. PMID:26179662

  17. Effect of targeted ovarian cancer therapy using amniotic fluid mesenchymal stem cells transfected with enhanced green fluorescent protein-human interleukin-2 in vivo.

    PubMed

    You, Qi; Yao, Yuan; Zhang, Yuanlong; Fu, Songbin; Du, Mei; Zhang, Guangmei

    2015-10-01

    The aim of the present study was to investigate the effect of using amniotic fluid mesenchymal stem cells (AF-MSCs) in targeted ovarian cancer therapy in vivo. AF-MSCs were isolated from human second trimester AF and a plasmid, enhanced green fluorescent protein‑human interleukin‑2 (pEGFP‑hIL‑2) was formed. The plasmid was stably transfected into the AF‑MSCs and the cells were intravenously injected into ovarian cancer nude mice models. Following stable transfection of the vector, tumor formation, and the expression and activity of hIL‑2 were investigated, and microscopic pathological examinations of the tumor were performed. It was found that AF‑MSCs exhibited high motility during migration in vivo, and the vector, pEGFP‑hIL‑2 can be stably transfected into AF‑MSCs. Following stable transfection, this type of stem cell is able to successfully transport the therapeutic gene, IL-2, migrate to the ovarian cancer tumor site to secrete the functional IL-2 and treat the tumor. Thus, AF-MSCs may serve as transporters for therapeutic genes targeting ovarian tumor sites and, therefore, be involved in the treatment of tumors.

  18. Perspective in infertility: the ovarian stem cells.

    PubMed

    Silvestris, Erica; D'Oronzo, Stella; Cafforio, Paola; D'Amato, Giuseppe; Loverro, Giuseppe

    2015-08-07

    Infertility is a medical and social condition that affects millions of women worldwide and is today considered so far as a new disease. A considerable progress has been recently pursued in the field of the reproductive medicine and the infertility treatment may account for novel and modern procedures such as in vitro oocyte fertilization, egg donation, pregnancy surrogacy and preimplantation diagnosis. However, great interest has lately been reserved to the ovarian stem cells (OSCs) whose existence in woman ovaries has been proven. OSCs are thus suitable for developmental studies in infertility and in other clinical applications as endocrine derangements due to premature ovarian failure, or for infertility treatment after cancer chemotherapies, as well as in restoring the hormonal balance in postmenopausal age.

  19. Intraperitoneal delivery of a novel liposome-encapsulated paclitaxel redirects metabolic reprogramming and effectively inhibits cancer stem cells in Taxol(®)-resistant ovarian cancer.

    PubMed

    Shen, Yao-An; Li, Wai-Hou; Chen, Po-Hung; He, Chun-Lin; Chang, Yen-Hou; Chuang, Chi-Mu

    2015-01-01

    Taxol(®) remained as the mainstay therapeutic agent in the treatment of ovarian cancer, however recurrence rate is still high. Cancer stem cells (CSCs) represent a subset of cells in the bulk of tumors and play a central role in inducing drug resistance and recurrence. Furthermore, cancer metabolism has been an area under intensive investigation, since accumulating evidence has shown that CSCs and cancer metabolism are closely linked, an effect named as metabolic reprogramming. In this work, we aimed to investigate the impacts of a novel liposome-encapsulated paclitaxel (Nano-Taxol) on the stemness phenotype and metabolic reprogramming. A paclitaxel-resistant cell line (TR) was established at first. Tumor growth was induced in the mice peritoneal cavity by inoculation of TR cells. A 2x2 factorial experiment was designed to test the therapeutic efficacy in which factor 1 represented the comparison of drugs (Taxol(®) versus Nano-Taxol), while factor 2 represented the delivery route (intravenous versus intraperitoneal delivery). In this work, we found that intraperitoneal delivery of Nano-Taxol redirects metabolic reprogramming, from glycolysis to oxidative phosphorylation, and effectively suppresses cancer stem cells. Also, intraperitoneal delivery of Nano-Taxol led to a significantly better control of tumor growth compared with intravenous delivery of Taxol(®) (current standard treatment). This translational research may serve as a novel pathway for the drug development of nanomedicine. In the future, this treatment modality may be extended to treat several relevant cancers that have been proved to be suitable for the loco-regional delivery of therapeutic agents, including colon cancer, gastric cancer, and pancreatic cancer.

  20. Genetics Home Reference: ovarian cancer

    MedlinePlus

    ... body are called metastatic cancers. Some ovarian cancers cluster in families. These cancers are described as hereditary ... during a person's lifetime, and they do not cluster in families. A predisposition to cancer caused by ...

  1. Knockdown of stem cell regulator Oct4A in ovarian cancer reveals cellular reprogramming associated with key regulators of cytoskeleton-extracellular matrix remodelling

    PubMed Central

    Samardzija, Chantel; Greening, David W.; Escalona, Ruth; Chen, Maoshan; Bilandzic, Maree; Luwor, Rodney; Kannourakis, George; Findlay, Jock K.; Ahmed, Nuzhat

    2017-01-01

    Oct4A is a master regulator of self-renewal and pluripotency in embryonic stem cells. It is a well-established marker for cancer stem cell (CSC) in malignancies. Recently, using a loss of function studies, we have demonstrated key roles for Oct4A in tumor cell survival, metastasis and chemoresistance in in vitro and in vivo models of ovarian cancer. In an effort to understand the regulatory role of Oct4A in tumor biology, we employed the use of an ovarian cancer shRNA Oct4A knockdown cell line (HEY Oct4A KD) and a global mass spectrometry (MS)-based proteomic analysis to investigate novel biological targets of Oct4A in HEY samples (cell lysates, secretomes and mouse tumor xenografts). Based on significant differential expression, pathway and protein network analyses, and comprehensive literature search we identified key proteins involved with biologically relevant functions of Oct4A in tumor biology. Across all preparations of HEY Oct4A KD samples significant alterations in protein networks associated with cytoskeleton, extracellular matrix (ECM), proliferation, adhesion, metabolism, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and drug resistance was observed. This comprehensive proteomics study for the first time presents the Oct4A associated proteome and expands our understanding on the biological role of this stem cell regulator in carcinomas. PMID:28406185

  2. Cell of Origin: Exploring an Alternative Contributor to Ovarian Cancer

    DTIC Science & Technology

    2013-09-01

    Contributor to Ovarian Cancer PRINCIPAL INVESTIGATOR: Bo R. Rueda, Ph.D. CONTRACTING ORGANIZATION: Massachusetts General Hospital...Exploring an Alternative Contributor to Ovarian Cancer 5b. GRANT NUMBER W81XWH-12-1-0192 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d...to that of primary human ovarian cancer . We have also successfully introduced in human oogonial stem cells genetic alterations commonly detected in

  3. Inhibitory effects of metformin at low concentration on epithelial-mesenchymal transition of CD44(+)CD117(+) ovarian cancer stem cells.

    PubMed

    Zhang, Rongrong; Zhang, Ping; Wang, Hong; Hou, Dongming; Li, Wentao; Xiao, Guishan; Li, Chenwei

    2015-12-30

    Although metformin, a first-line drug for treating diabetes, may play an important role in inhibition of epithelial ovarian cancer cell growth and cancer stem cells (CSCs), metformin at low dose showed less effect on the proliferation of ovarian cancer cells. In this study, we evaluated the effect of metformin at low dose on ovarian CSCs in order to understand the molecular mechanisms underlying. The inhibitory effects of metformin at los dose on proliferation and population of ovarian cancer cells including SKOV3 and A2780 were assessed by cell proliferation assay and flow cytometry. Quantitative real-time PCR assay on expression of Bcl-2, Survivin and Bax was performed to determine the effect of metformin at low dose on epithelial-mesenchymal transition (EMT) of cancer cells and CSCs. Tumor sphere formation assay was also performed to evaluate the effect of metformin on spheres forming ability of CSCs. The therapeutic efficacy and the anti-CSC effects of metformin at low dose were investigated by using both SKOV3 cells and primary tumor xenografts. In addition, the CSC frequency and EMT in tumor xenograft models were also assessed by flow cytometry and quantitative real-time PCR. Metformin at low dose did not affect the proliferation of ovarian cancer cells. However, it inhibited population of CD44(+)CD117(+) selectively, neither CD133(+) nor ALDH(+) cells. It suppressed expression of snail2, twist and vimentin significantly in cancer cells and CD44(+)CD117(+) CSCs in vitro. Low dose of metformin reduced survivin expression in CSCs. Low concentrations of metformin inhibited the secondary and the tertiary tumor sphere formation, decreased SKOV3 and primary ovarian tumor xenograft growth, enhanced the anticancer effect of cisplatin, and lowered the proportion of CD44(+)CD117(+) CSCs in the xenograft tissue. Metformin was also associated with a reduction of snail2, twist, and vimentin in CD44(+)CD117(+) ovarian CSCs in vivo. Our results implicate that metformin at

  4. Denileukin Diftitox Used in Treating Patients With Advanced Refractory Ovarian Cancer, Primary Peritoneal Carcinoma, or Epithelial Fallopian Tube Cancer

    ClinicalTrials.gov

    2016-05-02

    Fallopian Tube Cancer; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Peritoneal Cavity Cancer; Recurrent Ovarian Epithelial Cancer; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

  5. Ovarian Autoantibodies Predict Ovarian Cancer

    DTIC Science & Technology

    2010-11-01

    ovarian adenocarcinomas from laying hens. Gynecol Oncol, 2007; 104: 192-198. 506 25. Hales DB, Zhuge Y, Lagman JA, Ansenberger K, Mahon C, Barua A...Ultrasound Med 2010, 29:173-182. 479 (19) Hales DB, Zhuge Y, Lagman JA, Ansenberger K, Mahon C, Barua A et al: 480 Cyclooxygenases expression and...adenocarcinomas from laying hens. Gynecol Oncol 2007, 507 104:192-198. 508 (30) Ansenberger K, Zhuge Y, Lagman JA, Richards C, Barua A, Bahr JM

  6. Primary ovarian cancer cell inhibition by human Wharton's Jelly stem cells (hWJSCs): Mapping probable mechanisms and targets using systems oncology

    PubMed Central

    Kalamegam, Gauthaman; Pushparaj, Peter Natesan; Khan, Fazal; Sait, Khalid Hussein Wali; Anfinan, Nisreen; Al-Qahtani, Mohammed

    2015-01-01

    Ovarian cancer is one of the most lethal gynaecological cancers. Its subtle onset and absence of symptoms in early stages are associated with poor prognosis and high mortality. Identification of early biomarkers would aid in ovarian cancer control. Mesenchmal stem cells (MSCs) and/or their secretory products are identified to have cancer inhibitory properties. Therefore, it is of interest to study the anticancer properties of human Wharton's jelly stem cells conditioned medium (hWJSCs-CM) on primary ovarian carcinoma cells in vitro. Primary cultures of epithelial ovarian carcinoma cells (EOCs) and hWJSCs were used in this study. EOCs were exposed to hWJSC-CM (100%) for 24h-72h and changes in mophology and cell proliferation were monitored. Treatment with hWJSC-CM showed altered morphological changes that resulted in death of EOCs. Colorimetric assay [MTT, (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide)] showed mean decreases in EOC proliferation by 16.21%, 23.89% and 40.08% at 24h, 48h and 72h respectively compared to control. Ingenuity Pathway Analysis (IPA, Igenuity Systems, USA) deduced important molecular pathways and signaling networks associated with cancer cell death and these correlated with significant expression of tumour suppresors and apoptotic genes in hWJSCs. Secretory products of hWJSC-CM induced cell death of EOCs via apoptosis. IPA identification of canonical genes/pathways involved in EOCs that overlap with hWJSCs tumour suppressors and apoptosis genes further support this hypotheis. Additional in vitro and in vivo studies are necessary to validate EOCs inhibition with hWJSC-extracts towards their mechanism of action. PMID:26770026

  7. Functional study of risk loci of stem cell-associated gene lin-28B and associations with disease survival outcomes in epithelial ovarian cancer.

    PubMed

    Lu, Lingeng; Katsaros, Dionyssios; Mayne, Susan T; Risch, Harvey A; Benedetto, Chiara; Canuto, Emilie Marion; Yu, Herbert

    2012-11-01

    Several single-nucleotide polymorphisms (SNPs) of the stem cell-associated gene lin-28B have been identified in association with ovarian cancer and ovarian cancer-related risk factors. However, whether these SNPs are functional or might be potential biomarkers for ovarian cancer prognosis remains unknown. The purposes of this study were to investigate the functional relevance of the identified lin-28B SNPs, as well as the associations of genotype and phenotype with epithelial ovarian cancer (EOC) survival. We analyzed five SNPs and mRNA levels of lin-28B in 211 primary EOC tissues using Taqman(®) SNP genotyping assays and SYBR green-based real-time PCR, respectively. The RNA secondary structures at the region of a genome-wide association-identified intronic rs314276 were analyzed theoretically with mfold and experimentally with circular dichroism spectroscopy. We found that rs314276 was a cis-acting expression quantitative trait locus (eQTL) in both additive and dominant models, while rs7759938 and rs314277 were significant or of borderline significance in dominant models only. The rs314276 variant significantly affects RNA secondary structure. No SNPs alone were associated with patient survival. However, we found that among patients initially responding to chemotherapy, those with higher lin-28B expression had higher mortality risk (hazard ratio =3.27, 95% confidence interval: 1.63-6.56) and relapse risk (hazard ratio = 2.53, 95% confidence interval: 1.41-4.54) than those with lower expression, and these associations remained in multivariate analyses. These results suggest that rs314276 alters RNA secondary structure and thereby influences gene expression, and that lin-28B is a cancer stem cell-associated marker, which may be a pharmaceutical target in the management of EOC.

  8. 7-(O)-Carboxymethyl daidzein conjugated to N-t-Boc-hexylenediamine: A Novel Compound Capable of Inducing Cell Death in Epithelial Ovarian Cancer Stem Cells

    PubMed Central

    Green, Jamie M.; Alvero, Ayesha B.; Kohen, Fortune; Mor, Gil

    2009-01-01

    One of the major difficulties in the treatment of epithelial ovarian cancer (EOC) is the high rate of recurrent disease. This is thought to be due to the survival of a population of chemo-resistant cells within the tumor, the ovarian cancer stem cells (OCSCs), that are able to regenerate the tumor following chemotherapy. Therefore, the identification of a compund that can target the OCSCs is one of the main steps in improving overall survival of ovarian cancer patients. The objective of this study was to determine the effect of N-t-boc-Daidzein, a novel daidzain derivative, on OCSCs. The efficacy of this compound was evaluated in OCSC and mature ovarian cancer cell (mOCC) lines isolated from malignant ovarian cancer asicites. Cells were treated with increasing concentrations of N-t-boc-Daidzein (0.003–10 μM) and cell growth was monitored by “real time in vitro micro-imaging” using the IncuCyte system. Cell viability was measured using the CellTiter 96 Assay. Apoptosis was determined by Caspase-Glo 3/7, 8, and 9 assays. The components of the apoptotic cascade were characterized by Western blot analysis. N-t-boc-Daidzein was able to significantly inhibit cell growth and decrease cell viability of OCSC as well as mOCC cells in a dose and time dependent maner. This effect was due to the induction of apoptosis, which is characterized by caspase activation, XIAP and AKT degradation, and mitochondrial depolarization. This study describes a novel compound that can target the OCSCs. These findings may provide vital aide in improving overall survival in patients with EOC. PMID:19738422

  9. 7-(O)-Carboxymethyl daidzein conjugated to N-t-Boc-hexylenediamine: a novel compound capable of inducing cell death in epithelial ovarian cancer stem cells.

    PubMed

    Green, Jamie M; Alvero, Ayesha B; Kohen, Fortune; Mor, Gil

    2009-09-01

    One of the major difficulties in the treatment of epithelial ovarian cancer (EOC) is the high rate of recurrent disease. This is thought to be due to the survival of a population of chemo-resistant cells within the tumor, the ovarian cancer stem cells (OCSCs), that are able to regenerate the tumor following chemotherapy. Therefore, the identification of a compund that can target the OCSCs is one of the main steps in improving overall survival of ovarian cancer patients. The objective of this study was to determine the effect of N-t-boc-Daidzein, a novel daidzain derivative, on OCSCs. The efficacy of this compound was evaluated in OCSC and mature ovarian cancer cell (mOCC) lines isolated from malignant ovarian cancer asicites. Cells were treated with increasing concentrations of N-t-boc-Daidzein (0.003-10 microM) and cell growth was monitored by "real time in vitro micro-imaging" using the IncuCyte system. Cell viability was measured using the CellTiter 96 Assay. Apoptosis was determined by Caspase-Glo 3/7, 8 and 9 assays. The components of the apoptotic cascade were characterized by western blot analysis. N-t-boc-Daidzein was able to significantly inhibit cell growth and decrease cell viability of OCSC as well as mOCC cells in a dose and time dependent maner. This effect was due to the induction of apoptosis, which is characterized by caspase activation, XIAP and AKT degradation, and mitochondrial depolarization. This study describes a novel compound that can target the OCSCs. These findings may provide vital aide in improving overall survival in patients with EOC.

  10. Minireview: stem cell contribution to ovarian development, function, and disease.

    PubMed

    Tilly, Jonathan L; Rueda, Bo R

    2008-09-01

    By virtue of the fact that oocytes not only serve to produce embryos after fertilization but also can effectively reprogram adult somatic cell nuclei to a pluripotent state, much of the interest in the role of stem cells in ovarian biology has been focused on the germline. However, very recent studies have revealed that somatic stem cells may also be of considerable relevance to the study of normal ovarian function. Furthermore, stem cell dysfunction may underlie or contribute to disease states such as ovarian cancer and polycystic ovary syndrome. Our objective is to explore these concepts in greater detail, with the hope of stimulating further research efforts into understanding what role stem cells may play in the physiology and pathology of the mammalian female gonads.

  11. Tumor Stroma Engraftment of Gene-Modified Mesenchymal Stem Cells as Anti-Tumor Therapy against Ovarian Cancer

    PubMed Central

    Dembinski, Jennifer L.; Wilson, Shanna M.; Spaeth, Erika L.; Studeny, Matus; Zompetta, Claudia; Samudio, Ismael; Roby, Katherine; Andreeff, Michael; Marini, Frank C.

    2013-01-01

    Many ovarian cancers originate from ovarian surface epithelium, where they develop from cysts intermixed with stroma. The stromal layer is critical to the progression and survival of the neoplasm and consequently is recruited into the tumor microenvironment. Using both syngenic mouse tumors (ID8-R), and human xenograft (OVCAR3, SKOV3) tumor models, we first confirmed intraperitoneally-circulating MSC could target, preferentially engraft and differentiate into α-SMA+ myofibroblasts, suggesting their role as “reactive stroma” in ovarian carcinoma development and confirming their potential as a targeted delivery vehicle for the intratumoral production of interferon-beta (IFNβ). Then, mice with ovarian carcinomas received weekly IP injections of IFNβ expressing MSC, resulting in complete eradication of tumors in 70% of treated OVCAR3 mice (P = 0.004) and an increased survival of treated SKOV3 mice compared with controls (P = 0.01). Similar tumor growth control was observed using murine IFNβ delivered by murine MSC in ID8-R ovarian carcinoma. As a potential mechanism of tumor killing, MSC produced IFNβ induced caspase-dependent tumor cell apoptosis. Our results demonstrate that ovarian carcinoma engraft MSC to participate in myofibrovascular networks and that IFNβ produced by MSC intratumorally modulates tumor kinetics, resulting in prolonged survival. PMID:23260083

  12. Investigate the Role of Obesity in Ovarian Cancer Initiation and Progression

    DTIC Science & Technology

    2016-05-01

    AWARD NUMBER: W81XWH-15-1-0095 TITLE: Investigate the Role of Obesity in Ovarian Cancer Initiation and Progression PRINCIPAL INVESTIGATOR...TITLE AND SUBTITLE Investigate the Role of Obesity in Ovarian Cancer Initiation and Progression 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-15-1...pathways in ovarian stem cells and in transformed ovarian cells affected by obesity that lead to ovarian cancer initiation and progression. 15. SUBJECT

  13. Oncolytic virotherapy for ovarian cancer.

    PubMed

    Li, Shoudong; Tong, Jessica; Rahman, Masmudur M; Shepherd, Trevor G; McFadden, Grant

    2012-08-01

    In the past two decades, more than 20 viruses with selective tropism for tumor cells have been developed as oncolytic viruses (OVs) for treatments of a variety of malignancies. Of these viruses, eleven have been tested in human ovarian cancer models in preclinical studies. So far, nine phase I or II clinical trials have been conducted or initiated using four different types of OVs in patients with recurrent ovarian cancers. In this article, we summarize the different OVs that are being assessed as therapeutics for ovarian cancer. We also present an overview of recent advances in identification of key genetic or immune-response pathways involved in tumorigenesis of ovarian cancer, which provides a better understanding of the tumor specificities and oncolytic properties of OVs. In addition, we discuss how next-generation OVs could be genetically modified or integrated into multimodality regimens to improve clinical outcomes based on recent advances in ovarian cancer biology.

  14. Oncolytic virotherapy for ovarian cancer

    PubMed Central

    Li, Shoudong; Tong, Jessica; Rahman, Masmudur M; Shepherd, Trevor G; McFadden, Grant

    2012-01-01

    In the past two decades, more than 20 viruses with selective tropism for tumor cells have been developed as oncolytic viruses (OVs) for treatments of a variety of malignancies. Of these viruses, eleven have been tested in human ovarian cancer models in preclinical studies. So far, nine phase I or II clinical trials have been conducted or initiated using four different types of OVs in patients with recurrent ovarian cancers. In this article, we summarize the different OVs that are being assessed as therapeutics for ovarian cancer. We also present an overview of recent advances in identification of key genetic or immune-response pathways involved in tumorigenesis of ovarian cancer, which provides a better understanding of the tumor specificities and oncolytic properties of OVs. In addition, we discuss how next-generation OVs could be genetically modified or integrated into multimodality regimens to improve clinical outcomes based on recent advances in ovarian cancer biology. PMID:25977900

  15. Ovarian cancer: the neglected diagnosis.

    PubMed

    Yawn, Barbara P; Barrette, Brigitte A; Wollan, Peter C

    2004-10-01

    To investigate presenting signs and symptoms of ovarian cancer and stage of tumor in a community cohort of women with the diagnosis of ovarian cancer. We reviewed retrospectively the medical records of all women who sought primary and specialty care in Olmsted County, Minnesota, between January 1, 1985, and December 31, 1997, to evaluate presenting symptoms, time from first symptom to diagnosis of ovarian cancer, and stage of tumor at diagnosis. Of 107 women with a diagnosis of ovarian cancer, the most commonly documented presenting symptom was crampy abdominal pain. Urinary symptoms and abdominal pain were the most commonly documented presenting symptom in patients with stage I and II ovarian cancers, whereas abdominal pain and increased abdominal girth were the most commonly documented symptoms in patients with stage III and IV cancer. Approximately 15% of tumors (n = 15) were found during routine evaluations or during a procedure for another problem. Less than 25% of presenting symptoms (n = 24 women) related directly to the pelvis or were more traditional gynecologic symptoms. Delays in women seeking medical care, health care system issues, competing medical conditions, physicians' failure to follow up, and women not returning for follow-up were associated with longer time to diagnosis. Both stage I and II cancer are associated with symptoms, but few symptoms are directly related to the reproductive pelvic organs or unique to ovarian cancer. A longer interval from first sign or symptom to diagnosis of ovarian cancer is associated with both patient and health care system factors.

  16. Targeting Midbodies in Ovarian Cancer Stem Cells as a Therapeutic Strategy

    DTIC Science & Technology

    2014-12-01

    daughter cells (progenitors; 75%, n=8) and not in daughters with presumed committed fates5. MBds in the human hair follicle were also confined to a...PubMed: 20729831] 32. Morris RJ, et al. Capturing and profiling adult hair follicle stem cells. Nat Biotechnol. 2004; 22:411–7. [PubMed: 15024388...that abscission occurs apically in these cells. (e) A histological section through a hair follicle (left, phase-contrast microscopy) stained for the

  17. The Role of Mesenchymal Stem Cells in Promoting Ovarian Cancer Growth and Spread

    DTIC Science & Technology

    2014-12-01

    test the in vivo potency of any MSC. 21 PR141364 (Betancourt) 09/01/2015-8/31/ 2017 6.0 calendar DOD W81XWH-14-PRMRP-TTDA Invited Application...in the therapy of a mouse model of painful diabetic peripheral neuropathy [14]. This study also demonstrates the stability of these newly defined...Jenny M, Bobby DN, Anna ES, Aline MB (2012) Anti- Inflammatory Mesenchymal Stem Cells (MSC2) Attenuate Symptoms of Painful Diabetic Peripheral

  18. Subtypes of Ovarian Cancer and Ovarian Cancer Screening

    PubMed Central

    Koshiyama, Masafumi; Matsumura, Noriomi; Konishi, Ikuo

    2017-01-01

    Ovarian cancer is the foremost cause of gynecological cancer death in the developed world, as it is usually diagnosed at an advanced stage. In this paper we discuss current issues, the efficacy and problems associated with ovarian cancer screening, and compare the characteristics of ovarian cancer subtypes. There are two types of ovarian cancer: Type I carcinomas, which are slow-growing, indolent neoplasms thought to arise from a precursor lesion, which are relatively common in Asia; and Type II carcinomas, which are clinically aggressive neoplasms that can develop de novo from serous tubal intraepithelial carcinomas (STIC) and/or ovarian surface epithelium and are common in Europe and the USA. One of the most famous studies on the subject reported that annual screening using CA125/transvaginal sonography (TVS) did not reduce the ovarian cancer mortality rate in the USA. In contrast, a recent study in the UK showed an overall average mortality reduction of 20% in the screening group. Another two studies further reported that the screening was associated with decreased stage at detection. Theoretically, annual screening using CA125/TVS could easily detect precursor lesions and could be more effective in Asia than in Europe and the USA. The detection of Type II ovarian carcinoma at an early stage remains an unresolved issue. The resolving power of CA125 or TVS screening alone is unlikely to be successful at resolving STICs. Biomarkers for the early detection of Type II carcinomas such as STICs need to be developed. PMID:28257098

  19. Low uptake of fluorodeoxyglucose in positron emission tomography/computed tomography in ovarian clear cell carcinoma may reflect glutaminolysis of its cancer stem cell-like properties.

    PubMed

    Sato, Masakazu; Kawana, Kei; Adachi, Katsuyuki; Fujimoto, Asaha; Taguchi, Ayumi; Fujikawa, Tomona; Yoshida, Mitsuyo; Nakamura, Hiroe; Nishida, Haruka; Inoue, Tomoko; Ogishima, Juri; Eguchi, Satoko; Yamashita, Aki; Tomio, Kensuke; Arimoto, Takahide; Wada-Hiraike, Osamu; Oda, Katsutoshi; Nagamatsu, Takeshi; Osuga, Yutaka; Fujii, Tomoyuki

    2017-03-01

    The characteristics of ovarian cancers that showed low activation of glycolysis were investigated. Using medical records of patients with ovarian cancers who had undergone fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) prior to their primary surgery at the University of Tokyo Hospital between 2010 and 2015, we identified cases with a low uptake of FDG in PET/CT. We considered the maximum standardized uptake value (SUVmax) as the degree of glucose uptake. We investigated the properties which may account for the low activation of glycolysis in vitro. The expression level of alanine, serine, cysteine-preferring transporter 2 (ASCT2, a glutamine influx transporter), system L-type amino acid transporter 1 (LAT1, a glutamine efflux transporter) and glucose transporter 1 (GLUT1, a glucose influx transporter) were investigated by western blotting. The phosphorylation level of AMP-activated protein kinase (AMPK), which is one of the metabolic sensors, was also investigated. Most of the cases with a low uptake SUVmax were limited to patients with ovarian clear cell carcinoma (CCC). We obtained cancer stem cell (CSC)-like properties from CCC cell lines, and compared the expression levels of transporters between non-CSCs and CSCs. Whereas the expression level of ASCT2 was nearly unchanged between non-CSCs and CSCs, the expression levels of LAT1 and GLUT1 were decreased in CSCs compared to non-CSCs. The phosphorylation level of AMPK was reduced in CSCs compared to non-CSCs. In conclusion, we suggested that ovarian CCC showed low activation of glycolysis, and this may reflect glutaminolysis of its CSC-like properties.

  20. Polyglutamate Paclitaxel and Carboplatin in Treating Patients With Ovarian Epithelial, Peritoneal, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2015-05-07

    Fallopian Tube Carcinoma; Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Primary Peritoneal Carcinoma; Stage III Ovarian Cancer; Stage IV Ovarian Cancer; Undifferentiated Ovarian Carcinoma

  1. Genetic Modifiers of Ovarian Cancer

    DTIC Science & Technology

    2012-06-01

    association study ( GWAS ) for ovarian cancer in BRCA1 mutation carriers was initiated in an effort to identify common genetic variants that modify... GWAS of 1250 BRCA1 mutation carriers diagnosed with breast cancer and 1250 unaffected BRCA1 carriers using Human660W-Quad arrays. The 1250 unaffected...cancer on H uman660W-Quad arrays. In addition we acquired GWAS genotype data for 120 additional BRCA1 mutation carriers affected with ovarian

  2. The epidemiology of ovarian cancer.

    PubMed

    Tortolero-Luna, G; Mitchell, M F

    1995-01-01

    Ovarian cancer is the second most common cancer of the female reproductive system and the leading cause of death from gynecologic malignancies. In 1995, 26,600 women will be diagnosed with ovarian cancer in the U.S., and 14,500 women will die from the disease. Between 1986-1900, the overall age-adjusted incidence was 14.3/100,000 women; mortality was 7.8/100,000 women. Ovarian cancer, rare before age 40, increases steeply thereafter and peaks at ages 65-75. Incidence and mortality rates are higher among white women than among African-American women. Over the last three decades, ovarian cancer incidence has remained stable in high-risk countries, while an increasing trend has been reported in low-risk countries. Despite recent advancements in treatment, the overall five-year survival rates continues to be low (39%). Over 70% of ovarian tumors are diagnosed when regional or distant involvement has already occurred, causing survival rates to remain stable. The etiology of ovarian cancer is poorly understood. Most studies have focused on the epidemiology of invasive epithelial ovarian tumors, while few have explored the epidemiology of epithelial tumors of low malignant potential and nonepithelial tumors. Factors associated with an increased risk for invasive epithelial ovarian cancer include age, race, nulliparity, family history of ovarian cancer, and history of endometrial or breast cancer. Factors associated with a reduced risk are history of one or more full-term pregnancies, use of oral contraceptives, history of breast feeding, tubal ligation, and hysterectomy. Other factors such as infertility drugs, hormone replacement therapy, age at menarche, age at menopause, dietary factors, lactose intolerance, talc use, coffee and alcohol consumption have been suggested, but their role is still inconclusive.

  3. Claudin Proteins in Ovarian Cancer

    PubMed Central

    Morin, Patrice J.

    2007-01-01

    Members of the claudin family of tight junction proteins have been found altered in several malignancies, including ovarian cancer. Because claudin-3 and -4 are elevated in the vast majority of ovarian tumors, they may represent useful biomarkers for detection and prognosis, as well as ideal targets for therapy using the Clostridium perfringens enterotoxin. PMID:18057528

  4. Observation of ovarian cancer stem cell behavior and investigation of potential mechanisms of drug resistance in three-dimensional cell culture.

    PubMed

    Chen, Junsong; Wang, Jing; Zhang, Yunxia; Chen, Dengyu; Yang, Cuiping; Kai, Cai; Wang, Xiaoying; Shi, Fangfang; Dou, Jun

    2014-08-01

    Cancer cells behave differently in a three-dimensional (3D) cell culture compared with in the conventional two-dimensional (2D) one. Accumulated evidences indicate that the characteristics of cancer stem cells (CSCs) are different from common cancer cells due to their ability to produce tumors and resist chemoradiation. The objective of this work was to observe CSC behavior and investigate the potential mechanisms of CSC drug resistance in 3D versus 2D in vitro environment. We first demonstrated that the CD44(+)CD117(+)cells isolated from the human epithelial ovarian cancer HO8910 cell line have the properties of CSCs that revealed faster growth, larger tumorsphere and stronger survival potential in the hypoxic environment in 3D cell culture as well as more powerful tumorigenicity in a xenograft mice than the HO8910 cells. The CD44(+)CD117(+)CSCs also exhibited high chemoresistance to anticancer drugs when the cells were incubated with 5-fluorouracil, cisplatin and carboplatin, respectively in 3D versus 2D environment. This might be associated with the high expression of ABCG2, ABCB1 and the high expression of MMP-2 and MMP-9 in CD44(+)CD117(+)CSCs. Overall, these results suggest the advantages of using 3D culture model to accurately display CSC behavior in vitro. 3D model may improve the efficacy of screening anticancer drugs for treatment of ovarian CSCs.

  5. What's New in Ovarian Cancer Research and Treatment?

    MedlinePlus

    ... and Treatment? Ovarian Cancer About Ovarian Cancer What's New in Ovarian Cancer Research and Treatment? Risk factors ... This information eventually is expected to lead to new drugs for preventing and treating familial ovarian cancer. ...

  6. Genetic Modifiers of Ovarian Cancer

    DTIC Science & Technology

    2011-06-01

    ovarian cancer, a sizeable proportion of women who carry a deleteriou s mutation will not d evelop this disease . In addition, the findings show that...carriers. Carriers were censored at age of onset of disease for those affected with breast or ovarian cancer and age of last follow up or age at 5...Doerk T, Hillemanns P, Durst M, Runnebaum I, Thompson PJ, Carney ME, Goodman MT, Lurie G, Wang- Gohrke S , Hein R, Chang-Claude J, Rossing MA, Cushing

  7. Prognostic Biomarkers in Ovarian Cancer

    PubMed Central

    Huang, Jie; Hu, Wei; Sood, Anil K

    2014-01-01

    Epithelial ovarian cancer (EOC) remains the most lethal gynecological malignancy despite several decades of progress in diagnosis and treatment. Taking advantage of the robust development of discovery and utility of prognostic biomarkers, clinicians and researchers are developing personalized and targeted treatment strategies. This review encompasses recently discovered biomarkers of ovarian cancer, the utility of published prognostic biomarkers for EOC (especially biomarkers related to angiogenesis and key signaling pathways), and their integration into clinical practice. PMID:22045356

  8. Biological Basis for Chemoprevention of Ovarian Cancer

    DTIC Science & Technology

    2001-10-01

    Prevention may represent a feasible approach to decreasing ovarian cancer mortality . To achieve a better understanding of the etiology of ovarian...Progestins have a potent apoptotic effect on ovarian epithelial cells and we have shown that levonorgestrel dramatically decreases ovarian cancer incidence...effective chemoprevention strategies that might decrease mortality from this disease.

  9. What Should You Ask Your Doctor about Ovarian Cancer?

    MedlinePlus

    ... for Ovarian Cancer How Is Ovarian Cancer Staged? Survival Rates for Ovarian Cancer, by Stage What Should You Ask Your Doctor ... for Ovarian Cancer How Is Ovarian Cancer Staged? Survival Rates for Ovarian Cancer, by Stage What Should You Ask Your Doctor ...

  10. Ovarian Cancer Development and Metastasis

    PubMed Central

    Lengyel, Ernst

    2010-01-01

    The biology of ovarian carcinoma differs from that of hematogenously metastasizing tumors because ovarian cancer cells primarily disseminate within the peritoneal cavity and are only superficially invasive. However, since the rapidly proliferating tumors compress visceral organs and are only temporarily chemosensitive, ovarian carcinoma is a deadly disease, with a cure rate of only 30%. There are a number of genetic and epigenetic changes that lead to ovarian carcinoma cell transformation. Ovarian carcinoma could originate from any of three potential sites: the surfaces of the ovary, the fallopian tube, or the mesothelium-lined peritoneal cavity. Ovarian cacinoma tumorigenesis then either progresses along a stepwise mutation process from a slow growing borderline tumor to a well-differentiated carcinoma (type I) or involves a genetically unstable high-grade serous carcinoma that metastasizes rapidly (type II). During initial tumorigenesis, ovarian carcinoma cells undergo an epithelial-to-mesenchymal transition, which involves a change in cadherin and integrin expression and up-regulation of proteolytic pathways. Carried by the peritoneal fluid, cancer cell spheroids overcome anoikis and attach preferentially on the abdominal peritoneum or omentum, where the cancer cells revert to their epithelial phenotype. The initial steps of metastasis are regulated by a controlled interaction of adhesion receptors and proteases, and late metastasis is characterized by the oncogene-driven fast growth of tumor nodules on mesothelium covered surfaces, causing ascites, bowel obstruction, and tumor cachexia. PMID:20651229

  11. Survivorship Care Planning in Improving Quality of Life in Survivors of Ovarian Cancer

    ClinicalTrials.gov

    2017-02-19

    Cancer Survivor; Stage IA Ovarian Epithelial Cancer; Stage IB Ovarian Epithelial Cancer; Stage IC Ovarian Epithelial Cancer; Stage IIA Ovarian Epithelial Cancer; Stage IIB Ovarian Epithelial Cancer; Stage IIC Ovarian Epithelial Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIB Ovarian Epithelial Cancer; Stage IIIC Ovarian Epithelial Cancer

  12. HOX genes in ovarian cancer.

    PubMed

    Kelly, Zoë L; Michael, Agnieszka; Butler-Manuel, Simon; Pandha, Hardev S; Morgan, Richard Gl

    2011-09-09

    The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development. Here we review a number of recent studies showing that HOX genes are strongly expressed in ovarian cancer, and that in some cases the expression of specific HOX genes is sufficient to confer a particular identity and phenotype upon cancer cells. We also review the recent advances in elucidating the different functions of HOX genes in ovarian cancer. A literature search was performed using the search terms HOX genes (including specific HOX genes), ovarian cancer and oncogenesis. Articles were accessed through searches performed in ISI Web of Knowledge, PubMed and ScienceDirect. Taken together, these studies have shown that HOX genes play a role in the oncogenesis of ovarian cancer and function in the inhibition of apoptosis, DNA repair and enhanced cell motility. The function of HOX genes in ovarian cancer oncogenesis supports their potential role as prognostic and diagnostic markers, and as therapeutic targets in this disease.

  13. Identification of Small Molecule Inhibitors of microRNA Involved in Chemoresistance and Cancer Stem Cells for Ovarian Cancer Intervention

    DTIC Science & Technology

    2013-09-01

    F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA. The epithelial- mesenchymal transition generates cells with properties of stem cells. Cell. 133:704-15, 2008. Appendices None

  14. Targeted Therapy in Ovarian Cancer

    PubMed Central

    Lim, Hui Jun; Ledger, William

    2016-01-01

    Among female-specific cancers worldwide, ovarian cancer is the leading cause of death from gynecologic malignancy in the western world. Despite radical surgery and initial high response rates to first-line chemotherapy, up to 70% 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. This review aims to assess current understanding of targeted therapy in ovarian cancer and evaluate the evidence for targeting growth-dependent mechanisms involved in its pathogenesis. Of the many targeted therapies currently under evaluation, the most promising strategies developed thus far are antiangiogenic agents and PARP inhibitors. PMID:27215391

  15. Epigenetic Characterization of Ovarian Cancer

    DTIC Science & Technology

    2008-12-01

    cell lines A549 H1299 H2347 Lung cancer H460 H1993 AGS Gastric cancer HCT116 Colon...tumors. Cancer Res, 2008. 68(11): p. 4311-20. 4. Abecassis, I., et al., Re- expression of DNA methylation-silenced CD44 gene in a resistant NB4 cell line ...reactivate expression (Figure 2B). We examined the level of expression of CDH4 in 43 ovarian cell lines (41 cancer cell

  16. Ovarian Cancer Risk Prediction Models

    Cancer.gov

    Developing statistical models that estimate the probability of developing ovarian cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  17. Global ovarian cancer health disparities

    PubMed Central

    Chornokur, Ganna; Amankwah, Ernest K.; Schildkraut, Joellen M.; Phelan, Catherine M.

    2013-01-01

    Objective The objective of this article is to broadly review the scientific literature and summarize the most up-to-date findings on ovarian cancer health disparities worldwide and in the United States (U.S.). Methods The present literature on disparities in ovarian cancer was reviewed. Original research and relevant review articles were included. Results Ovarian cancer health disparities exist worldwide and in the U.S. Ovarian cancer disproportionately affect African American women at all stages of the disease, from presentation through treatment, and ultimately increased mortality and decreased survival, compared to non-Hispanic White women. Increased mortality is likely to be explained by unequal access to care and non-standard treatment regimens frequently administered to African American women, but may also be attributed to genetic susceptibility, acquired co-morbid conditions and increased frequency of modifiable risk factors, albeit to substantially lesser extent. Unequal access to care is, in turn, largely a consequence of lower socioeconomic status and lack of private health insurance coverage among the African American population. Conclusions Our findings suggest the need for policy changes aimed at facilitating equal access to quality medical care. At the same time, further research is necessary to fully resolve racial disparities in ovarian cancer. PMID:23266352

  18. Impact of the putative cancer stem cell markers and growth factor receptor expression on the sensitivity of ovarian cancer cells to treatment with various forms of small molecule tyrosine kinase inhibitors and cytotoxic drugs

    PubMed Central

    Puvanenthiran, Soozana; Essapen, Sharadah; Seddon, Alan M.; Modjtahedi, Helmout

    2016-01-01

    Increased expression and activation of human epidermal growth factor receptor (EGFR) and HER-2 have been reported in numerous cancers. The aim of this study was to determine the sensitivity of a large panel of human ovarian cancer cell lines (OCCLs) to treatment with various forms of small molecule tyrosine kinase inhibitors (TKIs) and cytotoxic drugs. The aim was to see if there was any association between the protein expression of various biomarkers including three putative ovarian cancer stem cell (CSC) markers (CD24, CD44, CD117/c-Kit), P-glycoprotein (P-gp), and HER family members and response to treatment with these agents. The sensitivity of 10 ovarian tumour cell lines to the treatment with various forms of HER TKIs (gefitinib, erlotinib, lapatinib, sapitinib, afatinib, canertinib, neratinib), as well as other TKIs (dasatinib, imatinib, NVP-AEW541, crizotinib) and cytotoxic agents (paclitaxel, cisplatin and doxorubicin), as single agents or in combination, was determined by SRB assay. The effect on these agents on the cell cycle distribution, and downstream signaling molecules and tumour migration were determined using flow cytometry, western blotting, and the IncuCyte Clear View cell migration assay respectively. Of the HER inhibitors, the irreversible pan-TKIs (canertinib, neratinib and afatinib) were the most effective TKIs for inhibiting the growth of all ovarian cancer cells, and for blocking the phosphorylation of EGFR, HER-2, AKT and MAPK in SKOV3 cells. Interestingly, while the majority of cancer cells were highly sensitive to treatment with dasatinib, they were relatively resistant to treatment with imatinib (i.e., IC50 >10 μM). Of the cytotoxic agents, paclitaxel was the most effective for inhibiting the growth of OCCLs, and of various combinations of these drugs, only treatment with a combination of NVP-AEW541 and paclitaxel produced a synergistic or additive anti-proliferative effect in all three cell lines examined (i.e., SKOV3, Caov3, ES2

  19. The effect of the immune system on ovarian function and features of ovarian germline stem cells.

    PubMed

    Ye, Haifeng; Li, Xiaoyan; Zheng, Tuochen; Liang, Xia; Li, Jia; Huang, Jian; Pan, Zezheng; Zheng, Yuehui

    2016-01-01

    In addition to its role in maintaining organism homeostasis, the immune system also plays a crucial role in the modulation of ovarian function, as it regulates ovarian development, follicular maturation, ovulation and the formation of the corpus luteum. Ovarian germline stem cells are pluripotent stem cells derived from the ovarian cortex that can differentiate into ovarian germ cells and primary granulosa cells. Recent work has demonstrated that the proliferation and differentiation of ovarian germline stem cells is regulated in part by immune cells and their secreted factors. This paper reviews the role of the immune system in the regulation of ovarian function, the relationship between immune components and ovarian germline stem cells and current research efforts in this field.

  20. Study of ovarian cancer management.

    PubMed

    Gaughan, E; Javaid, T; Cooley, S; Byrne, P; Gaughan, G

    2006-10-01

    Ovarian cancer is the most lethal gynecological malignancy. Many patients present at an advanced stage as the symptoms of early stage disease can be vague. AIM We evaluated the demographics, treatment regimens and survival rates of ovarian cancer patients attending Beaumont Hospital Dublin over a nine year period. A retrospective chart review of ovarian cancer patients attending Beaumont Hospital between 11/10/94 and 30/6/3 was performed. Patients were selected from pathology records. Patients with borderline histology and those who died of unrelated causes were excluded. 31% of individuals presented with distension as their only clinical sign. 20% presented with a mass as their only clinical sign. The most common cell type was papillary serous adenocarcinoma in two thirds of cases. 54% presented with advanced disease [stage IIl-IV]. Treatment involved surgical clearance or debulking +/- chemotherapy. 5 year survival for Stage I was 95% versus 19% for Stage IlI. This highlights the importance of early diagnosis.

  1. YAP/TEAD Co-Activator Regulated Pluripotency and Chemoresistance in Ovarian Cancer Initiated Cells

    PubMed Central

    Yu, Chao; Chang, Ting; Fan, Heng-Yu

    2014-01-01

    Recent evidence suggests that some solid tumors, including ovarian cancer, contain distinct populations of stem cells that are responsible for tumor initiation, growth, chemo-resistance, and recurrence. The Hippo pathway has attracted considerable attention and some investigators have focused on YAP functions for maintaining stemness and cell differentiation. In this study, we successfully isolated the ovarian cancer initiating cells (OCICs) and demonstrated YAP promoted self-renewal of ovarian cancer initiated cell (OCIC) through its downstream co-activator TEAD. YAP and TEAD families were required for maintaining the expression of specific genes that may be involved in OCICs' stemness and chemoresistance. Taken together, our data first indicate that YAP/TEAD co-activator regulated ovarian cancer initiated cell pluripotency and chemo-resistance. It proposed a new mechanism on the drug resistance in cancer stem cell that Hippo-YAP signal pathway might serve as therapeutic targets for ovarian cancer treatment in clinical. PMID:25369529

  2. YAP/TEAD co-activator regulated pluripotency and chemoresistance in ovarian cancer initiated cells.

    PubMed

    Xia, Yan; Zhang, Yin-Li; Yu, Chao; Chang, Ting; Fan, Heng-Yu

    2014-01-01

    Recent evidence suggests that some solid tumors, including ovarian cancer, contain distinct populations of stem cells that are responsible for tumor initiation, growth, chemo-resistance, and recurrence. The Hippo pathway has attracted considerable attention and some investigators have focused on YAP functions for maintaining stemness and cell differentiation. In this study, we successfully isolated the ovarian cancer initiating cells (OCICs) and demonstrated YAP promoted self-renewal of ovarian cancer initiated cell (OCIC) through its downstream co-activator TEAD. YAP and TEAD families were required for maintaining the expression of specific genes that may be involved in OCICs' stemness and chemoresistance. Taken together, our data first indicate that YAP/TEAD co-activator regulated ovarian cancer initiated cell pluripotency and chemo-resistance. It proposed a new mechanism on the drug resistance in cancer stem cell that Hippo-YAP signal pathway might serve as therapeutic targets for ovarian cancer treatment in clinical.

  3. Inflammatory Breast Cancer from Metastatic Ovarian Cancer

    PubMed Central

    Achariyapota, Vuthinun; Chuangsuwanich, Tuenjai

    2016-01-01

    Metastases to the breast from tumors other than breast carcinomas are extremely rare and represent only 0.2–1.3% of all diagnosed malignant breast tumors. Furthermore, while the most common sites for advanced ovarian cancer metastases are the liver, lung, and pleura, metastasis to the breast from a primary ovarian cancer is uncommon and has only been reported in 0.03–0.6% of all breast cancers. Here we describe a case report of a 50-year-old female patient with a rare case of breast metastases from an advanced ovarian cancer, presenting as inflammatory breast cancer. Our observations emphasize the clinical importance of distinguishing between primary and metastatic breast cancer during diagnosis for the purpose of appropriate prognosis and treatment. PMID:27047697

  4. MUC1 in endometriosis and ovarian cancer.

    PubMed

    Vlad, Anda M; Diaconu, Iulia; Gantt, Kira R

    2006-01-01

    Endometriosis is a chronic, debilitating disease, associated with pelvic pain and infertility. Recent epidemiological studies suggest that women with endometriosis are at increased risk for ovarian cancer. Although the causative factors for both endometriosis and ovarian cancer remain largely unknown, several similarities between the proposed etiology of ovarian cancer and the observed pathophysiology of endometriosis have been reported. MUC1 glycoprotein is present in endometriotic lesions and overexpressed in epithelial ovarian tumors. We are currently studying immunity to MUC1 antigen in newly emerging preclinical models for endometriosis and ovarian cancer and exploring the potential for immune therapy/prevention with MUC1 in both diseases.

  5. Can Ovarian Cancer Be Prevented?

    MedlinePlus

    ... need to be removed by the time the woman is 35. Some women who have a high risk of ovarian cancer due to BRCA gene mutations feel that having their ovaries and fallopian tubes removed is not right for them. Often doctors recommend that those women ...

  6. Human adipose mesenchymal stem cell-derived exosomal-miRNAs are critical factors for inducing anti-proliferation signalling to A2780 and SKOV-3 ovarian cancer cells

    PubMed Central

    Reza, Abu Musa Md Talimur; Choi, Yun-Jung; Yasuda, Hideyo; Kim, Jin-Hoi

    2016-01-01

    An enigmatic question exists concerning the pro- or anti-cancer status of mesenchymal stem cells (MSCs). Despite growing interest, this question remains unanswered, and the debate became intensified with new evidences backing each side. Here, we showed that human adipose MSC (hAMSC)-derived conditioned medium (CM) exhibited inhibitory effects on A2780 human ovarian cancer cells by blocking the cell cycle, and activating mitochondria-mediated apoptosis signalling. Explicitly, we demonstrated that exosomes, an important biological component of hAMSC-CM, could restrain proliferation, wound-repair and colony formation ability of A2780 and SKOV-3 cancer cells. Furthermore, hAMSC-CM-derived exosomes induced apoptosis signalling by upregulating different pro-apoptotic signalling molecules, such as BAX, CASP9, and CASP3, as well as downregulating the anti-apoptotic protein BCL2. More specifically, cancer cells exhibited reduced viability following fresh or protease-digested exosome treatment; however, treatment with RNase-digested exosomes could not inhibit the proliferation of cancer cells. Additionally, sequencing of exosomal RNAs revealed a rich population of microRNAs (miRNAs), which exhibit anti-cancer activities by targeting different molecules associated with cancer survival. Our findings indicated that exosomal miRNAs are important players involved in the inhibitory influence of hAMSC-CM towards ovarian cancer cells. Therefore, we believe that these comprehensive results will provide advances concerning ovarian cancer research and treatment. PMID:27929108

  7. Biological Basis for Chemoprevention of Ovarian Cancer

    DTIC Science & Technology

    2000-10-01

    Since reduction of ovulation is protective against ovarian cancer, prevention may represent a feasible approach to decreasing mortality . To achieve a...potent apoptotic effect on ovarian epithelial cells, the use of levonorgestrel in chemoprevention of ovarian cancer is being explored in chickens and women...A chemoprevention trial is ongoing in chickens and we will begin a trial to determine whether levonorgestrel induces apoptosis in the ovarian epithelium of women undergoing oophorectomy.

  8. Ovarian cancer: epidemiology and risk factors.

    PubMed

    La Vecchia, Carlo

    2017-01-01

    The present overview of ovarian cancer epidemiology summarizes the main results for a network of case-control studies in Italy and from the Collaborative Group on Epidemiological Studies of Ovarian Cancer. There are consistent inverse relations between parity, oral contraceptive use and the risk of ovarian cancer. For other menstrual and hormonal factors (i.e. early age at menarche and late menopause), there are established associations, but of limited impact on ovarian cancer incidence on a population level. Serous and endometrioid ovarian cancers (but not mucinous or clear cell types) are related to current and recent use of hormone replacement therapy in menopause. There are no strong associations with alcohol and tobacco overall, but a direct link for tobacco with (borderline) mucinous cancers, of limited impact, however, on overall ovarian cancer mortality. There are direct associations of ovarian cancer risk with height and BMI, as well as possible relations with selected dietary factors - in the absence, however, of consistent findings - and a possible inverse association with physical activity. There is a strong association with a family history of ovarian cancer (and a few selected other neoplasms, including colorectum and endometrium). Recognized risk factors explain only a limited proportion of ovarian cancer cases on a population level. A key reason for the recent favourable trends of ovarian cancer incidence and mortality in several high-income countries is the widespread use of oral contraceptive in the generations born after 1930.

  9. Ovarian cancer: targeting the untargetable.

    PubMed

    Birrer, Michael J

    2014-01-01

    The premise that all tumors are targetable has been met with some controversy in the approach to epithelial ovarian cancer (EOC). Genomic analysis shows that these tumors (specifically, high-grade serous carcinomas) are genomically unstable and lack actionable driver mutations, much like HER2 in breast and gastric cancers. In this paper, Michael Birrer, MD, PhD, Massachusetts General Hospital, argues that the interpretation of genomic data in ovarian cancer requires a more thoughtful approach that necessitates a closer inspection of the data beyond the mere presence or absence of mutations. We must look at the extensive genomic alterations in DNA and, to understand more about the role of those genes affected by these changes, look beyond the tumor to the role of the stroma. As such, Dr. Birrer is arguing for the importance of translational research. This will be the key to precision medicine in ovarian cancer, as we approach drug discovery and improvements in treatment. Dr. Birrer is a world-renowned scientist who has devoted his career to the study of gynecologic cancers. He has published over 200 papers and written over 27 book chapters and reviews, served on numerous leadership positions in gynecologic oncology (including as co-chair of the National Cancer Institute's Gynecologic Cancer Steering Committee), and remains a clinician-scientist with an active lab and an active clinic. His career trajectory has shown me it is possible to be engaged as a researcher and a clinician and the work he has done has already impacted the care of patients with ovarian cancer. Don S. Dizon, MD, ASCO Educational Book Editor.

  10. [Pancreatic cancer stem cell].

    PubMed

    Hamada, Shin; Masamune, Atsushi; Shimosegawa, Tooru

    2015-05-01

    Prognosis of pancreatic cancer remains dismal due to the resistance against conventional therapies. Metastasis and massive invasion toward surrounding organs hamper radical resection. Small part of entire cancer cells reveal resistance against chemotherapy or radiotherapy, increased tumorigenicity and migratory phenotype. These cells are called as cancer stem cells, as a counter part of normal stem cells. In pancreatic cancer, several cancer stem cell markers have been identified, which enabled detailed characterization of pancreatic cancer stem cells. Recent researches clarified that conventional chemotherapy itself could increase cancer cells with stem cell-phenotype, suggesting the necessity of cancer stem cell-targeting therapy. Based on these observations, pancreatic cancer stem cell-targeting therapies have been tested, which effectively eliminated cancer stem cell fraction and attenuated cancer progression in experimental models. Clinical efficacy of these therapies need to be evaluated, and cancer stem cell-targeting therapy will contribute to improve the prognosis of pancreatic cancer.

  11. Ovarian Cancer Is an Imported Disease: Fact or Fiction?

    PubMed Central

    Kuhn, Elisabetta; Kurman, Robert J.

    2012-01-01

    The cell of origin of ovarian cancer has been long debated. The current paradigm is that epithelial ovarian cancer (EOC) arises from the ovarian surface epithelium (OSE). OSE is composed of flat, nondescript cells more closely resembling the mesothelium lining the peritoneal cavity, with which it is continuous, rather than the various histologic types of ovarian carcinoma (serous, endometrioid, and clear cell carcinoma), which have a Müllerian phenotype. Accordingly, it has been argued that the OSE undergoes a process termed “metaplasia” to account for this profound morphologic transformation. Recent molecular and clinicopathologic studies not only have failed to support this hypothesis but also have provided evidence that EOC stems from Müllerian-derived extraovarian cells that involve the ovary secondarily, thereby calling into question the very existence of primary EOC. This new model of ovarian carcinogenesis proposes that fallopian tube epithelium (benign or malignant) implants on the ovary to give rise to both high-grade and low-grade serous carcinomas, and that endometrial tissue implants on the ovary and produces endometriosis, which can undergo malignant transformation into endometrioid and clear cell carcinoma. Thus, ultimately EOC is not ovarian in origin but rather is secondary, and it is logical to conclude that the only true primary ovarian neoplasms are germ cell and gonadal stromal tumors analogous to tumors in the testis. If this new model is confirmed, it has profound implications for the early detection and treatment of “ovarian cancer.” PMID:22506137

  12. Cisplatin and Flavopiridol in Treating Patients With Advanced Ovarian Epithelial Cancer or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2014-05-06

    Recurrent Ovarian Epithelial Cancer; Recurrent Primary Peritoneal Cavity Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIA Primary Peritoneal Cavity Cancer; Stage IIIB Ovarian Epithelial Cancer; Stage IIIB Primary Peritoneal Cavity Cancer; Stage IIIC Ovarian Epithelial Cancer; Stage IIIC Primary Peritoneal Cavity Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Primary Peritoneal Cavity Cancer

  13. Epigenomics of Ovarian Cancer and Its Chemoprevention

    PubMed Central

    Chen, Huaping; Hardy, Tabitha M.; Tollefsbol, Trygve O.

    2011-01-01

    Ovarian cancer is a major cause of death among gynecological cancers and its etiology is still unclear. Currently, the two principle obstacles in treating this life threatening disease are lack of effective biomarkers for early detection and drug resistance after initial chemotherapy. Similar to other cancers, the initiation and development of ovarian cancer is characterized by disruption of oncogenes and tumor suppressor genes by both genetic and epigenetic mechanisms. While it is well known that it is challenging to treat ovarian cancer through a genetic strategy due in part to its heterogeneity, the reversibility of epigenetic mechanisms involved in ovarian cancer opens exciting new avenues for treatment. The epigenomics of ovarian cancer has therefore become a rapidly expanding field leading to intense investigation. A review on the current status of the field is thus warranted. In this analysis, we will evaluate the current status of epigenomics of ovarian cancer and will include epigenetic mechanisms involved in ovarian cancer development such as DNA methylation, histone modifications, and non-coding microRNA. Development of biomarkers, the epigenetic basis for drug resistance and improved chemotherapy for ovarian cancer will also be assessed. In addition, the potential use of natural compounds as epigenetic modulators in chemotherapy shows promise in moving to the forefront of ovarian cancer treatment strategies. PMID:22303362

  14. Analysis of disseminated tumor cells before and after platinum based chemotherapy in primary ovarian cancer. Do stem cell like cells predict prognosis?

    PubMed Central

    Wimberger, Pauline; Neubauer, Hans; Fehm, Tanja; Kimmig, Rainer; Kasimir-Bauer, Sabine

    2016-01-01

    Background We recently reported that the presence of disseminated tumor cells (DTCs) in the bone marrow (BM) of primary ovarian cancer patients (POC pts) correlated with reduced progression free survival (PFS) and overall survival (OS). Here we analyzed whether the negative prognostic influence was related to DTC persistence after platinum based chemotherapy and/or due to DTCs associated with stem cell character. Results DTCs were detected in 33/79 pts (42%) before and in 32/79 pts (41%) AT. Persistent DTCs were found in 13 pts, 20 pts were only positive BT, 19 pts AT and 27 pts had no DTCs. Whereas the presence of DTCs BT significantly correlated with reduced OS (p = 0.02), pts initially DTCneg BT but DTCpos AT had a significantly shorter PFS (p = 0.03). DTC persistence resulted in a shorter PFS and OS reaching borderline significance (p = 0.06; p = 0.07). LIN-28-and SOX-2 positive cells were detected in all eight pts AT. Patients and Methods 79 POC pts were studied for DTCs before therapy (BT) and after therapy (AT) using immunocytochemistry. Eight pts harboring at least five DTCs AT were further analyzed on two additional slides by four-fold immunofluorescence staining for DAPI, Cytokeratin (CK), SOX-2 or LIN-28, CD45 and CD34 (Cy5). A stem-like tumor cell was classified as Dapipos, CD45neg, CD34neg, SOX-2pos/LIN-28pos and CKpos or CKneg. Conclusions Stem cell associated proteins are expressed in DTCs that are present AT and their presence seem to be correlated with a worse outcome. Additional therapeutic regimens may be necessary to eliminate these cells. PMID:27049920

  15. Role of epigenomics in ovarian and endometrial cancers.

    PubMed

    Balch, Curtis; Matei, Daniela E; Huang, Tim H-M; Nephew, Kenneth P

    2010-06-01

    Ovarian cancer is the most lethal gynecologic malignancy and while constituting only 3% of all female cancers, it causes 14,600 deaths in the USA annually. Endometrial cancer, the most diagnosed and second-most fatal gynecologic cancer, afflicts over 40,000 US women annually, causing an estimated 7780 deaths in 2009. In both advanced ovarian and endometrial carcinomas, the majority of initially therapy-responsive tumors eventually evolve to a fully drug-resistant phenotype. In addition to genetic mutations, epigenetic anomalies are frequent in both gynecologic malignancies, including aberrant DNA methylation, atypical histone modifications and dysregulated expression of distinct microRNAs, resulting in altered gene-expression patterns favoring cell survival. In this article, we summarize the most recent hypotheses regarding the role of epigenetics in ovarian and endometrial cancers, including a possible role in tumor 'stemness' and also evaluate the possible therapeutic benefits of reversal of these oncogenic chromatin aberrations.

  16. Ovarian cancer immunotherapy: opportunities, progresses and challenges

    PubMed Central

    2010-01-01

    Due to the low survival rates from invasive ovarian cancer, new effective treatment modalities are urgently needed. Compelling evidence indicates that the immune response against ovarian cancer may play an important role in controlling this disease. We herein summarize multiple immune-based strategies that have been proposed and tested for potential therapeutic benefit against advanced stage ovarian cancer. We will examine the evidence for the premise that an effective therapeutic vaccine against ovarian cancer is useful not only for inducing remission of the disease but also for preventing disease relapse. We will also highlight the questions and challenges in the development of ovarian cancer vaccines, and critically discuss the limitations of some of the existing immunotherapeutic strategies. Finally, we will summarize our own experience on the use of patient-specific tumor-derived heat shock protein-peptide complex for the treatment of advanced ovarian cancer. PMID:20146807

  17. Belinostat and Carboplatin in Treating Patients With Recurrent or Persistent Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer That Did Not Respond to Carboplatin or Cisplatin

    ClinicalTrials.gov

    2014-06-18

    Brenner Tumor; Fallopian Tube Cancer; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Primary Peritoneal Cavity Cancer; Recurrent Ovarian Epithelial Cancer

  18. Platelet effects on ovarian cancer.

    PubMed

    Davis, Ashley N; Afshar-Kharghan, Vahid; Sood, Anil K

    2014-06-01

    Growing understanding of the role of thrombocytosis, high platelet turnover, and the presence of activated platelets in the circulation in cancer progression and metastasis has brought megakaryocytes into focus. Platelet biology is essential to hemostasis, vascular integrity, angiogenesis, inflammation, innate immunity, wound healing, and cancer biology. However, before megakaryocyte/platelet-directed therapies can be considered for clinical use, understanding of the mechanism and biology of paraneoplastic thrombocytosis in malignancy is required. Here, we provide an overview of the clinical implications, biological significance, and mechanisms of paraneoplastic thrombocytosis in the context of ovarian cancer.

  19. Targeting Ovarian Cancer with Porphysome Nanotechnology

    DTIC Science & Technology

    2014-10-01

    platform that could enhance OC diagnosis by integrating PET / CT and fluorescence imaging, and improve OC therapeutic efficacy and specificity by tailoring...Oza) for Phase I clinical trials. 15. SUBJECT TERMS Ovarian cancer, Folate receptor, Porphysome, Targeting therapy, Fluorescence imaging, PET / CT ...G: Liver. Figure 13. Ovarian cancer metastasis detected by 64 Cu-PLP. a. Representative whole-body PET / CT image of mouse with ovarian cancer

  20. Targeting Ovarian Cancer with Porphysome Nanotechnology

    DTIC Science & Technology

    2016-10-01

    1 Award Number: W81XWH-13-1-0442 TITLE: Targeting Ovarian Cancer with Porphysome Nanotechnology PRINCIPAL INVESTIGATOR: Gang Zheng CONTRACTING...Ovarian Cancer with Porphysome Nanotechnology 5a. CONTRACT NUMBER W81XWH-13-1-0442 5b. GRANT NUMBER W91ZSQ9277N522 5c. PROGRAM ELEMENT NUMBER 6...Image Guided Surgery; Biodistribution; Ovarian Cancer ; Preclinical Models. 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF

  1. Early Preinvasive Lesions in Ovarian Cancer

    PubMed Central

    Chene, Gautier; Lamblin, Gery; Le Bail-Carval, Karine; Chabert, Philippe; Bakrin, Naoual; Mellier, Georges

    2014-01-01

    Faced with the catastrophic prognosis for ovarian cancer due to the fact that it is most often diagnosed late at the peritoneal carcinomatosis stage, screening and early detection could probably reduce the mortality rate. A better understanding of the molecular characteristics of the different ovarian cancer subtypes and their specific molecular signatures is indispensable prior to development of new screening strategies. We discuss here the early natural history of ovarian cancer and its origins. PMID:24804229

  2. Palliative Care in Improving Quality of Life and Symptoms in Patients With Stage III-IV Pancreatic or Ovarian Cancer

    ClinicalTrials.gov

    2014-12-18

    Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Stage III Pancreatic Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIA Ovarian Germ Cell Tumor; Stage IIIB Ovarian Epithelial Cancer; Stage IIIB Ovarian Germ Cell Tumor; Stage IIIC Ovarian Epithelial Cancer; Stage IIIC Ovarian Germ Cell Tumor; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Pancreatic Cancer

  3. Ovarian Cancer: Still Possible After Hysterectomy?

    MedlinePlus

    ... cancer Is ovarian cancer still possible after a hysterectomy? Answers from Yvonne Butler Tobah, M.D. Yes, ... primary peritoneal cancer) if you've had a hysterectomy. Your risk depends on the type of hysterectomy ...

  4. Practical considerations in ovarian cancer chemotherapy

    PubMed Central

    Cristea, Mihaela; Han, Ernest; Salmon, Lennie; Morgan, Robert J.

    2010-01-01

    Epithelial ovarian cancer remains the most lethal gynecologic malignancy despite advances in treatment. The standard management generally involves a combination of surgical tumor debulking and chemotherapy. Over the decades, chemotherapy for ovarian cancer has evolved and currently involves a combination of intravenous platinum and taxane chemotherapy. Over the past decade, three randomized phase III trials have been reported, and all have demonstrated a significant survival advantage for intraperitoneal compared with intravenous chemotherapy. However, there are potential barriers and controversies related to the administration of intraperitoneal chemotherapy in ovarian cancer patients. In this review, we discuss the evolution and current management considerations of chemotherapy for the treatment of epithelial ovarian cancer. PMID:21789133

  5. Molecular Epidemiology of Ovarian Cancer

    DTIC Science & Technology

    2006-07-01

    tissue and 10 blood samples have been collected to date. We are in the process of cross -checking with the local Gynaecology-Oncology register and the...ongoing basis (b) Data will be cleaned using frequency and range checks, implausible values will be cross -checked against the original questionnaires and...Initially, a cross -validated model of gene expression in primary ovarian cancer vs. over 100 other primary tumours was created and applied to LMP

  6. Ovarian Cancer Fact Sheet

    MedlinePlus

    ... other parts of the body. This is called metastasis. Cancer that starts in the ovaries and spreads ... other parts of the body. This is called metastasis (muh-TAS-tuh-sis). Cancer that starts in ...

  7. Ovarian Cancer in Hereditary Cancer Susceptibility Syndromes.

    PubMed

    Nakonechny, Quentin B; Gilks, C Blake

    2016-06-01

    Hereditary breast and ovarian cancer (HBOC) syndrome and Lynch syndrome (LS) are associated with increased risk of developing ovarian carcinoma. Patients with HBOC have a lifetime risk of up to 50% of developing high-grade serous carcinoma of tube or ovary; patients with LS have a 10% lifetime risk of developing endometrioid or clear cell carcinoma of the ovary. Testing all patients with tubo-ovarian high-grade serous carcinoma for mutations associated with HBOC syndrome, and all patients presenting with endometrioid or clear cell carcinoma of the ovary for mutations associated with LS can identify patients with undiagnosed underlying hereditary cancer susceptibility syndromes. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Human omental adipose-derived mesenchymal stem cell-conditioned medium alters the proteomic profile of epithelial ovarian cancer cell lines in vitro

    PubMed Central

    Zhang, Yanling; Dong, Weihong; Wang, Junjie; Cai, Jing; Wang, Zehua

    2017-01-01

    Mesenchymal stem cells (MSCs) have been reported to participate in the formation of supportive tumor stroma. The abilities of proliferation and invasion of human epithelial ovarian cancer (EOC) cells were significantly enhanced when indirectly cocultured with human omental adipose-derived MSCs (O-ADSCs) in vitro. However, the underlying mechanisms remain poorly understood. In this study, EOC cells were cultured with conditioned medium (CM) from O-ADSCs (O-ADSC), and the effect of O-ADSC CM on the proteomic profile of EOC cells was assessed by two-dimensional gel electrophoresis (2-DE), followed by liquid chromatography and tandem mass spectrometry. The 2-DE assays revealed a global increase in protein expression in the EOC cells treated with CM. Nine proteins were identified from 11 selected protein spots with differential expression after treatment with CM from O-ADSCs. All the nine proteins have been linked to carcinoma and apoptosis, and the migration ability of tumor cells can be regulated by these proteins. Moreover, the upregulation of prohibitin and serine/arginine-rich splicing factor 1 in EOC cells treated with CM was further confirmed by quantitative real-time polymerase chain reaction. These results suggest that O-ADSCs affect the proteomic profile of EOC cells via paracrine mechanism in favor of EOC progression. PMID:28360526

  9. Targeting tissue factor as a novel therapeutic oncotarget for eradication of cancer stem cells isolated from tumor cell lines, tumor xenografts and patients of breast, lung and ovarian cancer

    PubMed Central

    Hu, Zhiwei; Xu, Jie; Cheng, Jijun; McMichael, Elizabeth; Yu, Lianbo; Carson, William E.

    2017-01-01

    Targeting cancer stem cell (CSC) represents a promising therapeutic approach as it can potentially fight cancer at its root. The challenge is to identify a surface therapeutic oncotarget on CSC. Tissue factor (TF) is known as a common yet specific surface target for cancer cells and tumor neovasculature in several solid cancers. However, it is unknown if TF is expressed by CSCs. Here we demonstrate that TF is constitutively expressed on CD133 positive (CD133+) or CD24-CD44+ CSCs isolated from human cancer cell lines, tumor xenografts from mice and breast tumor tissues from patients. TF-targeted agents, i.e., a factor VII (fVII)-conjugated photosensitizer (fVII-PS for targeted photodynamic therapy) and fVII-IgG1Fc (Immunoconjugate or ICON for immunotherapy), can eradicate CSC via the induction of apoptosis and necrosis and via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, respectively. In conclusion, these results demonstrate that TF is a novel surface therapeutic oncotarget for CSC, in addition to cancer cell TF and tumor angiogenic vascular endothelial TF. Moreover, this research highlights that TF-targeting therapeutics can effectively eradicate CSCs, without drug resistance, isolated from breast, lung and ovarian cancer with potential to translate into other most commonly diagnosed solid cancer, in which TF is also highly expressed. PMID:27903969

  10. Targeting tissue factor as a novel therapeutic oncotarget for eradication of cancer stem cells isolated from tumor cell lines, tumor xenografts and patients of breast, lung and ovarian cancer.

    PubMed

    Hu, Zhiwei; Xu, Jie; Cheng, Jijun; McMichael, Elizabeth; Yu, Lianbo; Carson, William E

    2017-01-03

    Targeting cancer stem cell (CSC) represents a promising therapeutic approach as it can potentially fight cancer at its root. The challenge is to identify a surface therapeutic oncotarget on CSC. Tissue factor (TF) is known as a common yet specific surface target for cancer cells and tumor neovasculature in several solid cancers. However, it is unknown if TF is expressed by CSCs. Here we demonstrate that TF is constitutively expressed on CD133 positive (CD133+) or CD24-CD44+ CSCs isolated from human cancer cell lines, tumor xenografts from mice and breast tumor tissues from patients. TF-targeted agents, i.e., a factor VII (fVII)-conjugated photosensitizer (fVII-PS for targeted photodynamic therapy) and fVII-IgG1Fc (Immunoconjugate or ICON for immunotherapy), can eradicate CSC via the induction of apoptosis and necrosis and via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, respectively. In conclusion, these results demonstrate that TF is a novel surface therapeutic oncotarget for CSC, in addition to cancer cell TF and tumor angiogenic vascular endothelial TF. Moreover, this research highlights that TF-targeting therapeutics can effectively eradicate CSCs, without drug resistance, isolated from breast, lung and ovarian cancer with potential to translate into other most commonly diagnosed solid cancer, in which TF is also highly expressed.

  11. Aromatase expression in ovarian epithelial cancers.

    PubMed

    Cunat, S; Rabenoelina, F; Daurès, J-P; Katsaros, D; Sasano, H; Miller, W R; Maudelonde, T; Pujol, P

    2005-01-01

    Our study focused on aromatase cytochrome P450 (CYP19) expression in ovarian epithelial normal and cancer cells and tissues. Aromatase mRNA expression was analyzed by real-time PCR in ovarian epithelial cancer cell lines, in human ovarian surface epithelial (HOSE) cell primary cultures, and in ovarian tissue specimens (n=94), including normal ovaries, ovarian cysts and cancers. Aromatase mRNA was found to be expressed in HOSE cells, in BG1, PEO4 and PEO14, but not in SKOV3 and NIH:OVCAR-3 ovarian cancer cell lines. Correlation analysis of aromatase expression was performed according to clinical, histological and biological parameters. Aromatase expression in ovarian tissue specimens was higher in normal ovaries and cysts than in cancers (P<0.0001). Using laser capture microdissection in normal postmenopausal ovaries, aromatase was found to be predominantly expressed in epithelial cells as compared to stromal component. Using immunohistochemistry (IHC), aromatase was also detected in the epithelium component. There was an inverse correlation between aromatase and ERalpha expression in ovarian tissues (P<0.001, r=-0.34). In the cancer group, no significant differences in aromatase expression were observed according to tumor histotype, grade, stage and survival. Aromatase activity was evaluated in ovarian epithelial cancer (OEC) cell lines by the tritiated water assay and the effects of third-generation aromatase inhibitors (AIs) on aromatase activity and growth were studied. Letrozole and exemestane were able to completely inhibit aromatase activity in BG1 and PEO14 cell lines. Interestingly, both AI showed an antiproliferative effect on the estrogen responsive BG1 cell line co-expressing aromatase and ERalpha. Aromatase expression was found in ovarian epithelial normal tissues and in some ovarian epithelial cancer cells and tissues. This finding raises the possibility that some tumors may respond to estrogen and provides a basis for ascertaining an antimitogenic

  12. Lead, selenium and nickel concentrations in epithelial ovarian cancer, borderline ovarian tumor and healthy ovarian tissues.

    PubMed

    Canaz, Emel; Kilinc, Metin; Sayar, Hamide; Kiran, Gurkan; Ozyurek, Eser

    2017-09-01

    Wide variation exists in ovarian cancer incidence rates suggesting the importance of environmental factors. Due to increasing environmental pollution, trace elements and heavy metals have drawn attention in studies defining the etiology of cancer, but scant data is available for ovarian cancer. Our aim was to compare the tissue concentrations of lead, selenium and nickel in epithelial ovarian cancer, borderline tumor and healthy ovarian tissues. The levels of lead, selenium and nickel were estimated using atomic absorption spectrophotometry in formalin-fixed paraffin-embedded tissue samples. Tests were carried out in 20 malignant epithelial ovarian cancer, 15 epithelial borderline tumor and 20 non-neoplastic healthy ovaries. Two samples were collected for borderline tumors, one from papillary projection and one from the smooth surface of cyst wall. Pb and Ni concentrations were found to be higher both in malignant and borderline tissues than those in healthy ovaries. Concentrations of Pb and Ni in malignant tissues, borderline papillary projections and capsular tissue samples were not different. Comparison of Se concentrations of malignant, borderline and healthy ovarian tissues did not reveal statistical difference. Studied metal levels were not found to be different in either papillary projection or in cyst wall of the borderline tumors. This study revealed the accumulation of lead and nickel in ovarian tissue is associated with borderline and malignant proliferation of the surface epithelium. Accumulation of these metals in epithelial ovarian cancer and borderline ovarian tumor has not been demonstrated before. Copyright © 2017 Elsevier GmbH. All rights reserved.

  13. MiR-197 induces Taxol resistance in human ovarian cancer cells by regulating NLK.

    PubMed

    Zou, Dongling; Wang, Dong; Li, Rong; Tang, Ying; Yuan, Li; Long, Xingtao; Zhou, Qi

    2015-09-01

    Chemotherapy is the preferred therapeutic approach for the therapy of advanced ovarian cancer, but 5-year survival rate remains low due to the development of drug resistance. Increasing evidence has documented that microRNAs (miRNAs) act important roles in drug resistance in a variety types of cancer. However, the roles of miRNA in regulating Taxol resistance in ovarian cancer and the detailed mechanism are less reported. We used Taqman probe stem loop real-time PCR to accurately measure the levels of miR-197 in normal ovarian cells, ovarian cancer cells, and Taxol-resistant ovarian cancer cells and found that miR-197 was significantly increased in Taxol-resistant ovarian cancer cells. Enforced expression of miR-197 can promote Taxol resistance, cell proliferation, and invasion of ovarian cancer cells. Meanwhile, repression of miR-197 in ovarian cancer cells can sensitize its response to Taxol and also induced attenuated cell proliferation and invasion ability. Furthermore, investigation of the detailed mechanism showed that the promotion of miR-197 on drug resistance in ovarian cancer cells was partially mediated by downregulating NLK, a negative regulator of WNT signaling pathway. Taken together, our work first demonstrated that miR-197 can confer drug resistance to Taxol, by regulating tumor suppressor, NLK expression in ovarian cancer cells.

  14. What Are the Key Statistics about Ovarian Cancer?

    MedlinePlus

    ... cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of ... For reprint requests, please see our Content Usage Policy . About Ovarian Cancer What Is Ovarian Cancer? What ...

  15. Biological Basis for Chemoprevention of Ovarian Cancer

    DTIC Science & Technology

    1999-10-01

    Since reduction of ovulation is protective against ovarian cancer, prevention may represent a feasible approach to decreasing mortality . To achieve a...cells, the use of levonorgestrel in chemoprevention of ovarian cancer is being explored in chickens and women. A chernoprevention trial is ongoing in...chickens and we will begin a trial to determine whether levonorgestrel induces apoptosis in the ovarian epithelium of women undergoing oophorectomy.

  16. OVARIAN CANCER: INVOLVEMENT OF THE MATRIX METALLOPROTEINASES

    PubMed Central

    Al-Alem, Linah; Curry, Thomas E.

    2016-01-01

    Ovarian cancer is the leading cause of death from gynecologic malignancies. Reasons for the high mortality rate associated with ovarian cancer include a late diagnosis at which time the cancer has metastasized throughout the peritoneal cavity. Cancer metastasis is facilitated by the remodeling of the extracellular tumor matrix by a family of proteolytic enzymes known as the matrix metalloproteinases (MMPs). There are 23 members in the MMP family, many of which have been reported to be associated with ovarian cancer. In the current paradigm, ovarian tumor cells and the surrounding stromal cells stimulate the synthesis and/or activation of various MMPs to aid in tumor growth, invasion, and eventual metastasis. This review sheds light on the different MMPs in the various types of ovarian cancer and their impact on the progression of this gynecologic malignancy. PMID:25918438

  17. Ovarian cancer: involvement of the matrix metalloproteinases.

    PubMed

    Al-Alem, Linah; Curry, Thomas E

    2015-08-01

    Ovarian cancer is the leading cause of death from gynecologic malignancies. One of the reasons for the high mortality rate associated with ovarian cancer is its late diagnosis, which often occurs after the cancer has metastasized throughout the peritoneal cavity. Cancer metastasis is facilitated by the remodeling of the extracellular tumor matrix by a family of proteolytic enzymes known as the matrix metalloproteinases (MMPs). There are 23 members of the MMP family, many of which have been reported to be associated with ovarian cancer. In the current paradigm, ovarian tumor cells and the surrounding stromal cells stimulate the synthesis and/or activation of various MMPs to aid in tumor growth, invasion, and eventual metastasis. The present review sheds light on the different MMPs in the various types of ovarian cancer and on their impact on the progression of this gynecologic malignancy.

  18. An integrated analysis identifies STAT4 as a key regulator of ovarian cancer metastasis.

    PubMed

    Zhao, L; Ji, G; Le, X; Luo, Z; Wang, C; Feng, M; Xu, L; Zhang, Y; Lau, W B; Lau, B; Yang, Y; Lei, L; Yang, H; Xuan, Y; Chen, Y; Deng, X; Yi, T; Yao, S; Zhao, X; Wei, Y; Zhou, S

    2017-06-15

    Epithelial ovarian cancer (EOC) is one of the most common gynecological cancers, with diagnosis often at a late stage. Metastasis is a major cause of death in patients with EOC, but the underlying molecular mechanisms remain obscure. Here, we utilized an integrated approach to find potential key transcription factors involved in ovarian cancer metastasis and identified STAT4 as a critical player in ovarian cancer metastasis. We found that activated STAT4 was overexpressed in epithelial cells of ovarian cancer and STAT4 overexpression was associated with poor outcome of ovarian cancer patients, which promoted metastasis of ovarian cancer in both in vivo and in vitro. Although STAT4 mediated EOC metastasis via inducing epithelial-to-mesenchymal transition (EMT) of ovarian cancer cells in vivo, STAT4 failed to induce EMT directly in vitro, suggesting that STAT4 might mediate EMT process via cancer-stroma interactions. Further functional analysis revealed that STAT4 overexpression induced normal omental fibroblasts and adipose- and bone marrow-derived mesenchymal stem cells to obtain cancer-associated fibroblasts (CAF)-like features via induction of tumor-derived Wnt7a. Reciprocally, increased production of CAF-induced CXCL12, IL6 and VEGFA within tumor microenvironment could enable peritoneal metastasis of ovarian cancer via induction of EMT program. In summary, our study established a model that STAT4 promotes ovarian cancer metastasis via tumor-derived Wnt7a-induced activation of CAFs.

  19. Metabolic Regulation of Ovarian Cancer Cell Death

    DTIC Science & Technology

    2012-07-01

    Following treatment with chemotherapeutic agents, responsive ovarian cancer cells undergo apoptotic cell death . Several groups have shown that the...apoptotic protease, caspase 2 (C2), is an essential activator of cell death in ovarian cancer cells treated with cisplatin and we have found, by knock

  20. Rethinking Ovarian Cancer: Recommendations for Improving Outcomes

    PubMed Central

    Vaughan, Sebastian; Coward, Jermaine I.; Bast Jr., Robert C.; Berchuck, Andy; Berek, Jonathan S.; Brenton, James D.; Coukos, George; Crum, Christopher C.; Drapkin, Ronny; Etemadmoghadam, Dariush; Friedlander, Michael; Gabra, Hani; Kaye, Stan B.; Lord, Chris J.; Lengyel, Ernst; Levine, Douglas A.; McNeish, Iain A.; Menon, Usha; Mills, Gordon B.; Nephew, Kenneth P.; Oza, Amit M.; Sood, Anil K.; Stronach, Euan A.; Walczak, Henning; Bowtell, David D.; Balkwill, Frances R.

    2012-01-01

    There have been major advances in our understanding of the cellular and molecular biology of the human malignancies collectively referred to as ovarian cancer. At a recent Helene Harris Memorial Trust meeting, an international group of researchers considered actions that should be taken to improve the outcome for women with ovarian cancer. Nine major recommendations are outlined in this Perspective. PMID:21941283

  1. Ovarian cancer mortality and industrial pollution.

    PubMed

    García-Pérez, Javier; Lope, Virginia; López-Abente, Gonzalo; González-Sánchez, Mario; Fernández-Navarro, Pablo

    2015-10-01

    We investigated whether there might be excess ovarian cancer mortality among women residing near Spanish industries, according to different categories of industrial groups and toxic substances. An ecologic study was designed to examine ovarian cancer mortality at a municipal level (period 1997-2006). Population exposure to pollution was estimated by means of distance from town to facility. Using Poisson regression models, we assessed the relative risk of dying from ovarian cancer in zones around installations, and analyzed the effect of industrial groups and pollutant substances. Excess ovarian cancer mortality was detected in the vicinity of all sectors combined, and, principally, near refineries, fertilizers plants, glass production, paper production, food/beverage sector, waste treatment plants, pharmaceutical industry and ceramic. Insofar as substances were concerned, statistically significant associations were observed for installations releasing metals and polycyclic aromatic chemicals. These results support that residing near industries could be a risk factor for ovarian cancer mortality. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Inhibition of Ovarian Cancer Chemoresistance and Metastasis with Antagonists of Hyaluronan-CD44-CD147 Interactions

    DTIC Science & Technology

    2015-09-01

    CD147 interactions in cancer stem cell properties, especially drug resistance, to improvement of therapy for malignant ovarian carcinoma. In this grant...we have shown that: a) drug -resistant human ovarian carcinoma cell lines contain CD133-positive/ CD147-positive/ CD44-positive cancer stem-like...small hyaluronan oligosaccharides sensitize drug -resistant human ovarian carcinoma cells to various chemotherapeutic agents in culture and in vivo; c

  3. Cells of Origin of Epithelial Ovarian Cancers

    DTIC Science & Technology

    2015-09-01

    lethal malignancy of the female reproductive system , largely due to the fact that most EOCs are diagnosed only after the cancer has metastasized into the...Epithelial ovarian cancer (EOC) is the most lethal malignancy of the female reproductive system , largely due to the fact that most EOCs are diagnosed only...ovarian cancer by defined multiple genetic changes in a mouse model system . Cancer Cell 1, 53-62. Quartuccio, S.M., Lantvit, D.D., Bosland, M.C., and

  4. Levels of Distress in Women at Risk for Ovarian Cancer

    DTIC Science & Technology

    2008-01-01

    subjective risk status, their knowledge of ovarian cancer and risk factors, uncertainty about ovarian cancer, levels of anxiety and depression ...behaviors, anxiety, depression 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON...their subjective risk status, their knowledge of ovarian cancer and risk factors, uncertainty about ovarian cancer, levels of anxiety and depression

  5. Natural history of ovarian cancer.

    PubMed

    Vargas, Arturo Novoa

    2014-01-01

    Ovarian cancer is a disease laden with paradigms, and it is a serious health problem. It is important to know its natural history, as it is multifactorial in origin, and also to understand its behaviour given its risk factors which can lead to death from metastasis in patients. It continues to be a challenge for oncologists. An analytical literature review was performed to update the latest concepts of its origin, evolution, risk factors, pre-clinical horizon, and its clinical manifestations; until the death of the patient.

  6. Natural history of ovarian cancer

    PubMed Central

    Vargas, Arturo Novoa

    2014-01-01

    Ovarian cancer is a disease laden with paradigms, and it is a serious health problem. It is important to know its natural history, as it is multifactorial in origin, and also to understand its behaviour given its risk factors which can lead to death from metastasis in patients. It continues to be a challenge for oncologists. An analytical literature review was performed to update the latest concepts of its origin, evolution, risk factors, pre-clinical horizon, and its clinical manifestations; until the death of the patient. PMID:25371706

  7. Chemoprevention of Ovarian Cancer

    DTIC Science & Technology

    2005-10-01

    coupled device camera . The interrogated tissue area was 2 mm in diameter. Fluorescence emission spectra ranging from 320 to 850 nm were collected...properties of normal and neoplastic human cervical tissue," Laser Surg. Med. 13, 646-655 (1993). 48. K. T. Schomacker, J. K. Frisoli, C. C. Compton , T. J...undergo apoptosis in response to certain physio- in mitochondrial finction in both normal and cancer cells. In logical stimuli and cytotoxic agents

  8. Predictive and therapeutic markers in ovarian cancer

    DOEpatents

    Gray, Joe W.; Guan, Yinghui; Kuo, Wen-Lin; Fridlyand, Jane; Mills, Gordon B.

    2013-03-26

    Cancer markers may be developed to detect diseases characterized by increased expression of apoptosis-suppressing genes, such as aggressive cancers. Genes in the human chromosomal regions, 8q24, 11q13, 20q11-q13, were found to be amplified indicating in vivo drug resistance in diseases such as ovarian cancer. Diagnosis and assessment of amplification levels certain genes shown to be amplified, including PVT1, can be useful in prediction of poor outcome of patient's response and drug resistance in ovarian cancer patients with low survival rates. Certain genes were found to be high priority therapeutic targets by the identification of recurrent aberrations involving genome sequence, copy number and/or gene expression are associated with reduced survival duration in certain diseases and cancers, specifically ovarian cancer. Therapeutics to inhibit amplification and inhibitors of one of these genes, PVT1, target drug resistance in ovarian cancer patients with low survival rates is described.

  9. [Update on current care guidelines: ovarian cancer].

    PubMed

    Leminen, Arto; Auranen, Annika; Bützow, Ralf; Hietanen, Sakari; Komulainen, Marja; Kuoppala, Tapio; Mäenpää, Johanna; Puistola, Ulla; Vuento, Maarit; Vuorela, Piia; Yliskoski, Merja

    2012-01-01

    Ovarian cancer is the most lethal gynaecological cancer. It appears that seemingly ovarian or primary peritoneal carcinomas, in fact, originate from fimbriae. BRCA1/2 mutation carriers are recommended for the removal of ovaries and fimbriae, to reduce the risk of cancer. Treatment of epithelial ovarian cancer is based on the combination of surgery and chemotherapy. The residual tumour volume at the primary operation is the most important predictive factor of survival. The best response at the primary treatment is observed with combination chemotherapy with taxane and platinum. Adding bevacitzumab to first line chemotherapy may improve survival.

  10. What Are the Risk Factors for Ovarian Cancer?

    MedlinePlus

    ... a higher risk of developing ovarian cancer. Reproductive history Women who have been pregnant and carried it ... for women taking both estrogen and progesterone. Family history of ovarian cancer, breast cancer, or colorectal cancer ...

  11. Ovarian Cancer: Opportunity for Targeted Therapy

    PubMed Central

    Tagawa, Tomoko; Morgan, Robert; Yen, Yun; Mortimer, Joanne

    2012-01-01

    Ovarian cancer is a common cause of cancer mortality in women with limited treatment effectiveness in advanced stages. The limitation to treatment is largely the result of high rates of cancer recurrence despite chemotherapy and eventual resistance to existing chemotherapeutic agents. The objective of this paper is to review current concepts of ovarian carcinogenesis. We will review existing hypotheses of tumor origin from ovarian epithelial cells, Fallopian tube, and endometrium. We will also review the molecular pathogenesis of ovarian cancer which results in two specific pathways of carcinogenesis: (1) type I low-grade tumor and (2) type II high-grade tumor. Improved understanding of the molecular basis of ovarian carcinogenesis has opened new opportunities for targeted therapy. This paper will also review these potential therapeutic targets and will explore new agents that are currently being investigated. PMID:22235203

  12. EGEN-001 and Pegylated Liposomal Doxorubicin Hydrochloride in Treating Patients With Recurrent or Persistent Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2014-08-11

    Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Recurrent Fallopian Tube Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Primary Peritoneal Cavity Cancer

  13. Proliferation and maturation of intratumoral blood vessels in women with malignant ovarian tumors assessed with cancer stem cells marker nestin and platelet derived growth factor PDGF-B.

    PubMed

    Czekierdowska, Sylwia; Stachowicz, Norbert; Chróściel, Mieczysław; Czekierdowski, Artur

    2017-01-01

    Platelet-derived growth factor B (PDGF-B) and nestin have been suggested to be useful in the assessment of neoangiogenesis in malignant ovarian masses. We aimed to investigate a possible association of these markers with newly formed microcapillaries and perivascular cells in ovarian tumors. Microvessel density (MVD) and pericytes were studied in 82 women with ovarian neoplasms, including 7 benign cysts, 7 borderline masses, 64 epithelial ovarian cancers and 4 other malignant ovarian tumors. Immunohistochemical staining included antibodies to CD34, PDGF-B and nestin. Median values of CD34-positive and nestin-positive MVD were: 24,5 (range:17-32) and 21 (range: 12-31), respectively. No significant correlation between intratumoral CD-34 positive MVD and nestin-positive MVD was found. Benign and borderline lesions more frequently than malignant tumors displayed low or medium values of nestin-positive MVD (p = 0.01). Histological grading of malignant tumors was associated with nestin-positive MVD (p = 0.01). Nestin expression in tumor cells was not correlated with tumor grade or histological subtype. PDGF-B expression was found in tumor microves-sels in 72% of cases (59/82). High expression of PDGF in pericapillary cells was strongly associated with high expression of this marker in cancer cells (p = 0.007). Significant correlations between PDGF-B and nestin expression in malignant tumor microvessels were also found (p = 0.04). Nestin and PDGF-B expressions were strongly associated with high grade tumors when compared to low grade or benign masses. We conclude that the assessment of PDGF-B and nestin-positive MVD could be used to identify only highly active, angiogenic malignant ovarian masses, where tumor vasculature is formed.

  14. Metformin Hydrochloride, Carboplatin, and Paclitaxel in Treating Patients With Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2017-01-24

    Ovarian Papillary Serous Carcinoma; Ovarian Serous Cystadenocarcinoma; Recurrent Fallopian Tube Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Primary Peritoneal Cavity Cancer

  15. Ovarian Cancer Incidence Corrected for Oophorectomy

    PubMed Central

    Baldwin, Lauren A.; Chen, Quan; Tucker, Thomas C.; White, Connie G.; Ore, Robert N.; Huang, Bin

    2017-01-01

    Current reported incidence rates for ovarian cancer may significantly underestimate the true rate because of the inclusion of women in the calculations who are not at risk for ovarian cancer due to prior benign salpingo-oophorectomy (SO). We have considered prior SO to more realistically estimate risk for ovarian cancer. Kentucky Health Claims Data, International Classification of Disease 9 (ICD-9) codes, Current Procedure Terminology (CPT) codes, and Kentucky Behavioral Risk Factor Surveillance System (BRFSS) Data were used to identify women who have undergone SO in Kentucky, and these women were removed from the at-risk pool in order to re-assess incidence rates to more accurately represent ovarian cancer risk. The protective effect of SO on the population was determined on an annual basis for ages 5–80+ using data from the years 2009–2013. The corrected age-adjusted rates of ovarian cancer that considered SO ranged from 33% to 67% higher than age-adjusted rates from the standard population. Correction of incidence rates for ovarian cancer by accounting for women with prior SO gives a better understanding of risk for this disease faced by women. The rates of ovarian cancer were substantially higher when SO was taken into consideration than estimates from the standard population. PMID:28368298

  16. Functional Proteomics-Based Ovarian Cancer Biomarkers

    DTIC Science & Technology

    2010-11-01

    tissue , then incubating the samples at various time points to see the effect on RPPA –determined protein levels had already been done using breast tissue ...1985): 131. 27  Cao, Liyun, et al. " Tissue transglutaminase protects epithelial ovarian cancer cells from cisplatin-induced apoptosis by promoting...Dabholkar, Meenakshi, et al. "ERCC1 and ERCC2 expression in malignant tissues from ovarian cancer patients." Journal of the National Cancer Institute

  17. Bevacizumab and Intravenous or Intraperitoneal Chemotherapy in Treating Patients With Stage II-III Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2016-12-21

    Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Undifferentiated Ovarian Carcinoma

  18. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer

    PubMed Central

    Bowtell, David D.; Böhm, Steffen; Ahmed, Ahmed A.; Aspuria, Paul-Joseph; Bast, Robert C.; Beral, Valerie; Berek, Jonathan S.; Birrer, Michael J.; Blagden, Sarah; Bookman, Michael A.; Brenton, James; Chiappinelli, Katherine B.; Martins, Filipe Correia; Coukos, George; Drapkin, Ronny; Edmondson, Richard; Fotopoulou, Christina; Gabra, Hani; Galon, Jérôme; Gourley, Charlie; Heong, Valerie; Huntsman, David G.; Iwanicki, Marcin; Karlan, Beth Y.; Kaye, Allyson; Lengyel, Ernst; Levine, Douglas A.; Lu, Karen H.; McNeish, Iain A.; Menon, Usha; Narod, Steve A.; Nelson, Brad H.; Nephew, Kenneth P.; Pharoah, Paul; Powell, Daniel J.; Ramos, Pilar; Romero, Iris L.; Scott, Clare L.; Sood, Anil K.; Stronach, Euan A.; Balkwill, Frances R.

    2016-01-01

    High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths, and overall survival has not changed significantly for several decades. In this Opinion article, we outline a set of research priorities that we believe will reduce incidence and improve outcomes for women with this disease. This ‘roadmap’ for HGSOC was determined after extensive discussions at an Ovarian Cancer Action meeting in January 2015. PMID:26493647

  19. Mechanisms of Ovarian Cancer Metastasis: Biochemical Pathways

    PubMed Central

    Nakayama, Kentaro; Nakayama, Naomi; Katagiri, Hiroshi; Miyazaki, Kohji

    2012-01-01

    Ovarian cancer is the most lethal gynecologic malignancy. Despite advances in chemotherapy, the five-year survival rate of advanced ovarian cancer patients with peritoneal metastasis remains around 30%. The most significant prognostic factor is stage, and most patients present at an advanced stage with peritoneal dissemination. There is often no clearly identifiable precursor lesion; therefore, the events leading to metastatic disease are poorly understood. This article reviews metastatic suppressor genes, the epithelial-mesenchymal transition (EMT), and the tumor microenvironment as they relate to ovarian cancer metastasis. Additionally, novel chemotherapeutic agents targeting the metastasis-related biochemical pathways are discussed. PMID:23109879

  20. OPT-821 With or Without Vaccine Therapy in Treating Patients With Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Peritoneal Cancer in Second or Third Complete Remission

    ClinicalTrials.gov

    2016-03-16

    Stage IA Fallopian Tube Cancer; Stage IA Ovarian Cancer; Stage IB Fallopian Tube Cancer; Stage IB Ovarian Cancer; Stage IC Fallopian Tube Cancer; Stage IC Ovarian Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  1. Ovarian cancer stroma: pathophysiology and the roles in cancer development.

    PubMed

    Furuya, Mitsuko

    2012-07-18

    Ovarian cancer represents one of the cancers with the worst prognostic in adult women. More than half of the patients who present with clinical signs such as abdominal bloating and a feeling of fullness already show advanced stages. The majority of ovarian cancers grow as cystic masses, and cancer cells easily spread into the pelvic cavity once the cysts rupture or leak. When the ovarian cancer cells disseminate into the peritoneal cavity, metastatic nests may grow in the cul-de-sac, and in more advanced stages, the peritoneal surfaces of the upper abdomen become the next largest soil for cancer progression. Ascites is also produced frequently in ovarian cancers, which facilitates distant metastasis. Clinicopathologic, epidemiologic and molecular studies on ovarian cancers have improved our understanding and therapeutic approaches, but still further efforts are required to reduce the risks in the patients who are predisposed to this lethal disease and the mortality of the patients in advanced stages. Among various molecules involved in ovarian carcinogenesis, special genes such as TP53, BRCA1 and BRCA2 have been well investigated. These genes are widely accepted as the predisposing factors that trigger malignant transformation of the epithelial cells of the ovary. In addition, adnexal inflammatory conditions such as chronic salpingitis and ovarian endometriosis have been great research interests in the context of carcinogenic background of ovarian cancers. In this review, I discuss the roles of stromal cells and inflammatory factors in the carcinogenesis and progression of ovarian cancers.

  2. Genomic similarities between breast and ovarian cancers

    Cancer.gov

    One subtype of breast cancer shares many genetic features with high-grade serous ovarian cancer, a cancer that is very difficult to treat, according to researchers supported by the National Institutes of Health. The findings suggest that the two cancers a

  3. Therapeutic strategies in epithelial ovarian cancer

    PubMed Central

    2012-01-01

    Ovarian cancer is the most lethal gynecologic malignancy. It appears that the vast majority of what seem to be primary epithelial ovarian and primary peritoneal carcinomas is, in fact, secondary from the fimbria, the most distal part of the fallopian tube. Treatment of epithelial ovarian cancer is based on the combination of cytoreductive surgery and combination chemotherapy using taxane and platinum. Although clear cell type is categorized in indolent type, it is known to show relatively strong resistance to carboplatin and paclitaxel regimen and thus poor prognosis compared to serous adenocarcinoma, especially in advanced stages. Irinotecan plus cisplatin therapy may effective for the clear cell adenocarcinoma. The larger expectation for improved prognosis in ovarian carcinoma is related to the use of the new biological agents. One of the most investigated and promising molecular targeted drugs in ovarian cancer is bevacizumab, a monoclonal antibody directed against VEGF. PARP inhibitor is another one. A few recent studies demonstrated positive results of bevacizumab on progression-free survival in ovarian cancer patients, however, investigation of molecular targeting drugs in patients with ovarian cancer are still underway. PMID:22330607

  4. The Inner Workings of Ovarian Cancer

    SciTech Connect

    Rodland, Karin

    2016-06-29

    New research identifies critical proteins present in the tumors of women with ovarian cancer. Karin Rodland discusses the work led by PNNL and Johns Hopkins researchers, working with collaborators across the nation.

  5. The Inner Workings of Ovarian Cancer

    ScienceCinema

    Rodland, Karin

    2016-11-02

    New research identifies critical proteins present in the tumors of women with ovarian cancer. Karin Rodland discusses the work led by PNNL and Johns Hopkins researchers, working with collaborators across the nation.

  6. Belinostat in Treating Patients With Advanced Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer or Ovarian Low Malignant Potential Tumors

    ClinicalTrials.gov

    2016-10-20

    Fallopian Tube Carcinoma; Primary Peritoneal Carcinoma; Recurrent Borderline Ovarian Surface Epithelial-Stromal Tumor; Recurrent Ovarian Carcinoma; Stage III Borderline Ovarian Surface Epithelial-Stromal Tumor; Stage III Ovarian Cancer; Stage IV Borderline Ovarian Surface Epithelial-Stromal Tumor; Stage IV Ovarian Cancer

  7. History of Comorbidities and Survival of Ovarian Cancer Patients, Results from the Ovarian Cancer Association Consortium.

    PubMed

    Minlikeeva, Albina N; Freudenheim, Jo L; Eng, Kevin H; Cannioto, Rikki A; Friel, Grace; Szender, J Brian; Segal, Brahm; Odunsi, Kunle; Mayor, Paul; Diergaarde, Brenda; Zsiros, Emese; Kelemen, Linda E; Köbel, Martin; Steed, Helen; deFazio, Anna; Jordan, Susan J; Fasching, Peter A; Beckmann, Matthias W; Risch, Harvey A; Rossing, Mary Anne; Doherty, Jennifer A; Chang-Claude, Jenny; Goodman, Marc T; Dörk, Thilo; Edwards, Robert; Modugno, Francesmary; Ness, Roberta B; Matsuo, Keitaro; Mizuno, Mika; Karlan, Beth Y; Goode, Ellen L; Kjær, Susanne K; Høgdall, Estrid; Schildkraut, Joellen M; Terry, Kathryn L; Cramer, Daniel W; Bandera, Elisa V; Paddock, Lisa E; Kiemeney, Lambertus A; Massuger, Leon F A G; Sutphen, Rebecca; Anton-Culver, Hoda; Ziogas, Argyrios; Menon, Usha; Gayther, Simon A; Ramus, Susan J; Gentry-Maharaj, Aleksandra; Pearce, Celeste L; Wu, Anna H; Kupryjanczyk, Jolanta; Jensen, Allan; Webb, Penelope M; Moysich, Kirsten B

    2017-09-01

    Background: Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients.Methods: Among patients diagnosed with invasive ovarian carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival. Using Cox proportional hazards regression models adjusted for age at diagnosis, stage of disease, histology, and study site, we estimated pooled HRs and 95% confidence intervals to assess associations between each comorbidity and ovarian cancer outcomes.Results: None of the comorbidities were associated with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced).Conclusions: Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic diseases were not associated with ovarian cancer overall or progression-free survival.Impact: These previously diagnosed chronic diseases do not appear to affect ovarian cancer prognosis. Cancer Epidemiol Biomarkers Prev; 26(9); 1470-3. ©2017 AACR. ©2017 American Association for Cancer Research.

  8. Symptoms Relevant to Surveillance for Ovarian Cancer

    PubMed Central

    Ore, Robert M.; Baldwin, Lauren; Woolum, Dylan; Elliott, Erika; Wijers, Christiaan; Chen, Chieh-Yu; Miller, Rachel W.; DeSimone, Christopher P.; Ueland, Frederick R.; Kryscio, Richard J.; van Nagell, John R.; Pavlik, Edward J.

    2017-01-01

    To examine how frequently and confidently healthy women report symptoms during surveillance for ovarian cancer. A symptoms questionnaire was administered to 24,526 women over multiple visits accounting for 70,734 reports. A query of reported confidence was included as a confidence score (CS). Chi square, McNemars test, ANOVA and multivariate analyses were performed. 17,623 women completed the symptoms questionnaire more than one time and >9500 women completed it more than one four times for >43,000 serially completed questionnaires. Reporting ovarian cancer symptoms was ~245 higher than ovarian cancer incidence. The positive predictive value (0.073%) for identifying ovarian cancer based on symptoms alone would predict one malignancy for 1368 cases taken to surgery due to reported symptoms. Confidence on the first questionnaire (83.3%) decreased to 74% when more than five questionnaires were completed. Age-related decreases in confidence were significant (p < 0.0001). Women reporting at least one symptom expressed more confidence (41,984/52,379 = 80.2%) than women reporting no symptoms (11,882/18,355 = 64.7%), p < 0.0001. Confidence was unrelated to history of hormone replacement therapy or abnormal ultrasound findings (p = 0.30 and 0.89). The frequency of symptoms relevant to ovarian cancer was much higher than the occurrence of ovarian cancer. Approximately 80.1% of women expressed confidence in what they reported. PMID:28335512

  9. Unbalanced Estrogen Metabolism in Ovarian Cancer

    PubMed Central

    Zahid, Muhammad; Beseler, Cheryl L.; Hall, James B.; LeVan, Tricia; Cavalieri, Ercole L.; Rogan, Eleanor G.

    2013-01-01

    Greater exposure to estrogens is a risk factor for ovarian cancer. To investigate the role of estrogens in ovarian cancer, a spot urine sample and a saliva sample were obtained from 33 women with ovarian cancer and 34 age-matched controls. Thirty-eight estrogen metabolites, conjugates and DNA adducts were analyzed in the urine samples by using ultraperformance liquid chromatography/tandem mass spectrometry, and the ratio of adducts to metabolites and conjugates was calculated for each sample. The ratio of depurinating estrogen-DNA adducts to estrogen metabolites and conjugates was significantly higher in cases compared to controls (p<0.0001), demonstrating high specificity and sensitivity. DNA was purified from the saliva samples and analyzed for genetic polymorphisms in the genes for two estrogen-metabolizing enzymes. Women with two low-activity alleles of catechol-O-methyltransferase plus one or two high-activity alleles of cytochrome P450 1B1 had higher levels of estrogen-DNA adducts and were more likely to have ovarian cancer. These findings indicate that estrogen metabolism is unbalanced in ovarian cancer and suggest that formation of estrogen-DNA adducts plays a critical role in the initiation of ovarian cancer. PMID:24170413

  10. Paradigm Shift in the Management Strategy for Epithelial Ovarian Cancer.

    PubMed

    Fujiwara, Keiichi; McAlpine, Jessica N; Lheureux, Stephanie; Matsumura, Noriomi; Oza, Amit M

    2016-01-01

    The hypothesis on the pathogenesis of epithelial ovarian cancer continues to evolve. Although epithelial ovarian cancer had been assumed to arise from the coelomic epithelium of the ovarian surface, it is now becoming clearer that the majority of serous carcinomas arise from epithelium of the distal fallopian tube, whereas clear cell and endometrioid cancers arise from endometriosis. Molecular and genomic characteristics of epithelial ovarian cancer have been extensively investigated. Our understanding of pathogenesis of the various histologic types of ovarian cancer have begun to inform changes to the strategies for management of epithelial ovarian cancer, which represent a paradigm shift not only for treatment but also for prevention, which previously had not been considered achievable. In this article, we will discuss novel attempts at the prevention of high-grade serous ovarian cancer and treatment strategies for two distinct entities in epithelial ovarian cancer: low-grade serous and clear cell ovarian carcinomas, which are relatively rare and resistant to conventional chemotherapy.

  11. SEOM Clinical Guideline in ovarian cancer (2016).

    PubMed

    Santaballa, A; Barretina, P; Casado, A; García, Y; González-Martín, A; Guerra, E; Laínez, N; Martinez, J; Redondo, A; Romero, I

    2016-12-01

    Despite remarkable advances in the knowledge of molecular biology and treatment, ovarian cancer (OC) is the first cause of death due to gynecological cancer and the fifth cause of death for cancer in women in Spain. The aim of this guideline is to summarize the current evidence and to give evidence-based recommendations for clinical practice.

  12. Liver cancer stem cells.

    PubMed

    Sell, Stewart; Leffert, Hyam L

    2008-06-10

    In an effort to review the evidence that liver cancer stem cells exist, two fundamental questions must be addressed. First, do hepatocellular carcinomas (HCC) arise from liver stem cells? Second, do HCCs contain cells that possess properties of cancer stem cells? For many years the finding of preneoplastic nodules in the liver during experimental induction of HCCs by chemicals was interpreted to support the hypothesis that HCC arose by dedifferentiation of mature liver cells. More recently, recognition of the role of small oval cells in the carcinogenic process led to a new hypothesis that HCC arises by maturation arrest of liver stem cells. Analysis of the cells in HCC supports the presence of cells with stem-cell properties (ie, immortality, transplantability, and resistance to therapy). However, definitive markers for these putative cancer stem cells have not yet been found and a liver cancer stem cell has not been isolated.

  13. Targeting cancer stem cells: a new therapy to cure cancer patients.

    PubMed

    Hu, Yapeng; Fu, Liwu

    2012-01-01

    Cancer stem cells (CSCs) have been defined as cells within tumor that possess the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor. They have been identified in blood, breast, brain, colon, melanoma, pancreatic, prostate, ovarian, lung cancers and so on. It is often considered to be associated with chemo-resistance and radio-resistance that lead to the failure of traditional therapies. Most therapies are directed at the fast growing tumor mass but not the slow dividing cancer stem cells. Eradicating cancer stem cells, the root of cancer origin and recurrence, has been thought as a promising approach to improve cancer survival or even to cure cancer patients. Understanding the characteristics of cancer stem cells will help to develop novel therapies to eliminate the initiating cancer stem cell, and the relevant patents on the cancer stem cell and cancer therapy by cancer stem cells will be discussed.

  14. Exploring the clonal evolution of CD133/aldehyde-dehydrogenase-1 (ALDH1)-positive cancer stem-like cells from primary to recurrent high-grade serous ovarian cancer (HGSOC). A study of the Ovarian Cancer Therapy-Innovative Models Prolong Survival (OCTIPS) Consortium.

    PubMed

    Ruscito, Ilary; Cacsire Castillo-Tong, Dan; Vergote, Ignace; Ignat, Iulia; Stanske, Mandy; Vanderstichele, Adriaan; Ganapathi, Ram N; Glajzer, Jacek; Kulbe, Hagen; Trillsch, Fabian; Mustea, Alexander; Kreuzinger, Caroline; Benedetti Panici, Pierluigi; Gourley, Charlie; Gabra, Hani; Kessler, Mirjana; Sehouli, Jalid; Darb-Esfahani, Silvia; Braicu, Elena Ioana

    2017-07-01

    High-grade serous ovarian cancer (HGSOC) causes 80% of all ovarian cancer (OC) deaths. In this setting, the role of cancer stem-like cells (CSCs) is still unclear. In particular, the evolution of CSC biomarkers from primary (pOC) to recurrent (rOC) HGSOCs is unknown. Aim of this study was to investigate changes in CD133 and aldehyde dehydrogenase-1 (ALDH1) CSC biomarker expression in pOC and rOC HGSOCs. Two-hundred and twenty-four pOC and rOC intrapatient paired tissue samples derived from 112 HGSOC patients were evaluated for CD133 and ALDH1 expression using immunohistochemistry (IHC); pOCs and rOCs were compared for CD133 and/or ALDH1 levels. Expression profiles were also correlated with patients' clinicopathological and survival data. Some 49.1% of the patient population (55/112) and 37.5% (42/112) pOCs were CD133+ and ALDH1+ respectively. CD133+ and ALDH1+ samples were detected in 33.9% (38/112) and 36.6% (41/112) rOCs. CD133/ALDH1 coexpression was observed in 23.2% (26/112) and 15.2% (17/112) of pOCs and rOCs respectively. Pairwise analysis showed a significant shift of CD133 staining from higher (pOCs) to lower expression levels (rOCs) (p < 0.0001). Furthermore, all CD133 + pOC patients were International Federation of Gynaecology and Obstetrics (FIGO)-stage III/IV (p < 0.0001) and had significantly worse progression-free interval (PFI) (p = 0.04) and overall survival (OS) (p = 0.02). On multivariate analysis, CD133/ALDH1 coexpression in pOCs was identified as independent prognostic factor for PFI (HR: 1.64; 95% CI: 1.03-2.60; p = 0.036) and OS (HR: 1.71; 95% CI: 1.01-2.88; p = 0.045). Analysis on 52 pts patients with known somatic BRCA status revealed that BRCA mutations did not influence CSC biomarker expression. The study showed that CD133/ALDH1 expression impacts HGSOC patients' survival and first suggests that CSCs might undergo phenotypic change during the disease course similarly to non stem-like cancer cells, providing also a first

  15. Molecular Pathogenesis of Endometrial and Ovarian Cancer

    PubMed Central

    Merritt, Melissa A.; Cramer, Daniel W.

    2013-01-01

    Pregnancy, breastfeeding, and oral contraceptive pill use interrupt menstrual cycles and reduce endometrial and ovarian cancer risk. This suggests the importance of turnover within Mullerian tissues, where the accumulation of mutations in p53 and PTEN has been correlated with number of cycles. The most common type of endometrial cancer (Type I) is endometrioid and molecular abnormalities include mutations in PTEN, KRAS and β-catenin. The Type I precursor is Endometrial lntraepithelial Neoplasia which displays PTEN defects. Type II endometrial cancer (whose precursors are less clear) includes serous and clear cell tumors and the most common alteration is p53 mutation. For ovarian cancer, histopathologic types parallel endometrial cancer and include serous, mucinous, endometrioid, and clear cell; some molecular features are also shared. The most frequent type of ovarian cancer is high grade serous that often displays p53 mutation and its precursor lesions may originate from normal-appearing fallopian tube epithelium that contains a p53 “signature”. Mutations in KRAS, BRAF and PTEN are described in mucinous, endometrioid and low grade serous cancers and these may originate from ovarian cortical inclusion cysts. A consideration of molecular and other pathogenetic features, like epidemiology and histopathology, may provide a bener understanding of endometrial and ovarian cancer. PMID:22112481

  16. The genetics of breast and ovarian cancer.

    PubMed Central

    Ford, D.; Easton, D. F.

    1995-01-01

    A number of genes are known to be involved in inherited susceptibility to breast and/or ovarian cancer. In the context of high-risk families the most important genes are BRCA1 on chromosome 17q, which is associated with a high penetrance of both breast and ovarian cancer, and BRCA2 on chromosome 13q, which causes a high risk of breast cancer but a lower risk of ovarian cancer. Other high-risk cancer genes that confer increased risks of breast or ovarian cancer in addition to other cancers include the hereditary non-polyposis colorectal cancer genes and the TP53 gene, which causes breast cancer as part of the Li-Fraumeni syndrome. The predisposing mutations in these genes are relatively rare in the population. More common genes which are associated with an increased, but lower, risk of breast cancer are the ataxiatelangiectasia gene and the HRAS1 gene. This paper reviews recent progress in mapping and cloning of these susceptibility genes, and provides estimates of the cancer risks associated with each gene and the frequency of predisposing mutations. PMID:7547224

  17. Genetic heterogeneity of breast-ovarian cancer revisited

    SciTech Connect

    Narod, S.; Ford, D.; Easton, D.

    1995-10-01

    We have recently reported the results of a linkage analysis of 145 breast-ovarian cancer families. Each family has three or more cases of early-onset breast cancer (age {le}60) or of ovarian cancer, and all families have at least one case of ovarian cancer (there were nine site-specific ovarian cancer families). Overall, we estimated that 76% of the families were linked to the BRCA1 locus. 5 refs., 1 tab.

  18. 75 FR 54451 - National Ovarian Cancer Awareness Month, 2010

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-07

    ... family history of ovarian cancer or breast cancer, and those over age 55--to protect their health by... Documents#0;#0; ] Proclamation 8551 of August 31, 2010 National Ovarian Cancer Awareness Month, 2010 By the... against ovarian cancer, this disease continues to claim more lives than any other gynecologic...

  19. 77 FR 55095 - National Ovarian Cancer Awareness Month, 2012

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-06

    ..., who have a family history of ovarian or breast cancer, or who have had certain cancers in the past are... Documents#0;#0; ] Proclamation 8853 of August 31, 2012 National Ovarian Cancer Awareness Month, 2012 By the... their lives to ovarian cancer. They are mothers and daughters, sisters and grandmothers,...

  20. 78 FR 54741 - National Ovarian Cancer Awareness Month, 2013

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-06

    ... Documents#0;#0; ] Proclamation 9008 of August 30, 2013 National Ovarian Cancer Awareness Month, 2013 By the... Cancer Awareness Month, we lend our support to everyone touched by this disease, we remember those we... ovarian cancer. Because ovarian cancer often goes undetected until advanced stages, increasing...

  1. Organizing the Cellular and Molecular Heterogeneity in High-Grade Serous Ovarian Cancer by Mass Cytometry

    DTIC Science & Technology

    2014-10-01

    ovarian cancer (OC) represents a complex set of stem cell and cancer cell phenotypes embedded in a mixture of stromal and infiltrating immune cells ...clustering” strategy finds cell neighborhoods in high dimensional space reveals that 18 out of 20 samples had clusters of apparent stem- cell expressing...deterministic combinations of stem cell markers. (2) Two high dimensional antibody panels were optimized and assembled to interrogate the tumor and

  2. Cisplatin and Paclitaxel in Treating Patients With Stage IIB, Stage IIC, Stage III, or Stage IV Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cavity Cancer

    ClinicalTrials.gov

    2014-12-29

    Chemotherapeutic Agent Toxicity; Endometrial Adenocarcinoma; Fallopian Tube Carcinoma; Gastrointestinal Complication; Malignant Ovarian Mixed Epithelial Tumor; Neurotoxicity Syndrome; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Primary Peritoneal Carcinoma; Stage II Ovarian Cancer; Stage III Ovarian Cancer; Stage IV Ovarian Cancer; Undifferentiated Ovarian Carcinoma

  3. Paclitaxel, Cisplatin, and Topotecan With or Without Filgrastim in Treating Patients With Newly Diagnosed Stage III or Stage IV Epithelial Ovarian Cancer

    ClinicalTrials.gov

    2013-01-23

    Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

  4. Colon resection for ovarian cancer: intraoperative decisions.

    PubMed

    Hoffman, Mitchel S; Zervose, Emmanuel

    2008-11-01

    To discuss the benefits and morbidity of and indications for colon resection during cytoreductive operations for ovarian cancer. The history of cytoreductive surgery for ovarian cancer is discussed, with special attention to the incorporation of colon resection. Literature regarding cytoreductive surgery for ovarian cancer is then reviewed, again with attention to the role of colon resection. The focus of the review is directed at broad technical considerations and rationales, for both primary and secondary cytoreduction. Over the past 15 to 20 years the standard cytoreductive operation for ovarian cancer has shifted from an abdominal hysterectomy with bilateral salpingo-oophorectomy and omentectomy to an en bloc radical resection of the pelvic tumor and an omentectomy, and more recently to include increasing use of extensive upper abdominal surgery. En bloc pelvic resection frequently includes rectosigmoid resection, almost always accompanied by a primary anastomosis. Other portions of the colon are at risk for metastatic involvement and sometimes require resection in order to achieve optimal cytoreduction. The data regarding colon resection for the purpose of surgical cytoreduction of ovarian cancer are conflicting (in terms of benefit) and all retrospective. However, the preponderance of information supports a benefit in terms of survival when cytoreduction is clearly optimal. Similar to primary surgery, benefit from secondary cytoreduction of ovarian cancer occurs when only a small volume of disease is left behind. The preponderance of data suggests that colon resection to achieve optimal cytoreduction has a positive impact on survival. In order to better understand the role of colon resection as well as other extensive cytoreductive procedures for ovarian cancer, it will be important to continue to improve our understanding of prognostic variables such as the nuances of metastatic bowel involvement in order to better guide appropriate surgical management.

  5. Mathematical models of ovarian cancer incidence.

    PubMed

    Rosner, Bernard A; Colditz, Graham A; Webb, Penny M; Hankinson, Susan E

    2005-07-01

    Pike has proposed "protected time" as one summary method for modeling reproductive risk factors in relation to ovarian cancer incidence. We evaluate this and other approaches to summarizing risk for ovarian cancer. We identified 472 incident cases of ovarian cancer during 2,298,068 person-years of follow-up of 24- to 55-year-old premenopausal women at cohort inception. Reproductive exposures, use of oral contraceptives, and history of tubal ligation were evaluated. Age at menopause is directly related to cumulative risk of ovarian cancer up to age 70 years (age 55 vs. age 45, risk increase = 62%; 95% confidence interval = 36 to 96%) and age at menarche is inversely related to risk (age 15 vs. 11, risk reduction = 31%; 27-34%). Use of oral contraceptives for 5 years before age 30 decreases risk of ovarian cancer to age 70 by 37% (32 to 41%). Tubal ligation reduces risk up to age 70 by 21% (-2 to 38%). Parity reduces risk, independent of age at first birth and age at last birth. A model summarizing years of ovulation offers a fit comparable to a more complex modeling of reproductive variables. The model fit is good, with a concordance statistic of 0.60 (0.57 to 0.62) indicating reasonable ability to differentiate those who will develop ovarian cancer from those who will remain disease free. This model may be applied in the identification of women at high risk for ovarian cancer, for example, in selecting candidates for prevention trials.

  6. Veliparib for the treatment of ovarian cancer.

    PubMed

    Bogliolo, Stefano; Cassani, Chiara; Dominoni, Mattia; Musacchi, Valentina; Venturini, Pier Luigi; Spinillo, Arsenio; Ferrero, Simone; Gardella, Barbara

    2016-01-01

    Ovarian cancer represents the sixth most commonly diagnosed cancer among women, with an incidence of 6.1 cases per 100.000 women and a cumulative lifetime risk of 0.5%. Treatment is based on debulking surgery and platinum-based chemotherapy, with the potential combination with taxane. However, the recently available data on the genetic basis and aetiology of ovarian cancer has led to the development of new anticancer drugs. Poly(ADP-ribose) polymerase (PARP) inhibitors are one of the most promising new classes of targeted agents currently under investigation for the treatment of ovarian cancer. Veliparib is a small molecule that inhibits both PARP-1 and PARP-2 and was originally shown to be efficacious in BRCA-associated tumors. This manuscript reviews the Phase I and II studies investigating the use of veliparib in ovarian cancer. This article also provides and discusses the pharmacokinetics and pharmacodynamics of veliparib. It is still being discussed whether PARP inhibitors should be used in a front-line or relapsed setting, alone or in combination with cytotoxic chemotherapy or as maintenance treatment. In terms of veliparib, further investigations are needed to explore its full potential in ovarian cancer. It is hoped that the ongoing phase 3 trials will help to further elucidate it potential as a treatment option.

  7. HEALTHY EATING INDEX AND OVARIAN CANCER RISK

    PubMed Central

    Chandran, Urmila; Bandera, Elisa V.; Williams-King, Melony G.; Paddock, Lisa E.; Rodriguez-Rodriguez, Lorna; Lu, Shou-En; Faulkner, Shameka; Pulick, Katherine; Olson, Sara H.

    2011-01-01

    The evidence for a role of diet on ovarian cancer prevention remains inconclusive. While many studies have evaluated individual foods and food groups, the evaluation of a comprehensive dietary quality index for predicting cancer risk has received little attention. This study investigates the association between the Healthy Eating Index (HEI), which reflects adherence to the current USDA Dietary Guidelines for Americans, and ovarian cancer risk in a population-based case-control study in New Jersey. A total of 205 cases and 390 controls completed the Block 98.2 Food Frequency Questionnaire (FFQ) in addition to reporting on potential risk factors for ovarian cancer. FFQ data were then utilized to calculate the HEI score, and cup, ounce, gram, or caloric equivalents for the 12 different food groups comprising the index. In multivariate models the OR for the highest tertile of the HEI score compared to the lowest (reflecting a better diet compared to a worse diet) was 0.90 (95% CI: 0.55–1.47). There was limited evidence for a statistically significant association between any of the 12 individual food components and ovarian cancer risk. Based on this study’s results, neither individual food groups nor dietary quality showed potential for preventing ovarian cancer. PMID:21286802

  8. Breast and Ovarian Cancer and Family History Risk Categories

    MedlinePlus

    ... gov . Diseases Breast and Ovarian Cancer and Family History Risk Categories Recommend on Facebook Tweet Share Compartir ... Preventive Services Task Force. February 2016. Family Health History, Breast and Ovarian Cancer Risk, and Women of ...

  9. Most Women Should Forgo Ovarian Cancer Screening: Panel

    MedlinePlus

    ... fullstory_167271.html Most Women Should Forgo Ovarian Cancer Screening: Panel Test isn't accurate enough to justify ... 2017 (HealthDay News) -- The potential harms of ovarian cancer screening outweigh the benefits, so only very specific groups ...

  10. Granisetron, Aprepitant, and Dexamethasone in Preventing Nausea and Vomiting in Patients Receiving Chemotherapy for Stage II, III, or IV Ovarian Cancer

    ClinicalTrials.gov

    2017-05-02

    Nausea and Vomiting; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Cystadenocarcinoma; Stage II Ovarian Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Undifferentiated Ovarian Carcinoma

  11. Co-expression of the Follicle Stimulating Hormone Receptor and Stem Cell Markers: A Novel Approach to Target Ovarian Cancer Stem Cells

    DTIC Science & Technology

    2012-09-01

    Award Number: 11 1 0623 TITLE: Co-expression of the Follicle Stimulating Hormone Receptor and Stem...Annual 3. DATES COVERED 1 Sep 2011 – 31 Aug 2012 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Coexpression of the Follicle Stimulating Hormone ...Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The purpose of this project is to determine whether the Follicle-stimulating Hormone Receptor (FSHR) is co

  12. Ovarian cancer screening in menopausal females with a family history of breast or ovarian cancer.

    PubMed

    Lai, Tiffany; Kessel, Bruce; Ahn, Hyeong Jun; Terada, Keith Y

    2016-07-01

    To determine whether annual screening reduces ovarian cancer mortality in women with a family history of breast or ovarian cancer. Data was obtained from the Prostate, Lung, Colorectal, and Ovarian cancer trial, a randomized multi-center trial conducted to determine if screening could reduce mortality in these cancers. The trial enrolled 78,216 women, randomized into either a screening arm with annual serum cancer antigen 125 and pelvic ultrasounds, or usual care arm. This study identified a subgroup that reported a first degree relative with breast or ovarian cancer. Analysis was performed to compare overall mortality and disease specific mortality in the screening versus usual care arm. In patients diagnosed with ovarian cancer, stage distribution, and survival were analyzed as a secondary endpoint. There was no significant difference in overall mortality or disease specific mortality between the two arms. Ovarian cancer was diagnosed in 48 patients in the screening arm and 44 patients in the usual care arm. Screened patients were more likely to be diagnosed at an earlier stage than usual care patients. Patients in the screening arm diagnosed with ovarian cancer experienced a significantly improved survival compared to patients in the usual care arm; relative risk 0.66 (95% CI, 0.47 to 0.93). Screening did not appear to decrease ovarian cancer mortality in participants with a family history of breast or ovarian cancer. Secondary endpoints, however, showed notable differences. Significantly fewer patients were diagnosed with advanced stage disease in the screening arm; and survival was significantly improved. Further investigation is warranted to assess screening efficacy in women at increased risk.

  13. Olaparib in the management of ovarian cancer

    PubMed Central

    Bixel, Kristin; Hays, John L

    2015-01-01

    Alterations in the homologous repair pathway are thought to occur in 30%–50% of epithelial ovarian cancers. Cells deficient in homologous recombination rely on alternative pathways for DNA repair in order to survive, thereby providing a potential target for therapy. Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, capitalizes on this concept and is the first drug in its class approved for patients with ovarian cancer. This review article will provide an overview of the BRCA genes and homologous recombination, the role of PARP in DNA repair and the biological rationale for the use of PARP inhibitors as cancer therapy, and ultimately will focus on the use of olaparib in the management of ovarian cancer. PMID:26309417

  14. Pegylated liposomal doxorubicin in ovarian cancer

    PubMed Central

    Green, Andrew E; Rose, Peter G

    2006-01-01

    Pegylated liposomal doxorubicin is a formulation of doxorubicin in which the molecule itself is packaged in a liposome made of various lipids with an outer coating of polyethylene glycol. Liposomal technology is being used in increasing amounts in the therapy of a variety of cancers, including ovarian cancers. This article reviews the mechanistic actions of this formulation, the Phase II and Phase III data that helped define the role of pegylated liposomal doxorubicin in recurrent ovarian cancer, as well as a discussion of some of the side-effects and their management. PMID:17717964

  15. Sunitinib Malate in Treating Patients With Recurrent Ovarian Epithelial, Fallopian Tube, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2015-01-15

    Recurrent Fallopian Tube Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Primary Peritoneal Cavity Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIA Primary Peritoneal Cavity Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Epithelial Cancer; Stage IIIB Primary Peritoneal Cavity Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Epithelial Cancer; Stage IIIC Primary Peritoneal Cavity Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Primary Peritoneal Cavity Cancer

  16. Trials show delayed recurrence in ovarian cancer.

    PubMed

    Bender, Eric

    2013-06-01

    Phase I trials of 2 treatments for recurrent ovarian cancer-a 2-step immunotherapy treatment and an antibody-drug conjugate-demonstrated promising early results in delaying recurrence, in work presented at the American Association for Cancer Research Annual Meeting 2013.

  17. Tumor infiltrating lymphocytes in ovarian cancer.

    PubMed

    Santoiemma, Phillip P; Powell, Daniel J

    2015-01-01

    The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment.

  18. Tumor infiltrating lymphocytes in ovarian cancer

    PubMed Central

    Santoiemma, Phillip P; Powell, Daniel J

    2015-01-01

    The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment. PMID:25894333

  19. Ovarian Germline Stem Cells: An Unlimited Source of Oocytes?

    PubMed Central

    Hanna, Carol; Hennebold, Jon

    2014-01-01

    While there has been progress in directing the development of embryonic stem cells and induced pluripotent stem cells toward a germ cell state, their ability to serve as a source of functional oocytes in a clinically relevant model or situation has yet to be established. Recent studies suggest the adult mammalian ovary is not endowed with a finite number of oocytes, but instead possesses stem cells that contribute to their renewal. The ability to isolate and promote the growth and development of such ovarian germline stem cells (GSCs) would provide a novel means to treat infertility in women. While such ovarian GSCs are well-characterized in non-mammalian model organisms, the findings that support the existence of adult ovarian GSCs in mammals have been met with considerable evidence that disputes their existence. Thus, this review details the lessons provided by model organisms that successfully utilize ovarian GSCs to allow for a continual and high level of female germ cell production throughout their life, with a specific focus on the cellular mechanisms involved in GSC self-renewal and oocyte development. Such an overview of the role oogonial stem cells play in maintaining fertility in non-mammalian species serves as a backdrop for the data generated to-date that supports or disputes the existence of GSCs in mammals as well as the future of this area of research in terms of its potential for any application in reproductive medicine. PMID:24382341

  20. Psychosocial Stress and Ovarian Cancer Risk: Metabolomics and Perceived Stress

    DTIC Science & Technology

    2014-10-01

    AWARD NUMBER: W81XWH-13-1-0493 TITLE: Psychosocial Stress and Ovarian Cancer Risk: Metabolomics and...SUBTITLE Psychosocial Stress and Ovarian Cancer Risk: Metabolomics and Perceived Stress 5a. CONTRACT NUMBER Perceived Stress...SUBJECT TERMS ovarian cancer, psychosocial stress, depression, anxiety, social support, metabolomics 16. SECURITY CLASSIFICATION OF: 17. LIMITATION

  1. Changes in Brain Function in Patients With Stage I, Stage II, Stage III, or Stage IV Ovarian, Primary Peritoneal, or Fallopian Tube Cancer Who Are Receiving Chemotherapy

    ClinicalTrials.gov

    2016-10-26

    Cognitive Side Effects of Cancer Therapy; Malignant Ovarian Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Carcinosarcoma; Ovarian Choriocarcinoma; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Dysgerminoma; Ovarian Embryonal Carcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Germ Cell Tumor; Ovarian Mucinous Cystadenocarcinoma; Ovarian Polyembryoma; Ovarian Sarcoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Teratoma; Ovarian Yolk Sac Tumor; Stage I Ovarian Cancer; Stage IA Fallopian Tube Cancer; Stage IA Ovarian Cancer; Stage IA Ovarian Germ Cell Tumor; Stage IB Fallopian Tube Cancer; Stage IB Ovarian Cancer; Stage IB Ovarian Germ Cell Tumor; Stage IC Fallopian Tube Cancer; Stage IC Ovarian Cancer; Stage IC Ovarian Germ Cell Tumor; Stage II Ovarian Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIA Ovarian Germ Cell Tumor; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIB Ovarian Germ Cell Tumor; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIC Ovarian Germ Cell Tumor; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Ovarian Germ Cell Tumor; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Ovarian Germ Cell Tumor; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Ovarian Germ Cell Tumor; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Primary Peritoneal Cancer; Undifferentiated Ovarian Carcinoma

  2. Adjuvant ovarian suppression in premenopausal breast cancer.

    PubMed

    Francis, Prudence A; Regan, Meredith M; Fleming, Gini F; Láng, István; Ciruelos, Eva; Bellet, Meritxell; Bonnefoi, Hervé R; Climent, Miguel A; Da Prada, Gian Antonio; Burstein, Harold J; Martino, Silvana; Davidson, Nancy E; Geyer, Charles E; Walley, Barbara A; Coleman, Robert; Kerbrat, Pierre; Buchholz, Stefan; Ingle, James N; Winer, Eric P; Rabaglio-Poretti, Manuela; Maibach, Rudolf; Ruepp, Barbara; Giobbie-Hurder, Anita; Price, Karen N; Colleoni, Marco; Viale, Giuseppe; Coates, Alan S; Goldhirsch, Aron; Gelber, Richard D

    2015-01-29

    Suppression of ovarian estrogen production reduces the recurrence of hormone-receptor-positive early breast cancer in premenopausal women, but its value when added to tamoxifen is uncertain. We randomly assigned 3066 premenopausal women, stratified according to prior receipt or nonreceipt of chemotherapy, to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The primary analysis tested the hypothesis that tamoxifen plus ovarian suppression would improve disease-free survival, as compared with tamoxifen alone. In the primary analysis, 46.7% of the patients had not received chemotherapy previously, and 53.3% had received chemotherapy and remained premenopausal. After a median follow-up of 67 months, the estimated disease-free survival rate at 5 years was 86.6% in the tamoxifen-ovarian suppression group and 84.7% in the tamoxifen group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.83; 95% confidence interval [CI], 0.66 to 1.04; P=0.10). Multivariable allowance for prognostic factors suggested a greater treatment effect with tamoxifen plus ovarian suppression than with tamoxifen alone (hazard ratio, 0.78; 95% CI, 0.62 to 0.98). Most recurrences occurred in patients who had received prior chemotherapy, among whom the rate of freedom from breast cancer at 5 years was 82.5% in the tamoxifen-ovarian suppression group and 78.0% in the tamoxifen group (hazard ratio for recurrence, 0.78; 95% CI, 0.60 to 1.02). At 5 years, the rate of freedom from breast cancer was 85.7% in the exemestane-ovarian suppression group (hazard ratio for recurrence vs. tamoxifen, 0.65; 95% CI, 0.49 to 0.87). Adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population. However, for women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal, the addition of ovarian suppression improved disease outcomes. Further

  3. The epidemiology of endometrial and ovarian cancer.

    PubMed

    Cramer, Daniel W

    2012-02-01

    This review highlights similarities in the epidemiology of endometrial and ovarian cancer, including highly correlated incidence rates and similar risk factor profiles. Factors that decrease risk for both cancers include a late menarche, early age at first birth, giving birth and breastfeeding, and use of oral contraceptives. Short or irregular cycles and late menopause are associated with increased risk for both. Other risk factors that appear to operate in a similar direction include decreased risk associated with IUD use or a tubal ligation, and increased risk associated with obesity, lack of exercise, and use of talc powders in genital hygiene. Estrogen excess is proposed as the underlying mechanism for most endometrial cancers, whereas incessant ovulation has been suggested as the explanation for ovarian cancer. However, an increased number of estimated ovulatory cycles correlates directly with risk for both endometrial and ovarian cancer, suggesting that reproductive tissue turnover with an accumulation of PTEN or p53 mutations represents a possible common mechanism. An immune-based explanation involving mucin proteins represents another common mechanism that could explain additional risk factors. Maintenance of ideal weight, breastfeeding children, use of oral contraceptives, and avoidance of talc powders in genital hygiene are measures that could lower the risk for both types of cancer. Careful selection of patients for prophylactic oophorectomy for those women who are coming to hysterectomy for benign disease is an additional measure to consider for ovarian cancer. Copyright © 2012 Elsevier Inc. All rights reserved.

  4. Dietary factors and epithelial ovarian cancer.

    PubMed Central

    Shu, X. O.; Gao, Y. T.; Yuan, J. M.; Ziegler, R. G.; Brinton, L. A.

    1989-01-01

    Dietary data from a population-based case-control study of 172 epithelial ovarian cancer cases and 172 controls were analysed. A significant (P less than 0.01) dose-response relationship was found between intake of fat from animal sources and risk of ovarian cancer, but plant fat was not associated. Although the effect of animal fat was confounded by education, an adjusted odds ratio of 1.8 persisted for those in the upper quartile compared to the lower quartile of consumption (P for trend = 0.03). After adjustment for animal fat intake, calorific and protein intake had minimal effects on risk. Total vegetables were found to be somewhat protective, but the mechanism of action was unclear. Weight, height and relative weight (weight/height2) were not related to risk of ovarian cancer. PMID:2757927

  5. Olaparib for the treatment of ovarian cancer.

    PubMed

    Bornstein, E; Jimeno, A

    2016-01-01

    Olaparib, an oral poly(ADP-ribose) polymerase (PARP) inhibitor, is the first FDA-approved drug in its class for patients with ovarian cancer, specifically in a subset of patients with BRCA mutations and prior chemotherapy treatments. PARP inhibitors have had other implications in different solid tumor types including breast, gastric and pancreatic malignancies. In light of the recent FDA approval of olaparib for the treatment of ovarian cancer, this article aims to outline the mechanisms and implications of the drug. With a favorable adverse event profile and improved outcomes, including progression-free survival, olaparib has demonstrated augmentation to therapeutic options in the treatment of ovarian cancer. Copyright 2016 Prous Science, S.A.U. or its licensors. All rights reserved.

  6. Chemotherapeutic management of advanced ovarian cancer.

    PubMed

    Gordon, Alan N; Butler, Julie

    2003-08-01

    To review current treatment strategies for patients with advanced ovarian cancer. Factors for treatment selection are discussed. Research articles and textbooks. Research efforts continue to identify novel agents and/or combination therapies that can effect a cure or prolong survival. Several agents offer similar efficacy outcomes but vary in safety aspects and administration requirements. Numerous clinical trials have defined the efficacy and safety of chemotherapy in patients with ovarian cancer. Oncology nurses can prepare patients to make treatment decisions; educate them about treatment-related side effects; and develop an ongoing relationship as patient advocates to ensure quality of life.

  7. Ovarian cancer treatment: The end of empiricism?

    PubMed

    Lheureux, Stephanie; Karakasis, Katherine; Kohn, Elise C; Oza, Amit M

    2015-09-15

    The diagnosis, investigation, and management of ovarian cancer are in a state of flux-balancing ever rapid advances in our understanding of its biology with 3 decades of clinical trials. Clinical trials that started with empirically driven selections have evolved in an evidence-informed manner to gradually improve outcome. Has this improved understanding of the biology and associated calls to action led to appropriate changes in therapy? In this review, the authors discuss incorporating emerging data on biology, combinations, dose, and scheduling of new and existing agents with patient preferences in the management of women with ovarian cancer.

  8. Targeted Therapies in Epithelial Ovarian Cancer

    PubMed Central

    Barrena Medel, Nicanor I.; Wright, Jason D.; Herzog, Thomas J.

    2010-01-01

    Epithelial ovarian cancer remains a major women's health problem due to its high lethality. Despite great efforts to develop effective prevention and early detection strategies, most patients are still diagnosed at advanced stages of disease. This pattern of late presentation has resulted in significant challenges in terms of designing effective therapies to achieve long-term cure. One potential promising strategy is the application of targeted therapeutics that exploit a myriad of critical pathways involved in tumorigenesis and metastasis. This review examines three of the most provocative targeted therapies with current or future applicability in epithelial ovarian cancer. PMID:20111741

  9. Epithelial Ovarian Cancer Experimental Models

    PubMed Central

    Lengyel, E; Burdette, JE; Kenny, HA; Matei, D; Pilrose, J; Haluska, P.; Nephew, KP; Hales, DB; Stack, MS

    2014-01-01

    Epithelial ovarian cancer (OvCa) is associated with high mortality and, as the majority (>75%) of women with OvCa have metastatic disease at the time of diagnosis, rates of survival have not changed appreciably over 30 years. A mechanistic understanding of OvCa initiation and progression is hindered by the complexity of genetic and/or environmental initiating events and lack of clarity regarding the cell(s) or tissue(s) of origin. Metastasis of OvCa involves direct extension or exfoliation of cells and cellular aggregates into the peritoneal cavity, survival of matrix-detached cells in a complex ascites fluid phase, and subsequent adhesion to the mesothelium lining covering abdominal organs to establish secondary lesions containing host stromal and inflammatory components. Development of experimental models to recapitulate this unique mechanism of metastasis presents a remarkable scientific challenge and many approaches used to study other solid tumors (lung, colon, and breast, for example) are not transferable to OvCa research given the distinct metastasis pattern and unique tumor microenvironment. This review will discuss recent progress in the development and refinement of experimental models to study OvCa. Novel cellular, three-dimensional organotypic, and ex vivo models are considered and the current in vivo models summarized. The review critically evaluates currently available genetic mouse models of OvCa, the emergence of xenopatients, and the utility of the hen model to study OvCa prevention, tumorigenesis, metastasis, and chemoresistance. As these new approaches more accurately recapitulate the complex tumor microenvironment, it is predicted that new opportunities for enhanced understanding of disease progression, metastasis and therapeutic response will emerge. PMID:23934194

  10. Colorectal cancer stem cells.

    PubMed

    Salama, Paul; Platell, Cameron

    2009-10-01

    Somatic stem cells reside at the base of the crypts throughout the colonic mucosa. These cells are essential for the normal regeneration of the colonic epithelium. The stem cells reside within a special 'niche' comprised of intestinal sub-epithelial myofibroblasts that tightly control their function. It has been postulated that mutations within these adult colonic stem cells may induce neoplastic changes. Such cells can then dissociate from the epithelium and travel into the mesenchyme and thus form invasive cancers. This theory is based on the observation that within a colon cancer, less than 1% of the neoplastic cells have the ability to regenerate the tumour. It is this group of cells that exhibits characteristics of colonic stem cells. Although anti-neoplastic agents can induce remissions by inhibiting cell division, the stem cells appear to be remarkably resistant to both standard chemotherapy and radiotherapy. These stem cells may therefore persist after treatment and form the nucleus for cancer recurrence. Hence, future treatment modalities should focus specifically on controlling the cancer stem cells. In this review, we discuss the biology of normal and malignant colonic stem cells.

  11. Paclitaxel and Carboplatin With or Without Bevacizumab in Treating Patients With Stage II, Stage III, or Stage IV Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2015-12-21

    Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Adenocarcinofibroma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Undifferentiated Ovarian Carcinoma

  12. Evidence of a genetic link between endometriosis and ovarian cancer.

    PubMed

    Lee, Alice W; Templeman, Claire; Stram, Douglas A; Beesley, Jonathan; Tyrer, Jonathan; Berchuck, Andrew; Pharoah, Paul P; Chenevix-Trench, Georgia; Pearce, Celeste Leigh

    2016-01-01

    To evaluate whether endometriosis-associated genetic variation affects risk of ovarian cancer. Pooled genetic analysis. University hospital. Genetic data from 46,176 participants (15,361 ovarian cancer cases and 30,815 controls) from 41 ovarian cancer studies. None. Endometriosis-associated genetic variation and ovarian cancer. There was significant evidence of an association between endometriosis-related genetic variation and ovarian cancer risk, especially for the high-grade serous and clear cell histotypes. Overall we observed 15 significant burden statistics, which was three times more than expected. By focusing on candidate regions from a phenotype associated with ovarian cancer, we have shown a clear genetic link between endometriosis and ovarian cancer that warrants further follow-up. The functional significance of the identified regions and SNPs is presently uncertain, though future fine mapping and histotype-specific functional analyses may shed light on the etiologies of both gynecologic conditions. Copyright © 2016. Published by Elsevier Inc.

  13. Chemotherapy targeting cancer stem cells

    PubMed Central

    Liu, Haiguang; Lv, Lin; Yang, Kai

    2015-01-01

    Conventional chemotherapy is the main treatment for cancer and benefits patients in the form of decreased relapse and metastasis and longer overall survival. However, as the target therapy drugs and delivery systems are not wholly precise, it also results in quite a few side effects, and is less efficient in many cancers due to the spared cancer stem cells, which are considered the reason for chemotherapy resistance, relapse, and metastasis. Conventional chemotherapy limitations and the cancer stem cell hypothesis inspired our search for a novel chemotherapy targeting cancer stem cells. In this review, we summarize cancer stem cell enrichment methods, the search for new efficient drugs, and the delivery of drugs targeting cancer stem cells. We also discuss cancer stem cell hierarchy complexity and the corresponding combination therapy for both cancer stem and non-stem cells. Learning from cancer stem cells may reveal novel strategies for chemotherapy in the future. PMID:26045975

  14. Mathematical Models of Breast and Ovarian Cancers

    PubMed Central

    Botesteanu, Dana-Adriana; Lipkowitz, Stanley; Lee, Jung-Min; Levy, Doron

    2016-01-01

    Women constitute the majority of the aging United States (US) population, and this has substantial implications on cancer population patterns and management practices. Breast cancer is the most common women's malignancy, while ovarian cancer is the most fatal gynecological malignancy in the US. In this review we focus on these subsets of women's cancers, seen more commonly in postmenopausal and elderly women. In order to systematically investigate the complexity of cancer progression and response to treatment in breast and ovarian malignancies, we assert that integrated mathematical modeling frameworks viewed from a systems biology perspective are needed. Such integrated frameworks could offer innovative contributions to the clinical women's cancers community, since answers to clinical questions cannot always be reached with contemporary clinical and experimental tools. Here, we recapitulate clinically known data regarding the progression and treatment of the breast and ovarian cancers. We compare and contrast the two malignancies whenever possible, in order to emphasize areas where substantial contributions could be made by clinically inspired and validated mathematical modeling. We show how current paradigms in the mathematical oncology community focusing on the two malignancies do not make comprehensive use of, nor substantially reflect existing clinical data, and we highlight the modeling areas in most critical need of clinical data integration. We emphasize that the primary goal of any mathematical study of women's cancers should be to address clinically relevant questions. PMID:27259061

  15. The STAT3-miRNA-92-Wnt Signaling Pathway Regulates Spheroid Formation and Malignant Progression in Ovarian Cancer.

    PubMed

    Chen, Min-Wei; Yang, Shu-Ting; Chien, Ming-Hsien; Hua, Kuo-Tai; Wu, Chin-Jui; Hsiao, S M; Lin, Hao; Hsiao, Michael; Su, Jen-Liang; Wei, Lin-Hung

    2017-04-15

    Ovarian cancer spheroids constitute a metastatic niche for transcoelomic spread that also engenders drug resistance. Spheroid-forming cells express active STAT3 signaling and display stem cell-like properties that may contribute to ovarian tumor progression. In this study, we show that STAT3 is hyperactivated in ovarian cancer spheroids and that STAT3 disruption in this setting is sufficient to relieve chemoresistance. In an NSG murine model of human ovarian cancer, STAT3 signaling regulated spheroid formation and self-renewal properties, whereas STAT3 attenuation reduced tumorigenicity. Mechanistic investigations revealed that Wnt signaling was required for STAT3-mediated spheroid formation. Notably, the Wnt antagonist DKK1 was the most strikingly upregulated gene in response to STAT3 attenuation in ovarian cancer cells. STAT3 signaling maintained stemness and interconnected Wnt/β-catenin signaling via the miR-92a/DKK1-regulatory pathways. Targeting STAT3 in combination with paclitaxel synergistically reduced peritoneal seeding and prolonged survival in a murine model of intraperitoneal ovarian cancer. Overall, our findings define a STAT3-miR-92a-DKK1 pathway in the generation of cancer stem-like cells in ovarian tumors, with potential therapeutic applications in blocking their progression. Cancer Res; 77(8); 1955-67. ©2017 AACR. ©2017 American Association for Cancer Research.

  16. Role of mesenchymal cells in the natural history of ovarian cancer: a review.

    PubMed

    Touboul, Cyril; Vidal, Fabien; Pasquier, Jennifer; Lis, Raphael; Rafii, Arash

    2014-10-11

    Ovarian cancer is the deadliest gynaecologic malignancy. Despite progresses in chemotherapy and ultra-radical surgeries, this locally metastatic disease presents a high rate of local recurrence advocating for the role of a peritoneal niche. For several years, it was believed that tumor initiation, progression and metastasis were merely due to the changes in the neoplastic cell population and the adjacent non-neoplastic tissues were regarded as bystanders. The importance of the tumor microenvironment and its cellular component emerged from studies on the histopathological sequence of changes at the interface between putative tumor cells and the surrounding non-neoplastic tissues during carcinogenesis. In this review we aimed to describe the pro-tumoral crosstalk between ovarian cancer and mesenchymal stem cells. A PubMed search was performed for articles published pertaining to mesenchymal stem cells and specific to ovarian cancer. Mesenchymal stem cells participate to an elaborate crosstalk through direct and paracrine interaction with ovarian cancer cells. They play a role at different stages of the disease: survival and peritoneal infiltration at early stage, proliferation in distant sites, chemoresistance and recurrence at later stage. The dialogue between ovarian and mesenchymal stem cells induces the constitution of a pro-tumoral mesencrine niche. Understanding the dynamics of such interaction in a clinical setting might propose new therapeutic strategies.

  17. Ovarian ecdysteroid biosynthesis and female germline stem cells.

    PubMed

    Ameku, Tomotsune; Yoshinari, Yuto; Fukuda, Ruriko; Niwa, Ryusuke

    2017-07-03

    The germline stem cells (GSCs) are critical for gametogenesis throughout the adult life. Stem cell identity is maintained by local signals from a specialized microenvironment called the niche. However, it is unclear how systemic signals regulate stem cell activity in response to environmental cues. In our previous article, we reported that mating stimulates GSC proliferation in female Drosophila. The mating-induced GSC proliferation is mediated by ovarian ecdysteroids, whose biosynthesis is positively controlled by Sex peptide signaling. Here, we characterized the post-eclosion and post-mating expression pattern of the genes encoding the ecdysteroidogenic enzymes in the ovary. We further investigated the biosynthetic functions of the ovarian ecdysteroid in GSC maintenance in the mated females. We also briefly discuss the regulation of the ecdysteroidogenic enzyme-encoding genes and the subsequent ecdysteroid biosynthesis in the ovary of the adult Drosophila.

  18. Epithelial ovarian cancer: testing the 'androgens hypothesis'.

    PubMed

    Olsen, Catherine M; Green, Adèle C; Nagle, Christina M; Jordan, Susan J; Whiteman, David C; Bain, Christopher J; Webb, Penelope M

    2008-12-01

    In 1998, Risch proposed a hypothesis for the pathogenesis of ovarian cancer relating to the role of androgens in stimulating epithelial cell proliferation. Although this hypothesis has been widely discussed, direct evidence to support it is scant. To address this issue, we have conducted a detailed analysis of factors possibly associated with high circulating levels of androgens, including polycystic ovary syndrome (PCOS), hirsutism and acne (all clinically associated with hyperandrogenism) using the data collected in an Australia-wide, population-based case-control study. Cases aged 18-79 years with a new diagnosis of invasive epithelial ovarian cancer (n=1276) or borderline malignant tumour (n=315) were identified through a network of clinics and cancer registries throughout Australia. Controls (n=1508) were selected from the National Electoral Roll. Women self-reported a history of PCOS, acne, hirsutism and also use of testosterone supplements or the androgenic medication Danazol. We found no evidence that a history of PCOS, acne or hirsutism was associated with ovarian cancer overall, or with specific subtypes, with the exception of serous borderline tumours that were positively associated with a history of PCOS (OR 2.6; 95% CI 1.0-6.1). Women who had ever used testosterone supplements had an increased risk of ovarian cancer (OR 3.7; 95% CI 1.1-12.0); however, use of the androgenic medication Danazol did not increase risk (OR 1.0; 95% CI 0.4-2.9). Overall, our results do not support the hypothesis that androgen-related disorders increase the risk of ovarian cancer.

  19. Targeted Immune Therapy of Ovarian Cancer

    PubMed Central

    Knutson, Keith L.; Karyampudi, Lavakumar; Lamichhane, Purushottam; Preston, Claudia

    2014-01-01

    Clinical outcomes, such as recurrence free survival and overall survival, in ovarian cancer are quite variable, independent of common characteristics such as stage, response to therapy and grade. This disparity in outcomes warrants further exploration and therapeutic targeting into the interaction between the tumor and host. One compelling host characteristic that contributes both to the initiation and progression of ovarian cancer is the immune system. Hundreds of studies have confirmed a prominent role for the immune system in modifying the clinical course of the disease. Recent studies also show that anti-tumor immunity is often negated by immune regulatory cells present in the tumor microenvironment. Regulatory immune cells also directly enhance the pathogenesis through the release of various cytokines and chemokines, which together form an integrated pathologic network. Thus, in the future, research into immunotherapy targeting ovarian cancer will probably become increasingly focused on combination approaches that simultaneously augment immunity while preventing local immune suppression. In this article, we summarize important immunological targets that influence ovarian cancer outcome as well as include an update on newer immunotherapeutic strategies. PMID:25544369

  20. Targeted immune therapy of ovarian cancer.

    PubMed

    Knutson, Keith L; Karyampudi, Lavakumar; Lamichhane, Purushottam; Preston, Claudia

    2015-03-01

    Clinical outcomes, such as recurrence-free survival and overall survival, in ovarian cancer are quite variable, independent of common characteristics such as stage, response to therapy, and grade. This disparity in outcomes warrants further exploration and therapeutic targeting into the interaction between the tumor and host. One compelling host characteristic that contributes both to the initiation and progression of ovarian cancer is the immune system. Hundreds of studies have confirmed a prominent role for the immune system in modifying the clinical course of the disease. Recent studies also show that anti-tumor immunity is often negated by immune regulatory cells present in the tumor microenvironment. Regulatory immune cells also directly enhance the pathogenesis through the release of various cytokines and chemokines, which together form an integrated pathological network. Thus, in the future, research into immunotherapy targeting ovarian cancer will probably become increasingly focused on combination approaches that simultaneously augment immunity while preventing local immune suppression. In this article, we summarize important immunological targets that influence ovarian cancer outcome as well as include an update on newer immunotherapeutic strategies.

  1. Management of recurrent epithelial ovarian cancer

    PubMed Central

    Moreno-Eutimio, Mario Adan; Acosta-Altamirano, Gustavo; Vargas-Aguilar, Víctor Manuel

    2014-01-01

    Epithelial ovarian cancer is the fifth most common cancer in women. It is usually diagnosed at an advanced stage and is the leading cause of death from gynecologic cancers in women. The overall survival rate at five years is 50% and its treatment is still poor. We need new treatments for patients with recurrent ovarian cancer who are incurable with current management. We review the effectiveness of new biological agents and morbidity and mortality of cytoreductive surgery. Since the hyperthermic increases the effectiveness of chemotherapy and the chance of survival, hyperthermic intraperitoneal chemotherapy has been proven to be a promising option, however it still requires further study to be the standard treatment. PMID:25207212

  2. Targeting cancer stem cell lines as a new treatment of human cancer.

    PubMed

    Giuffrida, D; Rogers, I M

    2010-11-01

    Many studies have demonstrated that most cancers are clonal and are maintained by a cancer stem cell. Cancer stem cells have been identified in blood, breast, brain, lungs, gastrointestinal, prostate and ovarian cancer. Under normal homeostasis tissue specific stem cell division would be under strict control. When proliferation becomes independent of normal cellular controls, cancer develops. Studies indicate that cancer stem cells maintain their ability to differentiate, which explains the variety of cell types observed in tumors. Most therapies are directed at the fast growing tumor mass but not the slow dividing cancer stem cells and therefore the cancer is not eradicated. Understanding the process of transformation from a highly regulated stem cell to a cancer stem cell requires an understanding of genetic and epigenetic processes as well as having an understanding of the stem cell niche and the interaction of the stem cells with supportive cells in the niche. Current research is helping us to understand stem cells and stem cell regulation and in turn this will help to develop novel therapies to eliminate cancer and the initiating cancer stem cell. The relevant patents on the stem cell regulation and cancer therapy by stem cells are discussed.

  3. Quality of Life and Care Needs of Patients With Persistent or Recurrent Ovarian Cancer, Fallopian Tube Cancer, or Peritoneal Cancer

    ClinicalTrials.gov

    2017-05-03

    Anxiety; Fatigue; Nausea and Vomiting; Neurotoxicity Syndrome; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Stage I Ovarian Cancer; Stage IA Fallopian Tube Cancer; Stage IB Fallopian Tube Cancer; Stage IC Fallopian Tube Cancer; Stage II Ovarian Cancer; Stage IIA Fallopian Tube Cancer; Stage IIB Fallopian Tube Cancer; Stage IIC Fallopian Tube Cancer; Stage III Ovarian Cancer; Stage III Primary Peritoneal Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIC Fallopian Tube Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  4. Coping with ovarian cancer: do coping styles affect outcomes?

    PubMed

    Hopkins, M Laura; McDowell, Ian; Le, Tien; Fung, Michael Fung Kee

    2005-05-01

    The majority of patients with ovarian cancer face a long road of persistent hardship and strain. Treatment of this disease is intense, involving aggressive debulking surgery and multiple chemotherapy regimens. Coping with the disease and its treatment challenges patients on many levels. This review was developed to summarize the evidence concerning the impact of coping strategies on outcomes in patients with ovarian cancer. A comprehensive search of the literature in the field of coping and ovarian cancer was undertaken. Using the Ovid interface, 3 electronic databases, including Medline, Cinahl, and PsycINFO, were searched using the search terms "coping," "cancer," and "ovarian cancer." In addition, a critical appraisal of the 2 most widely used scales to assess coping strategies was a component of this work. This review highlights the relative lack of knowledge on coping in ovarian cancer, the methodologic challenges to its study, and the need to develop an instrument that is tailored to evaluate coping strategies used by patients with ovarian cancer. A validated instrument to assess coping strategies used by patients with ovarian cancer is needed. Identification of strategies that are maladaptive or destructive in patients with ovarian cancer could be used to improve quality of care for patients burdened by this disease. Obstetricians & Gynecologists, Family Physicians. After completion of this article, the reader should be able to list the potential coping strategies for patients with ovarian cancer, to explain the various coping assessment scales, and to summarize the evidence concerning the impact of coping strategies on outcomes in ovarian cancer patients.

  5. Hawaii natural compounds are promising to reduce ovarian cancer deaths.

    PubMed

    Fei-Zhang, David J; Li, Chunshun; Cao, Shugeng

    2016-07-02

    The low survival rate of patients with ovarian cancer largely results from the advanced ovarian tumors as well as tumor resistance to chemotherapy, leading to metastasis and recurrence. However, it is missing as to an effective therapeutic approach that focuses on these aspects to prolong progression-free survival and to decrease mortality in ovarian cancer patients. Here, based on our cancer drug discovery studies, we provide prospective insights into the development of a future line of drugs to effectively reduce ovarian cancer deaths. Pathways that increase the probability of cancer, such as the defective Fanconi anemia (FA) pathway, may render cancer cells more sensitive to new drug targeting.

  6. Risk of Subsequent Ovarian Cancer After Ovarian Conservation in Young Women With Stage I Endometrioid Endometrial Cancer.

    PubMed

    Matsuo, Koji; Machida, Hiroko; Stone, Rebecca L; Soliman, Pamela T; Thaker, Premal H; Roman, Lynda D; Wright, Jason D

    2017-08-01

    To examine the cumulative incidence of subsequent ovarian cancer among young women with stage I endometrioid endometrial cancer who had ovarian conservation at surgical treatment. This retrospective study examined the Surveillance, Epidemiology, and End Results Program to identify women aged younger than 50 years who underwent hysterectomy with ovarian conservation for stage I endometrioid endometrial cancer between 1983 and 2013. Time-dependent risk of ovarian cancer diagnosed during the follow-up after endometrial cancer diagnosis was examined. Among 1,322 women in the study cohort, 16 women developed subsequent ovarian cancer with 5- and 10-year cumulative incidences of 1.0% and 1.3%, respectively. Median time to develop subsequent ovarian cancer was 2.4 years, and the majority of subsequent ovarian cancer was diagnosed within the first 3 years from the diagnosis of endometrial cancer (68.8%). The majority of subsequent ovarian cancer was endometrioid type (81.3%) and stage I disease (75.0%). With a median follow-up time of 11.6 years, there were no ovarian cancer deaths. Younger age at endometrial cancer diagnosis was significantly associated with increased risk of subsequent ovarian cancer (10-year cumulative incidences: age younger than 40 compared with 40-49 years, 2.6% compared with 0.4%, hazard ratio 5.00, 95% confidence interval [CI] 1.60-15.7, P=.002). Young women with stage I endometrioid endometrial cancer have an approximately 1% risk of developing subsequent ovarian cancer after ovarian conservation at the time of hysterectomy that was associated with favorable tumor factors resulting in good ovarian cancer-specific survival. Our results endorse the importance of genetic testing and close follow-up when counseling about this procedure, especially for those who are younger than 40 years.

  7. Paclitaxel, Polyglutamate Paclitaxel, or Observation in Treating Patients With Stage III or Stage IV Ovarian Epithelial, Peritoneal Cancer, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2017-05-03

    Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Serous Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Ovarian Brenner Tumor; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma

  8. Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2017-01-05

    Chemotherapeutic Agent Toxicity; Neuropathy; Neurotoxicity Syndrome; Pain; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  9. Recent Advances in Understanding, Diagnosing, and Treating Ovarian Cancer

    PubMed Central

    Mills, Kathryn; Fuh, Katherine

    2017-01-01

    Ovarian cancer, a term that encompasses ovarian, fallopian, and peritoneal cancers, is the leading cause of gynecologic cancer mortality. To improve patient outcomes, the field is currently focused on defining the mechanisms of cancer formation and spread, early diagnosis and prevention, and developing novel therapeutic options. This review summarizes recent advances in these areas. PMID:28184293

  10. Sargramostim and Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Patients With Advanced Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer That Did Not Respond to Previous Chemotherapy

    ClinicalTrials.gov

    2014-01-15

    Brenner Tumor; Fallopian Tube Cancer; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Peritoneal Cavity Cancer; Recurrent Ovarian Epithelial Cancer; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

  11. FAU regulates carboplatin resistance in ovarian cancer.

    PubMed

    Moss, Esther L; Mourtada-Maarabouni, Mirna; Pickard, Mark R; Redman, Charles W; Williams, Gwyn T

    2010-01-01

    The development of chemotherapy resistance by cancer cells is complex, using different mechanisms and pathways. The gene FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV)-associated ubiquitously expressed gene) was identified through functional expression cloning and previous data have shown that overexpression enhances apoptosis in several cell types. We demonstrate that the expression of FAU was reduced in the A2780cis (cisplatin resistant subclone of A2780) cell line compared with the A2780 ovarian cancer cell line, and was directly related to the cell line's sensitivity to carboplatin. Downregulation of FAU in the A2780 cell line by transfection with two predesigned short-interfering RNAs (siRNAs) to FAU resulted in a significant increase in resistance to carboplatin-induced cell death. Downregulation resulted in increased cell viability and reduced apoptosis after 72 hr of drug treatment compared with the negative controls (Kruskal-Wallis P = 0.0002). Transfection of the A2780cis cell line with the pcDNA3 plasmid containing FAU was associated with increased sensitivity to carboplatin-induced apoptosis, with decreased cell viability and increased apoptosis (Mann Whitney P < 0.0001). The expression of FAU was examined by quantitative real-time reverse transcriptase polymerase chain reaction in normal and malignant ovarian tissue. A significant reduction in the expression of FAU was seen in the malignant compared with normal ovarian samples (Kruskal-Wallis P = 0.0261). These data support a role for FAU in the regulation of platinum-resistance in ovarian cancer. Further research is needed into the apoptotic pathway containing FAU to investigate the potential for targeted therapies to increase or restore the platinum sensitivity of ovarian cancer.

  12. BRCA1 founder mutations compared to ovarian cancer in Belarus.

    PubMed

    Savanevich, Alena; Oszurek, Oleg; Lubiński, Jan; Cybulski, Cezary; Dębniak, Tadeusz; Narod, Steven A; Gronwald, Jacek

    2014-09-01

    In Belarus and other Slavic countries, founder mutations in the BRCA1 gene are responsible for a significant proportion of breast cancer cases, but the data on contribution of these mutations to ovarian cancers are limited. To estimate the proportion of ovarian cancers in Belarus, which are dependent on BRCA1 Slavic founder mutations, we sought the presence of three most frequent mutations (BRCA1: 5382insC, C61G and, 4153delA) in 158 consecutive unselected cases of ovarian cancer. One of the three founder mutations was present in 25 of 158 unselected cases of ovarian cancer (15.8 %). We recommend that all cases of ovarian cancer in Belarus be offered genetic testing for these founder mutations. Furthermore, genetic testing of the Belarusian population will provide the opportunity to prevent a significant proportion of ovarian cancer.

  13. Oncogenic pathways implicated in ovarian epithelial cancer.

    PubMed

    Nicosia, Santo V; Bai, Wenlong; Cheng, Jin Q; Coppola, Domenico; Kruk, Patricia A

    2003-08-01

    Characterization of intracellular signaling pathways should lead to a better understanding of ovarian epithelial carcinogenesis and provide an opportunity to interfere with signal transduction targets involved in ovarian tumor cell growth, survival, and progression. Challenges toward such an effort are significant because many of these signals are part of cascades within an intricate and likely redundant intracellular signaling network (Fig.1). For instance, a given signal may activate a dual intracellular pathway (ie, MEK1-MAPK and PI3K/Akt required for fibronectin-dependent activation of matrix metalloproteinase 9). A single pathway also may transduce more than one biologic or oncogenic signal (ie, PI3K signaling in epithelial and endothelial cell growth and sprouting of neovessels). Despite these challenges, evidence for therapeutic targeting of signal transduction pathways is accumulating in human cancer. For instance, the EGF-specific tyrosine kinase inhibitor ZD 1839 (Iressa) may have a beneficial therapeutic effect on ovarian epithelial cancer. Therapy of this cancer may include inhibitors of PI kinase (quercetin), ezrin and PIP kinase (genistein). The G protein-coupled family of receptors, including LPA, also is an attractive target to drugs, although their frequent pleiotropic functions may be at times toxic and lack specificity. Because of the lack of notable toxicity, PI3K/Akt pathway inhibitors such as FTIs are a promising targeted therapy of ovarian epithelial cancer. Increasing insight into the oncogenic pathways involved in ovarian epithelial cancer also is helping clinicians to understand better the phenomenon of chemoresistance in this malignancy. Oncogenic activation of gamma-synuclein promotes cell survival and provides resistance to paclitaxel, but such a resistance is partially overcome by an MEK inhibitor that suppresses ERK activity. Ovarian epithelial cancer is a complex group of neoplasms with an overall poor prognosis. Comprehension of

  14. How Is Ovarian Cancer Diagnosed?

    MedlinePlus

    ... Cancer Risk? Written by References The American Cancer Society medical and editorial content team Our team is ... 2014 Last Revised: March 20, 2017 American Cancer Society medical information is copyrighted material. For reprint requests, ...

  15. [Olaparib in ovarian cancer with BRCA mutation].

    PubMed

    Pujade-Lauraine, Éric; Combe, Pierre

    2015-06-01

    With 4500 new cases and 3200 death each year, ovarian cancer is the first cause of mortality for gynecological cancer in France. Without any efficient screening, it is usually diagnosed around the age of 60 years at an advanced stage. The emergence of olaparib, a new targeted therapy, represents a major opportunity. Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.

  16. Inherited Determinants of Ovarian Cancer Survival

    PubMed Central

    Goode, Ellen L.; Maurer, Matthew J.; Sellers, Thomas A.; Phelan, Catherine M.; Kalli, Kimberly R.; Fridley, Brooke L.; Vierkant, Robert A.; Armasu, Sebastian M.; White, Kristin L.; Keeney, Gary L.; Cliby, William A.; Rider, David N.; Kelemen, Linda E.; Jones, Monica B.; Peethambaram, Prema P.; Lancaster, Johnathan M.; Olson, Janet E.; Schildkraut, Joellen M.; Cunningham, Julie M.; Hartmann, Lynn C.

    2010-01-01

    Purpose Due to variation of outcome among cases, we sought to examine whether overall survival in ovarian cancer was associated with common inherited variants in 227 candidate genes from ovarian cancer-related pathways including angiogenesis, inflammation, detoxification, glycosylation, one-carbon transfer, apoptosis, cell cycle regulation, and cellular senescence. Experimental Design Blood samples were obtained from 325 women with invasive epithelial ovarian cancer diagnosed at the Mayo Clinic from 1999 to 2006. During a median follow-up of 3.8 years (range, 0.1 – 8.6 years), 157 deaths were observed. Germline DNA was analyzed at 1,416 single nucleotide polymorphisms (SNPs). For all patients, and for 203 with serous subtype, we assessed the overall significance of each gene and pathway, and estimated risk of death via hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for known prognostic factors. Results Variation within angiogenesis was most strongly associated with survival time overall (p=0.03) and among patients with serous cancer (p=0.05), particularly for EIF2B5 rs4912474 (all patients HR 0.69, 95% CI 0.54-0.89, p=0.004), VEGFC rs17697305 (serous subtype HR 2.29, 95% CI 1.34-3.92, p=0.003), and four SNPs in VHL. Variation within the inflammation pathway was borderline significant (all patients, p=0.09), and SNPs in CCR3, IL1B, IL18, CCL2, and ALOX5 which correlated with survival time are worthy of follow-up. Conclusion An extensive multiple-pathway assessment found evidence that inherited differences may play a role in outcome of ovarian cancer patients, particularly in genes within the angiogenesis and inflammation pathways. Our work supports efforts to target such mediators for therapeutic gain. PMID:20103664

  17. Targeted therapy for epithelial ovarian cancer.

    PubMed

    Sharma, Sameer; Odunsi, Kunle

    2005-06-01

    Ovarian cancer is the leading cause of death in women with gynecological malignancies and overall survival for patients with advanced epithelial ovarian cancer (EOC) remains poor. The majority of patients recur after initial treatment. A strategy for improving outcome is to minimise recurrence via targeted therapy in patients after front-line therapy, or more appropriately as consolidation therapy. EOC represents an attractive target because of the biology of the disease and that the bulk of disease occurs in the peritoneal cavity. To initiate targeted therapy, a candidate target must be identified. Innovative approaches via targeted therapy to control metastatic residual EOC are currently under investigation. The targets are molecules and pathways, on which cancer cells depend to proliferate, invade, metastasise and prevent apoptosis. Potential targeted therapies include: proapoptototic therapy, suicide gene therapy, signal transduction, antiangiogenesis, immunotherapy and cytokine therapy. The utilisation of these targets in the clinic demands carefully conducted, well-coordinated but discovery-oriented translational research in the form of clinical trials that can quickly assess alternative strategies or combination of strategies that could result in clinical benefit. Therefore, targeted therapy for epithelial ovarian cancer, especially after complete response to standard regimens, represents a paradigm whose time has come to be nurtured.

  18. Inflammation and cancer stem cells.

    PubMed

    Shigdar, Sarah; Li, Yong; Bhattacharya, Santanu; O'Connor, Michael; Pu, Chunwen; Lin, Jia; Wang, Tao; Xiang, Dongxi; Kong, Lingxue; Wei, Ming Q; Zhu, Yimin; Zhou, Shufeng; Duan, Wei

    2014-04-10

    Cancer stem cells are becoming recognised as being responsible for metastasis and treatment resistance. The complex cellular and molecular network that regulates cancer stem cells and the role that inflammation plays in cancer progression are slowly being elucidated. Cytokines, secreted by tumour associated immune cells, activate the necessary pathways required by cancer stem cells to facilitate cancer stem cells progressing through the epithelial-mesenchymal transition and migrating to distant sites. Once in situ, these cancer stem cells can secrete their own attractants, thus providing an environment whereby these cells can continue to propagate the tumour in a secondary niche. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  19. Targeting the Mevalonate Pathway to Reduce Mortality from Ovarian Cancer

    DTIC Science & Technology

    2015-10-01

    protect these women from developing ovarian cancer. In addition, oral contraceptives , which reduce the frequency of ovulation, have been shown to be...effective in reducing the incidence and mortality of ovarian cancer (1). However, neither of these approaches is without concern. Oral contraceptive use...Hermon C, Peto R, Reeves G. Ovarian cancer and oral contraceptives : collaborative reanalysis of data from 45 epidemiological studies including 23,257

  20. Therapeutic Strategies against Cyclin E1-Amplified Ovarian Cancers

    DTIC Science & Technology

    2016-10-01

    AWARD NUMBER: W81XWH-15-1-0566 TITLE: Therapeutic Strategies against Cyclin E1-Amplified Ovarian Cancers PRINCIPAL INVESTIGATOR: Dipanjan...SUBTITLE 5a. CONTRACT NUMBER Therapeutic Strategies against Cyclin E1-Amplified Ovarian Cancers 5b. GRANT NUMBER W81XWH-15-1-0566 5c. PROGRAM...resistance to platinum, management of CCNE1- amplified ovarian cancers is challenging. In this research, we evaluate three novel strategies against CCNE1

  1. Anal fissures associated with targeted therapies in ovarian cancer.

    PubMed

    Squires, Jennifer

    2009-12-01

    Although ovarian cancer remains a leading cause of gynecologic cancer death, targeted therapies are improving patient outcomes. Anal fissures are a side effect of targeted therapies that can disrupt or stop treatment regimens. Diagnosis and management of anal fissures by advanced practice nurses are crucial for maintaining the quality of life of patients with ovarian cancer.

  2. Targeting the tumour microenvironment in ovarian cancer.

    PubMed

    Hansen, Jean M; Coleman, Robert L; Sood, Anil K

    2016-03-01

    The study of cancer initiation, growth, and metastasis has traditionally been focused on cancer cells, and the view that they proliferate due to uncontrolled growth signalling owing to genetic derangements. However, uncontrolled growth in tumours cannot be explained solely by aberrations in cancer cells themselves. To fully understand the biological behaviour of tumours, it is essential to understand the microenvironment in which cancer cells exist, and how they manipulate the surrounding stroma to promote the malignant phenotype. Ovarian cancer is the leading cause of death from gynaecologic cancer worldwide. The majority of patients will have objective responses to standard tumour debulking surgery and platinum-taxane doublet chemotherapy, but most will experience disease recurrence and chemotherapy resistance. As such, a great deal of effort has been put forth to develop therapies that target the tumour microenvironment in ovarian cancer. Herein, we review the key components of the tumour microenvironment as they pertain to this disease, outline targeting opportunities and supporting evidence thus far, and discuss resistance to therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium.

    PubMed

    Olsen, Catherine M; Nagle, Christina M; Whiteman, David C; Ness, Roberta; Pearce, Celeste Leigh; Pike, Malcolm C; Rossing, Mary Anne; Terry, Kathryn L; Wu, Anna H; Risch, Harvey A; Yu, Herbert; Doherty, Jennifer A; Chang-Claude, Jenny; Hein, Rebecca; Nickels, Stefan; Wang-Gohrke, Shan; Goodman, Marc T; Carney, Michael E; Matsuno, Rayna K; Lurie, Galina; Moysich, Kirsten; Kjaer, Susanne K; Jensen, Allan; Hogdall, Estrid; Goode, Ellen L; Fridley, Brooke L; Vierkant, Robert A; Larson, Melissa C; Schildkraut, Joellen; Hoyo, Cathrine; Moorman, Patricia; Weber, Rachel P; Cramer, Daniel W; Vitonis, Allison F; Bandera, Elisa V; Olson, Sara H; Rodriguez-Rodriguez, Lorna; King, Melony; Brinton, Louise A; Yang, Hannah; Garcia-Closas, Montserrat; Lissowska, Jolanta; Anton-Culver, Hoda; Ziogas, Argyrios; Gayther, Simon A; Ramus, Susan J; Menon, Usha; Gentry-Maharaj, Aleksandra; Webb, Penelope M

    2013-04-01

    Whilst previous studies have reported that higher BMI increases a woman's risk of developing ovarian cancer, associations for the different histological subtypes have not been well defined. As the prevalence of obesity has increased dramatically, and classification of ovarian histology has improved in the last decade, we sought to examine the association in a pooled analysis of recent studies participating in the Ovarian Cancer Association Consortium. We evaluated the association between BMI (recent, maximum and in young adulthood) and ovarian cancer risk using original data from 15 case-control studies (13 548 cases and 17 913 controls). We combined study-specific adjusted odds ratios (ORs) using a random-effects model. We further examined the associations by histological subtype, menopausal status and post-menopausal hormone use. High BMI (all time-points) was associated with increased risk. This was most pronounced for borderline serous (recent BMI: pooled OR=1.24 per 5 kg/m(2); 95% CI 1.18-1.30), invasive endometrioid (1.17; 1.11-1.23) and invasive mucinous (1.19; 1.06-1.32) tumours. There was no association with serous invasive cancer overall (0.98; 0.94-1.02), but increased risks for low-grade serous invasive tumours (1.13, 1.03-1.25) and in pre-menopausal women (1.11; 1.04-1.18). Among post-menopausal women, the associations did not differ between hormone replacement therapy users and non-users. Whilst obesity appears to increase risk of the less common histological subtypes of ovarian cancer, it does not increase risk of high-grade invasive serous cancers, and reducing BMI is therefore unlikely to prevent the majority of ovarian cancer deaths. Other modifiable factors must be identified to control this disease.

  4. EGFL6 Regulates the Asymmetric Division, Maintenance, and Metastasis of ALDH+ Ovarian Cancer Cells.

    PubMed

    Bai, Shoumei; Ingram, Patrick; Chen, Yu-Chih; Deng, Ning; Pearson, Alex; Niknafs, Yashar; O'Hayer, Patrick; Wang, Yun; Zhang, Zhong-Yin; Boscolo, Elisa; Bischoff, Joyce; Yoon, Euisik; Buckanovich, Ronald J

    2016-11-01

    Little is known about the factors that regulate the asymmetric division of cancer stem-like cells (CSC). Here, we demonstrate that EGFL6, a stem cell regulatory factor expressed in ovarian tumor cells and vasculature, regulates ALDH(+) ovarian CSC. EGFL6 signaled at least in part via the oncoprotein SHP2 with concomitant activation of ERK. EGFL6 signaling promoted the migration and asymmetric division of ALDH(+) ovarian CSC. As such, EGFL6 increased not only tumor growth but also metastasis. Silencing of EGFL6 or SHP2 limited numbers of ALDH(+) cells and reduced tumor growth, supporting a critical role for EGFL6/SHP2 in ALDH(+) cell maintenance. Notably, systemic administration of an EGFL6-neutralizing antibody we generated restricted tumor growth and metastasis, specifically blocking ovarian cancer cell recruitment to the ovary. Together, our results offer a preclinical proof of concept for EGFL6 as a novel therapeutic target for the treatment of ovarian cancer. Cancer Res; 76(21); 6396-409. ©2016 AACR. ©2016 American Association for Cancer Research.

  5. Risk factors for ovarian cancer: a case-control study.

    PubMed Central

    Booth, M.; Beral, V.; Smith, P.

    1989-01-01

    A hospital-based case-control study of ovarian cancer was conducted in London and Oxford between October 1978 and February 1983. Menstrual characteristics, reproductive and contraceptive history and history of exposure to various environmental factors were compared between 235 women with histologically diagnosed epithelial ovarian cancer and 451 controls. High gravidity, hysterectomy, female sterilisation and oral contraceptive use were associated with a reduced risk of ovarian cancer. Infertility and late age at menopause were associated with an increase in risk. While these factors were related, they were each found to be independently associated with ovarian cancer risk after adjusting for the effect of the other factors. PMID:2679848

  6. Validating a mouse model of ovarian cancer for early detection through imaging | Division of Cancer Prevention

    Cancer.gov

    DESCRIPTION (provided by applicant): Despite advances in treatment strategies, ovarian cancer remains the deadliest gynecological malignancy and the 5th largest cancer killer in women. Located deep in the body, with few early symptoms and no effective screening technique, ovarian cancer has remained stubbornly difficult to understand, much less effectively combat. Ovarian cancer is almost always discovered at an advanced stage. |

  7. Three-photon imaging of ovarian cancer

    NASA Astrophysics Data System (ADS)

    Barton, Jennifer K.; Amirsolaimani, Babak; Rice, Photini; Hatch, Kenneth; Kieu, Khanh

    2016-02-01

    Optical imaging methods have the potential to detect ovarian cancer at an early, curable stage. Optical imaging has the disadvantage that high resolution techniques require access to the tissue of interest, but miniature endoscopes that traverse the natural orifice of the reproductive tract, or access the ovaries and fallopian tubes through a small incision in the vagina wall, can provide a minimally-invasive solution. We have imaged both rodent and human ovaries and fallopian tubes with a variety of endoscope-compatible modalities. The recent development of fiber-coupled femtosecond lasers will enable endoscopic multiphoton microscopy (MPM). We demonstrated two- and three-photon excited fluorescence (2PEF, 3PEF), and second- and third-harmonic generation microscopy (SHG, THG) in human ovarian and fallopian tube tissue. A study was undertaken to understand the mechanisms of contrast in these images. Six patients (normal, cystadenoma, and ovarian adenocarcinoma) provided ovarian and fallopian tube biopsies. The tissue was imaged with three-dimensional optical coherence tomography, multiphoton microscopy, and frozen for histological sectioning. Tissue sections were stained with hematoxylin and eosin, Masson's trichrome, and Sudan black. Approximately 1 μm resolution images were obtained with an excitation source at 1550 nm. 2PEF signal was absent. SHG signal was mainly from collagen. 3PEF and THG signal came from a variety of sources, including a strong signal from fatty connective tissue and red blood cells. Adenocarcinoma was characterized by loss of SHG signal, whereas cystic abnormalities showed strong SHG. There was limited overlap of two- and three- photon signals, suggesting that three-photon imaging can provide additional information for early diagnosis of ovarian cancer.

  8. Metabolic Regulation of Ovarian Cancer Cell Death

    DTIC Science & Technology

    2013-07-01

    2013 4 . TITLE AND SUBTITLE 5a. CONTRACT NUMBER Metabolic Regulation of Ovarian Cancer cell death 5b. GRANT NUMBER W81XWH-10-1...Introduction 3 2. Keywords 3 3. Overall Project Summary 3-6 4 . Key Research Accomplishments 6-7 5. Conclusion 7 6. Publications, Abstracts, and...synthase inhibitors Fig. 4 ). We were slightly delayed in submitting this work for publication as the first author had to finish his PhD thesis and

  9. 'Genetic profiling' and ovarian cancer therapy (review).

    PubMed

    Vella, Nadia; Aiello, Marco; Russo, Alessia Erika; Scalisi, Aurora; Spandidos, Demetrios A; Toffoli, Giuseppe; Sorio, Roberto; Libra, Massimo; Stivala, Franca

    2011-01-01

    High variability observed among ovarian cancer patients in response to the same therapy and the related toxicity may be correlated to gene polymorphisms and genetic alterations affecting the metabolism of drugs commonly used to treat this tumor. Recent studies have shown a correlation between the polymorphisms characterizing GSTM1-T1 detoxifying enzymes and poor outcome in advanced ovarian cancer patients treated with platinum/paclitaxel-based chemotherapy. Multidrug resistance 1 (mdr-1) polymorphisms were found to be associated with resistance to paclitaxel treatment. Polymorphisms of MRP2, a protein involved in methotrexate, cisplatin and irinotecan active metabolite glucuronide transport, negatively affect platinum-based chemotherapy response. A similar occurrence has been observed with CYP1A1 Ile462Val and ercc1 C118T polymorphisms while patients who were carriers of MTHFR C677T polymorphism had a better response to methotrexate therapy, but an elevated risk of toxicity. Biological therapy with Bevacizumab, the anti-vascular endothelial growth factor has been shown to be less efficient in ovarian cancer patients carrying the polymorphism of the Interleukin-8 gene. Instead, polymorphisms in the XPD gene (Lys751Gln and Asp312Asn), a member of the nucleotide excision repair pathway, positively affects the response to therapy with carboplatin/paclitaxel. Therefore, the study of 'genetic profiling' is crucial to improving the clinician's ability to tailor effective therapy to the molecular profile of the patient while minimizing toxicities. This review describes clinical applications of the above genetic polymorphisms in ovarian cancer patients treated with platinum/paclitaxel-based chemotherapy.

  10. Sirolimus and Vaccine Therapy in Treating Patients With Stage II-IV Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2017-09-25

    Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  11. Ovarian Cancer Biomarker Discovery Based on Genomic Approaches

    PubMed Central

    Lee, Jung-Yun; Kim, Hee Seung; Suh, Dong Hoon; Kim, Mi-Kyung; Chung, Hyun Hoon; Song, Yong-Sang

    2013-01-01

    Ovarian cancer presents at an advanced stage in more than 75% of patients. Early detection has great promise to improve clinical outcomes. Although the advancing proteomic technologies led to the discovery of numerous ovarian cancer biomarkers, no screening method has been recommended for early detection of ovarian cancer. Complexity and heterogeneity of ovarian carcinogenesis is a major obstacle to discover biomarkers. As cancer arises due to accumulation of genetic change, understanding the close connection between genetic changes and ovarian carcinogenesis would provide the opportunity to find novel gene-level ovarian cancer biomarkers. In this review, we summarize the various gene-based biomarkers by genomic technologies, including inherited gene mutations, epigenetic changes, and differential gene expression. In addition, we suggest the strategy to discover novel gene-based biomarkers with recently introduced next generation sequencing. PMID:25337559

  12. Salpingectomy as a Means to Reduce Ovarian Cancer Risk

    PubMed Central

    Daly, Mary B.; Dresher, Charles W.; Yates, Melinda S.; Jeter, Joanne M.; Karlan, Beth Y.; Alberts, David S.; Lu, Karen H.

    2015-01-01

    Bilateral salpingo-oophorectomy (BSO) has become the standard of care for risk reduction in women at hereditary risk of ovarian cancer. While this procedure significantly decreases both the incidence of and mortality from ovarian cancer, it impacts quality of life, and the premature cessation of ovarian function may have long term health hazards. Recent advances in our understanding of the molecular pathways of ovarian cancer point to the fallopian tube epithelium as the origin of most high grade serous cancers (HGSC). This evolving appreciation of the role of the fallopian tube in HGSC has led to the consideration of salpingectomy alone as an option for risk management, especially in premenopausal women. In addition, it is postulated that bilateral salpingectomy with ovarian retention (BSOR), may have a public health benefit for women undergoing benign gynecologic surgery. In this review we provide the rationale for salpingectomy as an ovarian cancer risk reduction strategy. PMID:25586903

  13. YAP Promotes Ovarian Cancer Cell Tumorigenesis and Is Indicative of a Poor Prognosis for Ovarian Cancer Patients

    PubMed Central

    Xia, Yan; Liu, Yixiong; Li, Wenhui; Li, Ming; Fan, Heng-Yu

    2014-01-01

    YAP is a key component of the Hippo signaling pathway and plays a critical role in the development and progression of multiple cancer types, including ovarian cancer. However, the effects of YAP on ovarian cancer development in vivo and its downstream effectors remain uncertain. In this study we found that strong YAP expression was associated with poor ovarian cancer patient survival. Specifically, we showed for the first time that high YAP expression levels were positively correlated with TEAD4 gene expression, and their co-expression was a prognostic marker for poor ovarian cancer survival. Hyperactivation of YAP by mutating its five inhibitory phosphorylation sites (YAP-5SA) increased ovarian cancer cell proliferation, resistance to chemotherapeutic drugs, cell migration, and anchorage-independent growth. In contrast, expression of a dominant negative YAP mutant reversed these phenotypes in ovarian cancer cells both in vitro and in vivo. Our results suggested that YAP caused these effects by promoting an epithelial-to-mesenchymal transition. Thus, YAP promotes ovarian cancer cell growth and tumorigenesis both in vitro and in vivo. Further, high YAP and TEAD4 expression is a prognostic marker for ovarian cancer progression and a potential target for ovarian cancer treatment. PMID:24622501

  14. Metformin Hydrochloride and Combination Chemotherapy in Treating Patients With Stage III-IV Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2016-11-28

    Brenner Tumor; Malignant Ascites; Malignant Pleural Effusion; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Recurrent Fallopian Tube Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Primary Peritoneal Cavity Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIA Ovarian Germ Cell Tumor; Stage IIIA Primary Peritoneal Cavity Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Epithelial Cancer; Stage IIIB Ovarian Germ Cell Tumor; Stage IIIB Primary Peritoneal Cavity Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Epithelial Cancer; Stage IIIC Ovarian Germ Cell Tumor; Stage IIIC Primary Peritoneal Cavity Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Primary Peritoneal Cavity Cancer

  15. Whence High-Grade Serous Ovarian Cancer.

    PubMed

    Kohn, Elise C; Ivy, S Percy

    2017-01-01

    Our understanding of epithelial ovarian cancer has blossomed, and we now recognize that it is a collection of varied histologic and molecularly different malignancies, many of which may not derive from a true ovarian anatomic precursor. High-grade serous ovarian cancer (HGSOC) is a unique type of epithelial cancer. It is characterized by nearly universal mutation in and dysfunction of p53, genomic instability rather than driver mutations, advanced stage at onset, and probable fallopian tube epithelium origin, with a serous tubal in situ carcinoma precursor. Germline deleterious mutations in BRCA1 and BRCA2, as well as other less prevalent genes involved in DNA repair, such as PALB2 and RAD51c, are associated with its carcinogenesis and may predict susceptibility to classes of treatment agents, including DNA-damaging agents and DNA repair inhibitors. Loss of function of these genes is associated with homologous recombination dysfunction (HRD). It is now recognized that there may be HGSOC with wild-type BRCA1 and BRCA2 with an identifiable HRD phenotype. Such HRD tumors also may be more susceptible to certain classes of treatments and may be phenotypically detectable with a composite molecular biomarker that has been shown to be predictive for response to PARP inhibitors. Use of this new knowledge of the anatomic and molecular background of HGSOC has led to the rational design of novel combinations of treatment classes to create an HRD-like cellular environment and thus drive treatment benefits.

  16. Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium

    PubMed Central

    Nagle, C M; Dixon, S C; Jensen, A; Kjaer, S K; Modugno, F; deFazio, A; Fereday, S; Hung, J; Johnatty, S E; Fasching, P A; Beckmann, M W; Lambrechts, D; Vergote, I; Van Nieuwenhuysen, E; Lambrechts, S; Risch, H A; Rossing, M A; Doherty, J A; Wicklund, K G; Chang-Claude, J; Goodman, M T; Ness, R B; Moysich, K; Heitz, F; du Bois, A; Harter, P; Schwaab, I; Matsuo, K; Hosono, S; Goode, E L; Vierkant, R A; Larson, M C; Fridley, B L; Høgdall, C; Schildkraut, J M; Weber, R P; Cramer, D W; Terry, K L; Bandera, E V; Paddock, L; Rodriguez-Rodriguez, L; Wentzensen, N; Yang, H P; Brinton, L A; Lissowska, J; Høgdall, E; Lundvall, L; Whittemore, A; McGuire, V; Sieh, W; Rothstein, J; Sutphen, R; Anton-Culver, H; Ziogas, A; Pearce, C L; Wu, A H; Webb, P M

    2015-01-01

    Background: Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer. Methods: We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype. Results: Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30–34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99–1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01–1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m−2) and endometrioid subtypes (pHR: 1.08 per 5 kg m−2), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m−2) subtype, but only the association with high-grade serous cancers was significant. Conclusions: Higher BMI is associated with adverse survival among the majority of women with ovarian cancer. PMID:26151456

  17. Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium.

    PubMed

    Nagle, C M; Dixon, S C; Jensen, A; Kjaer, S K; Modugno, F; deFazio, A; Fereday, S; Hung, J; Johnatty, S E; Fasching, P A; Beckmann, M W; Lambrechts, D; Vergote, I; Van Nieuwenhuysen, E; Lambrechts, S; Risch, H A; Rossing, M A; Doherty, J A; Wicklund, K G; Chang-Claude, J; Goodman, M T; Ness, R B; Moysich, K; Heitz, F; du Bois, A; Harter, P; Schwaab, I; Matsuo, K; Hosono, S; Goode, E L; Vierkant, R A; Larson, M C; Fridley, B L; Høgdall, C; Schildkraut, J M; Weber, R P; Cramer, D W; Terry, K L; Bandera, E V; Paddock, L; Rodriguez-Rodriguez, L; Wentzensen, N; Yang, H P; Brinton, L A; Lissowska, J; Høgdall, E; Lundvall, L; Whittemore, A; McGuire, V; Sieh, W; Rothstein, J; Sutphen, R; Anton-Culver, H; Ziogas, A; Pearce, C L; Wu, A H; Webb, P M

    2015-09-01

    Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer. We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype. Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant. Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.

  18. Single cell sequencing reveals heterogeneity within ovarian cancer epithelium and cancer associated stromal cells.

    PubMed

    Winterhoff, Boris J; Maile, Makayla; Mitra, Amit Kumar; Sebe, Attila; Bazzaro, Martina; Geller, Melissa A; Abrahante, Juan E; Klein, Molly; Hellweg, Raffaele; Mullany, Sally A; Beckman, Kenneth; Daniel, Jerry; Starr, Timothy K

    2017-03-01

    The purpose of this study was to determine the level of heterogeneity in high grade serous ovarian cancer (HGSOC) by analyzing RNA expression in single epithelial and cancer associated stromal cells. In addition, we explored the possibility of identifying subgroups based on pathway activation and pre-defined signatures from cancer stem cells and chemo-resistant cells. A fresh, HGSOC tumor specimen derived from ovary was enzymatically digested and depleted of immune infiltrating cells. RNA sequencing was performed on 92 single cells and 66 of these single cell datasets passed quality control checks. Sequences were analyzed using multiple bioinformatics tools, including clustering, principle components analysis, and geneset enrichment analysis to identify subgroups and activated pathways. Immunohistochemistry for ovarian cancer, stem cell and stromal markers was performed on adjacent tumor sections. Analysis of the gene expression patterns identified two major subsets of cells characterized by epithelial and stromal gene expression patterns. The epithelial group was characterized by proliferative genes including genes associated with oxidative phosphorylation and MYC activity, while the stromal group was characterized by increased expression of extracellular matrix (ECM) genes and genes associated with epithelial-to-mesenchymal transition (EMT). Neither group expressed a signature correlating with published chemo-resistant gene signatures, but many cells, predominantly in the stromal subgroup, expressed markers associated with cancer stem cells. Single cell sequencing provides a means of identifying subpopulations of cancer cells within a single patient. Single cell sequence analysis may prove to be critical for understanding the etiology, progression and drug resistance in ovarian cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Re-implantation of cryopreserved ovarian cortex resulting in restoration of ovarian function, natural conception and successful pregnancy after haematopoietic stem cell transplantation for Wilms tumour.

    PubMed

    Dunlop, C E; Brady, B M; McLaughlin, M; Telfer, E E; White, J; Cowie, F; Zahra, S; Wallace, W H B; Anderson, R A

    2016-12-01

    With the improvement of long-term cancer survival rates, growing numbers of female survivors are suffering from treatment-related premature ovarian insufficiency (POI). Although pre-treatment embryo and oocyte storage are effective fertility preservation strategies, they are not possible for pre-pubertal girls or women who cannot delay treatment. In these cases, the only available treatment option is ovarian cortex cryopreservation and subsequent re-implantation. A 32-year-old woman had ovarian cortex cryopreserved 10 years previously before commencing high-dose chemotherapy and undergoing a haematopoietic stem cell transplant for recurrent adult Wilms tumour, which resulted in POI. She underwent laparoscopic orthotopic transplantation of cryopreserved ovarian cortex to the original site of biopsy on the left ovary. She ovulated at 15 and 29 weeks post-re-implantation with AMH detectable, then rising, from 21 weeks, and conceived naturally following the second ovulation. The pregnancy was uncomplicated and a healthy male infant was born by elective Caesarean section at 36(+4) weeks gestation. This is the first report of ovarian cortex re-implantation in the UK. Despite the patient receiving low-risk chemotherapy prior to cryopreservation and the prolonged tissue storage duration, the re-implantation resulted in rapid restoration of ovarian function and natural conception with successful pregnancy.

  20. Ovarian Cancer Risk Factors by Histologic Subtype: An Analysis From the Ovarian Cancer Cohort Consortium.

    PubMed

    Wentzensen, Nicolas; Poole, Elizabeth M; Trabert, Britton; White, Emily; Arslan, Alan A; Patel, Alpa V; Setiawan, V Wendy; Visvanathan, Kala; Weiderpass, Elisabete; Adami, Hans-Olov; Black, Amanda; Bernstein, Leslie; Brinton, Louise A; Buring, Julie; Butler, Lesley M; Chamosa, Saioa; Clendenen, Tess V; Dossus, Laure; Fortner, Renee; Gapstur, Susan M; Gaudet, Mia M; Gram, Inger T; Hartge, Patricia; Hoffman-Bolton, Judith; Idahl, Annika; Jones, Michael; Kaaks, Rudolf; Kirsh, Victoria; Koh, Woon-Puay; Lacey, James V; Lee, I-Min; Lundin, Eva; Merritt, Melissa A; Onland-Moret, N Charlotte; Peters, Ulrike; Poynter, Jenny N; Rinaldi, Sabina; Robien, Kim; Rohan, Thomas; Sandler, Dale P; Schairer, Catherine; Schouten, Leo J; Sjöholm, Louise K; Sieri, Sabina; Swerdlow, Anthony; Tjonneland, Anna; Travis, Ruth; Trichopoulou, Antonia; van den Brandt, Piet A; Wilkens, Lynne; Wolk, Alicja; Yang, Hannah P; Zeleniuch-Jacquotte, Anne; Tworoger, Shelley S

    2016-08-20

    An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3). Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competing-risks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test. Most risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] < .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het ≤ .01). Family history of breast cancer (P-het = .008) had modest heterogeneity. Smoking was associated with an increased risk of mucinous (RR per 20 pack-years, 1.26; 95% CI, 1.08 to 1.46) but a decreased risk of clear cell (RR, 0.72; 95% CI, 0.55 to 0.94) tumors (P-het = .004). Unsupervised clustering by risk factors separated endometrioid, clear cell, and low-grade serous carcinomas from high-grade serous and mucinous carcinomas. The heterogeneous associations of risk factors with ovarian cancer subtypes emphasize the importance of conducting etiologic studies by ovarian cancer subtypes. Most established risk factors were more strongly associated with nonserous carcinomas, which demonstrate challenges for risk prediction of serous cancers, the most fatal subtype. © 2016 by American Society of Clinical Oncology.

  1. Ovarian Cancer Risk Factors by Histologic Subtype: An Analysis From the Ovarian Cancer Cohort Consortium

    PubMed Central

    Poole, Elizabeth M.; Trabert, Britton; White, Emily; Arslan, Alan A.; Patel, Alpa V.; Setiawan, V. Wendy; Visvanathan, Kala; Weiderpass, Elisabete; Adami, Hans-Olov; Black, Amanda; Bernstein, Leslie; Brinton, Louise A.; Buring, Julie; Butler, Lesley M.; Chamosa, Saioa; Clendenen, Tess V.; Dossus, Laure; Fortner, Renee; Gapstur, Susan M.; Gaudet, Mia M.; Gram, Inger T.; Hartge, Patricia; Hoffman-Bolton, Judith; Idahl, Annika; Jones, Michael; Kaaks, Rudolf; Kirsh, Victoria; Koh, Woon-Puay; Lacey, James V.; Lee, I-Min; Lundin, Eva; Merritt, Melissa A.; Onland-Moret, N. Charlotte; Peters, Ulrike; Poynter, Jenny N.; Rinaldi, Sabina; Robien, Kim; Rohan, Thomas; Sandler, Dale P.; Schairer, Catherine; Schouten, Leo J.; Sjöholm, Louise K.; Sieri, Sabina; Swerdlow, Anthony; Tjonneland, Anna; Travis, Ruth; Trichopoulou, Antonia; van den Brandt, Piet A.; Wilkens, Lynne; Wolk, Alicja; Yang, Hannah P.; Zeleniuch-Jacquotte, Anne; Tworoger, Shelley S.

    2016-01-01

    Purpose An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3). Patients and Methods Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competing-risks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test. Results Most risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] < .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het ≤ .01). Family history of breast cancer (P-het = .008) had modest heterogeneity. Smoking was associated with an increased risk of mucinous (RR per 20 pack-years, 1.26; 95% CI, 1.08 to 1.46) but a decreased risk of clear cell (RR, 0.72; 95% CI, 0.55 to 0.94) tumors (P-het = .004). Unsupervised clustering by risk factors separated endometrioid, clear cell, and low-grade serous carcinomas from high-grade serous and mucinous carcinomas. Conclusion The heterogeneous associations of risk factors with ovarian cancer subtypes emphasize the importance of conducting etiologic studies by ovarian cancer subtypes. Most established risk factors were more strongly associated with nonserous carcinomas, which demonstrate challenges for risk prediction of serous cancers, the most fatal subtype. PMID:27325851

  2. Biological Basis for Chemoprevention of Ovarian Cancer

    DTIC Science & Technology

    2004-10-01

    birth control pill use are strongly protective. To achieve a better understanding of the etiology of ovarian cancer, which can then be translated into effective prevention strategies, we have initiated a case-control study that considers genetic susceptibility, epidemiologic risk factors and acquired genetic alterations. Subjects are interviewed in their homes and about 750 cases and 750 controls have been accrued thus far. Blood and cancer samples have been collected and molecular analyses of genetic polymorphisms (BRCA1/2, progesterone receptor, vitamin D receptor,

  3. Biological Basis for Chemoprevention of Ovarian Cancer

    DTIC Science & Technology

    2003-10-01

    birth control pill use are strongly protective. To achieve a better understanding of the etiology of ovarian cancer, which can then be translated into effective prevention strategies, we have initiated a case-control study that considers genetic susceptibility, epidemiologic risk factors and acquired genetic alterations. Subjects are interviewed in their homes and about 650 cases and 650 controls have been accrued thus far. Blood and cancer samples have been collected and molecular analyses of genetic polymorphisms (BRCA1/2, progesterone receptor) have been performed. An

  4. Ovarian and breast cancer spheres are similar in transcriptomic features and sensitive to fenretinide.

    PubMed

    Wang, Haiwei; Zhang, Yuxing; Du, Yanzhi

    2013-01-01

    Cancer stem cells (CSCs) are resistant to chemotherapy and are ability to regenerate cancer cell populations, thus attracting much attention in cancer research. In this report, we first demonstrated that sphere cells from ovarian cancer cell line A2780 shared many features of CSCs, such as resistance to cisplatin and able to initiate tumors in an efficient manner. Then, we conducted cDNA microarray analysis on spheres from ovarian A2780 cells, and from breast MCF7 and SUM159 cells, and found that molecular pathways underlying spheres from these cancer cell lines were similar to a large extent, suggesting that similar mechanisms are involved in the genesis of CSCs in both ovarian and breast cancer types. In addition, we showed that spheres from these cancer types were highly sensitive to fenretinide, a stimulus of oxidative stress-mediated apoptosis in cancer cells. Thus, our results not only provide important insights into mechanisms underlying CSCs in ovarian and breast cancer, but also lead to the development of more sophisticated protocols of cancer therapy in near future.

  5. Ovarian and Breast Cancer Spheres Are Similar in Transcriptomic Features and Sensitive to Fenretinide

    PubMed Central

    Wang, Haiwei; Zhang, Yuxing; Du, Yanzhi

    2013-01-01

    Cancer stem cells (CSCs) are resistant to chemotherapy and are ability to regenerate cancer cell populations, thus attracting much attention in cancer research. In this report, we first demonstrated that sphere cells from ovarian cancer cell line A2780 shared many features of CSCs, such as resistance to cisplatin and able to initiate tumors in an efficient manner. Then, we conducted cDNA microarray analysis on spheres from ovarian A2780 cells, and from breast MCF7 and SUM159 cells, and found that molecular pathways underlying spheres from these cancer cell lines were similar to a large extent, suggesting that similar mechanisms are involved in the genesis of CSCs in both ovarian and breast cancer types. In addition, we showed that spheres from these cancer types were highly sensitive to fenretinide, a stimulus of oxidative stress-mediated apoptosis in cancer cells. Thus, our results not only provide important insights into mechanisms underlying CSCs in ovarian and breast cancer, but also lead to the development of more sophisticated protocols of cancer therapy in near future. PMID:24222909

  6. Genetically-defined ovarian cancer mouse models.

    PubMed

    Morin, Patrice J; Weeraratna, Ashani T

    2016-01-01

    Epithelial ovarian cancer (EOC), the deadliest of gynaecological cancers, is a disease that remains difficult to detect early and treat efficiently. A significant challenge for researchers in the field is that the aetiology of EOC and the molecular pathways important for its development are poorly understood. Moreover, precursor lesions have not been readily identifiable, making the mechanisms of EOC progression difficult to delineate. In order to address these issues, several genetically-defined ovarian mouse models have been generated in the past 15 years. However, because of the recent suggestion that most EOCs may not originate from the ovarian surface 'epithelium', but from other tissues of the female genital tract, some models may need to be re-evaluated within this new paradigm. In this review, we examine several genetically-defined EOC models and discuss how the new paradigm may explain some of the features of these models. A better understanding of the strengths and limitations of the current EOC mouse models will undoubtedly allow us to utilize these tools to better understand the biology of the disease and develop new approaches for EOC prevention, detection, and treatment. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  7. Segregation analysis of epithelial ovarian cancer in Finland.

    PubMed Central

    Auranen, A.; Iselius, L.

    1998-01-01

    Epithelial ovarian cancer is known to aggregate in families. The dominantly inherited ovarian cancer predisposing genes, BRCA1, BRCA2 and genes involved in the hereditary non-polyposis colorectal cancer (HNPCC) syndrome, have recently been identified. However, in the majority of families with more than one case of ovarian cancer, dominant inheritance cannot be recognized. We investigated familial clustering of epithelial ovarian cancer in a population-based sample of 663 Finnish ovarian cancer patients. A segregation analysis with the POINTER software was conducted on the 937 nuclear families from these 663 pedigrees. The major gene model was favoured, and the sporadic and multifactorial models were strongly rejected. In the studied population, the best fitting model was a recessive mode of inheritance, and 8% of ovarian cancer patients were estimated to be homozygous for the deleterious genotype. This evidence for recessively inherited ovarian cancer predisposition should be interpreted cautiously, as the analysis is subject to certain errors, which are discussed in the article. Results of this analysis, however, strongly emphasize the role of genetic factors in all familial aggregation of epithelial ovarian cancer. PMID:9652774

  8. Pancreatic cancer stem cells.

    PubMed

    Zhu, Ya-Yun; Yuan, Zhou

    2015-01-01

    Studies are emerging in support of the cancer stem cells (CSCs) theory which considers that a tiny subset of cancer cells is exclusively responsible for the initiation and malignant behavior of a cancer. This cell population, also termed CSCs, possesses the capacity both to self-renew, producing progeny that have the identical tumorigenic potential, and to differentiate into the bulk of cancer cells, helping serve the formation of the tumor entities, which, altogether, build the hierarchically organized structure of a cancer. In this review, we try to articulate the complicated signaling pathways regulating the retention of the characteristics of pancreatic CSCs, and in the wake of which, we seek to offer insights into the CSCs-relevant targeted therapeutics which are, in the meantime, confronted with bigger challenges than ever.

  9. Development of a Mouse Model of Menopausal Ovarian Cancer

    PubMed Central

    Smith, Elizabeth R.; Wang, Ying; Xu, Xiang-Xi

    2014-01-01

    Despite significant understanding of the genetic mutations involved in ovarian epithelial cancer and advances in genomic approaches for expression and mutation profiling of tumor tissues, several key questions in ovarian cancer biology remain enigmatic: the mechanism for the well-established impact of reproductive factors on ovarian cancer risk remains obscure; cell of origin of ovarian cancer continue to be debated; and the precursor lesion, sequence, or events in progression remain to be defined. Suitable mouse models should complement the analysis of human tumor tissues and may provide clues to these questions currently perplexing ovarian cancer biology. A potentially useful model is the germ cell-deficient Wv (white spotting variant) mutant mouse line, which may be used to study the impact of menopausal physiology on the increased risk of ovarian cancer. The Wv mice harbor a point mutation in c-Kit that reduces the receptor tyrosine kinase activity to about 1–5% (it is not a null mutation). Homozygous Wv mutant females have a reduced ovarian germ cell reservoir at birth and the follicles are rapidly depleted upon reaching reproductive maturity, but other biological phenotypes are minimal and the mice have a normal life span. The loss of ovarian function precipitates changes in hormonal and metabolic activity that model features of menopause in humans. As a consequence of follicle depletion, the Wv ovaries develop ovarian tubular adenomas, a benign epithelial tumor corresponding to surface epithelial invaginations and papillomatosis that mark human ovarian aging. Ongoing work will test the possibility of converting the benign epithelial tubular adenomas into neoplastic tumors by addition of an oncogenic mutation, such as of Tp53, to model the genotype and biology of serous ovarian cancer. Model based on the Wv mice may have the potential to gain biological and etiological insights into ovarian cancer development and prevention. PMID:24616881

  10. Comparison of Expression Profiles in Ovarian Epithelium In Vivo and Ovarian Cancer Identifies Novel Candidate Genes Involved in Disease Pathogenesis

    PubMed Central

    Emmanuel, Catherine; Gava, Natalie; Kennedy, Catherine; Balleine, Rosemary L.; Sharma, Raghwa; Wain, Gerard; Brand, Alison; Hogg, Russell; Etemadmoghadam, Dariush; George, Joshy; Birrer, Michael J.; Clarke, Christine L.; Chenevix-Trench, Georgia; Bowtell, David D. L.; Harnett, Paul R.; deFazio, Anna

    2011-01-01

    Molecular events leading to epithelial ovarian cancer are poorly understood but ovulatory hormones and a high number of life-time ovulations with concomitant proliferation, apoptosis, and inflammation, increases risk. We identified genes that are regulated during the estrous cycle in murine ovarian surface epithelium and analysed these profiles to identify genes dysregulated in human ovarian cancer, using publically available datasets. We identified 338 genes that are regulated in murine ovarian surface epithelium during the estrous cycle and dysregulated in ovarian cancer. Six of seven candidates selected for immunohistochemical validation were expressed in serous ovarian cancer, inclusion cysts, ovarian surface epithelium and in fallopian tube epithelium. Most were overexpressed in ovarian cancer compared with ovarian surface epithelium and/or inclusion cysts (EpCAM, EZH2, BIRC5) although BIRC5 and EZH2 were expressed as highly in fallopian tube epithelium as in ovarian cancer. We prioritised the 338 genes for those likely to be important for ovarian cancer development by in silico analyses of copy number aberration and mutation using publically available datasets and identified genes with established roles in ovarian cancer as well as novel genes for which we have evidence for involvement in ovarian cancer. Chromosome segregation emerged as an important process in which genes from our list of 338 were over-represented including two (BUB1, NCAPD2) for which there is evidence of amplification and mutation. NUAK2, upregulated in ovarian surface epithelium in proestrus and predicted to have a driver mutation in ovarian cancer, was examined in a larger cohort of serous ovarian cancer where patients with lower NUAK2 expression had shorter overall survival. In conclusion, defining genes that are activated in normal epithelium in the course of ovulation that are also dysregulated in cancer has identified a number of pathways and novel candidate genes that may contribute

  11. Ovarian cancer epidemiology in the era of collaborative team science.

    PubMed

    Cannioto, Rikki A; Trabert, Britton; Poole, Elizabeth M; Schildkraut, Joellen M

    2017-05-01

    Over the past decade, a number of consortia have formed to further investigate genetic associations, pathogenesis, and epidemiologic risk and prognostic factors for ovarian cancer. Here, we review the benefits that ovarian cancer consortia provide as well as challenges that have arisen. Methods for managing key challenges are also discussed. We review the structural organization and some of the milestone epidemiologic publications of five consortia dedicated to the study of ovarian cancer, including the Ovarian Cancer Association Consortium (OCAC), the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Ovarian Cancer Cohort Consortium (OC3), the Collaborative Group on Epidemiological Studies of Ovarian Cancer (The Oxford Collaborative Group), and the Ovarian Cancer in Women of African Ancestry (OCWAA) consortium. As ovarian cancer is a rare and heterogeneous disease, consortia have made important contributions in the study of risk factors by improving statistical power beyond what any single study, or even a few studies, would provide. Thus, a major accomplishment of consortial research is enhanced characterization of histotype-specific risk factor associations. In addition, consortia have facilitated impressive synergy between researchers across many institutions, spawning new collaborative research. Importantly, through these efforts, many challenges have been met, including difficulties with data harmonization and analysis, laying a road map for future collaborations. While ovarian cancer consortia have made valuable contributions to the ovarian cancer epidemiological literature over the past decade, additional efforts comprising of new, well-designed case-control studies are needed to further elucidate novel, histotype-specific risk, and prognostic factors which are not consistently available in existing studies.

  12. Ovarian vein thrombosis after debulking surgery for ovarian cancer: epidemiology and clinical significance.

    PubMed

    Mantha, Simon; Sarasohn, Debra; Ma, Weining; Devlin, Sean M; Chi, Dennis S; Roche, Kara Long; Suidan, Rudy S; Woo, Kaitlin; Soff, Gerald A

    2015-08-01

    Ovarian vein thrombosis is associated with pregnancy and pelvic surgery. Postpartum ovarian vein thrombosis is associated with infection and a high morbidity rate and is treated with anticoagulant and intravenous antibiotic therapy. The natural history of such thrombotic events after debulking surgery for ovarian cancer has not been well described. Our objective was to characterize the presentation and outcomes for patients with this condition at our institution. We conducted a retrospective study of patients who underwent surgical debulking for ovarian cancer at Memorial Sloan Kettering Cancer Center between the years 2001 and 2010. Patients were included if contrast computed tomography scans of both the abdomen and pelvis were performed within 12 weeks before and 12 weeks after the surgery. The images were reviewed to assess for the presence and extent of a new postoperative ovarian vein thrombosis. When available, subsequent studies were assessed for thrombus progression. Medical records were reviewed to determine whether anticoagulation was used for treatment of the thrombotic episode and to record the occurrence of any new significant venous thromboembolic event in the next year. One hundred fifty-nine patients had satisfactory imaging. New ovarian vein thrombosis was a common complication of debulking surgery, as found in 41 of patients (25.8%). Only 5 women with ovarian vein thrombosis were started on anticoagulation, of which 2 individuals had an independent venous thromboembolic event as indication for treatment. Only 2 of the ovarian vein thromboses (4.9%) progressed to the inferior vena cava or left renal vein on subsequent scan. The estimated cumulative incidence of venous thromboembolism 1 year after the first postoperative scan was 17.1% for patients in the new ovarian vein thrombosis group vs 15.3% of individuals for the group without a postoperative ovarian vein thrombosis (P = .78). Ovarian vein thrombosis is commonly encountered after debulking

  13. BRCA1 Regulates Follistatin Function in Ovarian Cancer and Human Ovarian Surface Epithelial Cells

    PubMed Central

    Sneed, Rosie; Salamanca, Clara; Li, Xin; Xu, Jingwen; Kumar, Deepak; Rosen, Eliot M.; Saha, Tapas

    2012-01-01

    Follistatin (FST), a folliculogenesis regulating protein, is found in relatively high concentrations in female ovarian tissues. FST acts as an antagonist to Activin, which is often elevated in human ovarian carcinoma, and thus may serve as a potential target for therapeutic intervention against ovarian cancer. The breast cancer susceptibility gene 1 (BRCA1) is a known tumor suppressor gene in human breast cancer; however its role in ovarian cancer is not well understood. We performed microarray analysis on human ovarian carcinoma cell line SKOV3 that stably overexpress wild-type BRCA1 and compared with the corresponding empty vector-transfected clones. We found that stable expression of BRCA1 not only stimulates FST secretion but also simultaneously inhibits Activin expression. To determine the physiological importance of this phenomenon, we further investigated the effect of cellular BRCA1 on the FST secretion in immortalized ovarian surface epithelial (IOSE) cells derived from either normal human ovaries or ovaries of an ovarian cancer patient carrying a mutation in BRCA1 gene. Knock-down of BRCA1 in normal IOSE cells demonstrates down-regulation of FST secretion along with the simultaneous up-regulation of Activin expression. Furthermore, knock-down of FST in IOSE cell lines as well as SKOV3 cell line showed significantly reduced cell proliferation and decreased cell migration when compared with the respective controls. Thus, these findings suggest a novel function for BRCA1 as a regulator of FST expression and function in human ovarian cells. PMID:22685544

  14. Stemness and chemoresistance in epithelial ovarian carcinoma cells under shear stress

    PubMed Central

    Ip, Carman K. M.; Li, Shan-Shan; Tang, Matthew Y. H.; Sy, Samuel K. H.; Ren, Yong; Shum, Ho Cheung; Wong, Alice S. T.

    2016-01-01

    One of greatest challenges to the successful treatment of cancer is drug resistance. An exciting approach is the eradication of cancer stem cells (CSCs). However, little is known about key signals regulating the formation and expansion of CSCs. Moreover, lack of a reliable predictive preclinical model has been a major obstacle to discover new cancer drugs and predict their clinical activity. Here, in ovarian cancer, a highly chemoresistant tumor that is rapidly fatal, we provide the first evidence demonstrating the causal involvement of mechanical stimulus in the CSC phenotype using a customizable microfluidic platform and three-dimensional spheroids, which most closely mimic tumor behavior. We found that ovarian cancer cells significantly acquired the expression of epithelial-to-mesenchymal transition and CSC markers and a remarkable chemoresistance to clinically relevant doses of frontline chemotherapeutic drugs cisplatin and paclitaxel when grown under fluid shear stress, which corroborates with the physiological attainable levels in the malignant ascites, but not under static condition. Furthermore, we uncovered a new link of microRNA-199a-3p, phosphatidylinositol 3-kinase/Akt, and multidrug transporter activation in shear stress-induced CSC enrichment. Our findings shed new light on the significance of hydrodynamics in cancer progression, emphasizing the need of a flow-informed framework in the development of therapeutics. PMID:27245437

  15. Psychosocial Stress and Ovarian Cancer Risk: Metabolomics and Perceived Stress

    DTIC Science & Technology

    2015-10-01

    respectively). Depression was significantly associated with increased ovarian cancer risk (hazard ratio: 1.26), as was being widowed (hazard ratio: 1.38...TERMS ovarian cancer, psychosocial stress, depression , anxiety, social support, metabolomics 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF...examine whether self-reported stress exposures ( depressive symptoms, phobic anxiety, social support, job strain, care-giving stress) are associated with

  16. Preclinical activity of melflufen (J1) in ovarian cancer

    PubMed Central

    Viktorsson, Kristina; Velander, Ebba; Nygren, Peter; Uustalu, Maria; Juntti, Therese; Lewensohn, Rolf; Larsson, Rolf; Spira, Jack; De Vlieghere, Elly; Ceelen, Wim P.; Gullbo, Joachim

    2016-01-01

    Ovarian cancer carries a significant mortality. Since symptoms tend to be minimal, the disease is often diagnosed when peritoneal metastases are already present. The standard of care in advanced ovarian cancer consists of platinum-based chemotherapy combined with cytoreductive surgery. Unfortunately, even after optimal cytoreduction and adjuvant chemotherapy, most patients with stage III disease will develop a recurrence. Intraperitoneal administration of chemotherapy is an alternative treatment for patients with localized disease. The pharmacological and physiochemical properties of melflufen, a peptidase potentiated alkylator, raised the hypothesis that this drug could be useful in ovarian cancer and particularily against peritoneal carcinomatosis. In this study the preclinical effects of melflufen were investigated in different ovarian cancer models. Melflufen was active against ovarian cancer cell lines, primary cultures of patient-derived ovarian cancer cells, and inhibited the growth of subcutaneous A2780 ovarian cancer xenografts alone and when combined with gemcitabine or liposomal doxorubicin when administered intravenously. In addition, an intra- and subperitoneal xenograft model showed activity of intraperitoneal administered melflufen for peritoneal carcinomatosis, with minimal side effects and modest systemic exposure. In conclusion, results from this study support further investigations of melflufen for the treatment of peritoneal carcinomatosis from ovarian cancer, both for intravenous and intraperitoneal administration. PMID:27528037

  17. Epithelial ovarian cancer: A case report

    PubMed Central

    GAO, JIANYUAN; FANG, HAIYING; WANG, XIAOMING; WU, LIPING; ZHANG, RONGHUAI; HAN, YAJUN

    2014-01-01

    An 82-year-old female was diagnosed with ovarian cancer in May 2004. Following gynecological surgery, pathological evaluation showed stage IIIC epithelial ovarian cancer. From June 2004 to January 2005, the patient received six cycles of conventional treatment combined with intravenous paclitaxel (Taxol®) and cisplatin. The patient developed abdominal distension and experienced a gradual deterioration in health during 2007, with admission to The First Affiliated Hospital in May 2007. The patient presented with severe abdominal distension and breathing difficulty on May 15 and appeared to be in critical condition. Ultrasound examination revealed massive ascites and left-side pleural effusion. Thoracentesis and abdominocentesis were performed, and 300 mg carboplatin was administered intraperitoneally on May 19, followed by a second abdominocentesis on May 21. However, these treatments did not alleviate the symptoms, and 200 mg bevacizumab was administered by intravenous infusion on May 27. The condition of the patient gradually improved and 400 mg bevacizumab was administered by intravenous infusion every two weeks from June 9. From December, the dosage of bevacizumab was reduced to 200 mg every two weeks. In addition, 300 mg carboplatin was administered intraperitoneally on November 4 and intraperitoneal carboplatin chemotherapy was repeated thereafter. The patient exhibited disease-free survival until July 2009, at which time disease progression was observed and the cancer recurred in August 2009. The patient died of multiple organ failure in September 2009. Bevacizumab rapidly eliminated the patient’s massive ascites and pleural effusion, and achieved an effect that was not possible with other treatments. Therefore, bevacizumab is an effective therapy for late-stage relapse and refractory ovarian cancer. PMID:25289055

  18. Dietary influences on survival after ovarian cancer.

    PubMed

    Nagle, Christina M; Purdie, David M; Webb, Penelope M; Green, Adèle; Harvey, Philip W; Bain, Christopher J

    2003-08-20

    We evaluated the effects of various food groups and micronutrients in the diet on survival among women who originally participated in a population-based case-control study of ovarian cancer conducted across 3 Australian states between 1990 and 1993. This analysis included 609 women with invasive epithelial ovarian cancer, primarily because there was negligible mortality in women with borderline tumors. The women's usual diet was assessed using a validated food frequency questionnaire. Deaths in the cohort were identified using state-based cancer registries and the Australian National Death Index (NDI). Crude 5-year survival probabilities were estimated using the Kaplan-Meier technique, and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained from Cox regression models. After adjusting for important confounding factors, a survival advantage was observed for those who reported higher intake of vegetables in general (HR = 0.75, 95% CI = 0.57-0.99, p-value trend 0.01 for the highest third, compared to the lowest third), and cruciferous vegetables in particular (HR = 0.75, 95% CI = 0.57-0.98, p-value trend 0.03), and among women in the upper third of intake of vitamin E (HR = 0.76, 95% CI = 0.58-1.01, p-value trend 0.04). Inverse associations were also seen with protein (p-value trend 0.09), red meat (p-value trend 0.06) and white meat (p-value trend 0.07), and modest positive trends (maximum 30% excess) with lactose (p-value trend 0.04), calcium and dairy products. Although much remains to be learned about the influence of nutritional factors after a diagnosis of ovarian cancer, our study suggests the possibility that a diet high in vegetable intake may help improve survival.

  19. Risk of Ovarian Cancer Relapse Score

    PubMed Central

    Rizzuto, Ivana; Stavraka, Chara; Chatterjee, Jayanta; Borley, Jane; Hopkins, Thomas Glass; Gabra, Hani; Ghaem-Maghami, Sadaf; Huson, Les; Blagden, Sarah P.

    2015-01-01

    Objective The aim of this study was to construct a prognostic index that predicts risk of relapse in women who have completed first-line treatment for ovarian cancer (OC). Methods A database of OC cases from 2000 to 2010 was interrogated for International Federation of Gynecology and Obstetrics stage, grade and histological subtype of cancer, preoperative and posttreatment CA-125 level, presence or absence of residual disease after cytoreductive surgery and on postchemotherapy computed tomography scan, and time to progression and death. The strongest predictors of relapse were included into an algorithm, the Risk of Ovarian Cancer Relapse (ROVAR) score. Results Three hundred fifty-four cases of OC were analyzed to generate the ROVAR score. Factors selected were preoperative serum CA-125, International Federation of Gynecology and Obstetrics stage and grade of cancer, and presence of residual disease at posttreatment computed tomography scan. In the validation data set, the ROVAR score had a sensitivity and specificity of 94% and 61%, respectively. The concordance index for the validation data set was 0.91 (95% confidence interval, 0.85-0.96). The score allows patient stratification into low (<0.33), intermediate (0.34–0.67), and high (>0.67) probability of relapse. Conclusions The ROVAR score stratifies patients according to their risk of relapse following first-line treatment for OC. This can broadly facilitate the appropriate tailoring of posttreatment care and support. PMID:25647256

  20. Paclitaxel targets VEGF-mediated angiogenesis in ovarian cancer treatment

    PubMed Central

    Ai, Bin; Bie, Zhixin; Zhang, Shuai; Li, Ailing

    2016-01-01

    Ovarian cancer is one of the gynecologic cancers with the highest mortality, wherein vascular endothelial growth factor (VEGF) is involved in regulating tumor vascularization, growth, migration, and invasion. VEGF-mediated angiogenesis in tumors has been targeted in various cancer treatments, and anti-VEGF therapy has been used clinically for treatment of several types of cancer. Paclitaxel is a natural antitumor agent in the standard front-line treatment that has significant efficiency to treat advanced cancers, including ovarian cancer. Although platinum/paclitaxel-based chemotherapy has good response rates, most patients eventually relapse because the disease develops drug resistance. We aim to review the recent advances in paclitaxel treatment of ovarian cancer via antiangiogenesis. Single-agent therapy may be used in selected cases of ovarian cancer. However, to prevent drug resistance, drug combinations should be identified for optimal effectiveness and existing therapies should be improved. PMID:27648354

  1. Combining Drugs to Treat Ovarian Cancer - Annual Plan

    Cancer.gov

    Approximately 70 percent of women diagnosed with ovarian cancer will die from the disease. Read about the NCI-funded combination drug trial that has successfully treated Betsy Brauser's recurrent cancer.

  2. DNA methylation changes in epithelial ovarian cancer histotypes

    PubMed Central

    Earp, Madalene A.; Cunningham, Julie M.

    2016-01-01

    Survival after a diagnosis of ovarian cancer has not improved, and despite histological differences, treatment is similar for all cases. Understanding the molecular basis for ovarian cancer risk and prognosis is fundamental, and to this end much has been gleaned about genetic changes contributing to risk, and to a lesser extent, survival. There’s considerable evidence for genetic differences between the four pathologically defined histological subtypes; however, the contribution of epigenetics is less well documented. In this report, we review alterations in DNA methylation in ovarian cancer, focusing on histological subtypes, and studies examining the roles of methylation in determining therapy response. As epigenetics is making its way into clinical care, we review the application of cell free DNA methylation to ovarian cancer diagnosis and care. Finally, we comment on recurrent limitations in the DNA methylation literature for ovarian cancer, which can and should be addressed to mature this field. PMID:26363302

  3. Cytokeratin 5 positive cells represent a therapy resistant subpopulation in epithelial ovarian cancer

    PubMed Central

    Corr, Bradley R.; Finlay-Schultz, Jessica; Rosen, Rachel B.; Qamar, Lubna; Post, Miriam D.; Behbakht, Kian; Spillman, Monique A.; Sartorius, Carol A.

    2015-01-01

    Objective Cytokeratin 5 (CK5) is an epithelial cell marker implicated in stem and progenitor cell activity in glandular reproductive tissues and endocrine and chemotherapy resistance in estrogen receptor (ER)+ breast cancer. The goal of this study was to determine the prevalence of CK5 expression in ovarian cancer and the response of CK5+ cell populations to cisplatin therapy. Materials and Methods CK5 expression was evaluated in two ovarian tissue microarrays, representing 137 neoplasms, and six ovarian cancer cell lines. Cell lines were treated with IC50 cisplatin and the prevalence of CK5+ cells pre- and post-treatment determined. Proliferation of CK5+ vs. CK5− cell populations was determined using bromodeoxyuridine (BrdU) incorporation. Chemotherapy induced apoptosis in CK5+ vs. CK5− cells was measured using immunohistochemical staining for cleaved caspase-3. Results CK5 was expressed in 39.3% (42/107) of epithelial ovarian cancers with a range of 1-80% positive cells. Serous and endometrioid histologic subtypes had the highest percentage of CK5+ specimens. CK5 expression correlated with ER positivity (38/42 CK5+ tumors were also ER+). CK5 was expressed in 5/6 overall and 4/4 ER+ epithelial ovarian cancer cell lines ranging from 2.4-52.7% positive cells. CK5+ compared to CK5− cells were slower proliferating. The prevalence of CK5+ cells increased following 48 hour cisplatin treatment in 4/5 cell lines tested. CK5+ compared to CK5− ovarian cancer cells were more resistant to cisplatin induced apoptosis. Conclusions CK5 is expressed in a significant proportion of epithelial ovarian cancers and represents a slower proliferating, chemoresistant subpopulation that may warrant co-targeting in combination therapy. PMID:26495758

  4. Tumor vascular proteins as biomarkers in ovarian cancer.

    PubMed

    Buckanovich, Ronald J; Sasaroli, Dimitra; O'Brien-Jenkins, Anne; Botbyl, Jeffrey; Hammond, Rachel; Katsaros, Dionysios; Sandaltzopoulos, Raphael; Liotta, Lance A; Gimotty, Phyllis A; Coukos, George

    2007-03-01

    This study aimed to identify novel ovarian cancer biomarkers and potential therapeutic targets through molecular analysis of tumor vascular cells. Immunohistochemistry-guided laser-capture microdissection and genome-wide transcriptional profiling were used to identify genes that were differentially expressed between vascular cells from human epithelial ovarian cancer and healthy ovaries. Tumor vascular markers (TVMs) were validated through quantitative real-time polymerase chain reaction (qRT-PCR) of immunopurified tumor endothelial cells, in situ hybridization, immunohistochemistry, and Western blot analysis. TVM expression in tumors and noncancerous tissues was assessed by qRT-PCR and was profiled using gene expression data. We identified a tumor vascular cell profile of ovarian cancer that was distinct from the vascular profile of normal ovary and other tumors. We validated 12 novel ovarian TVMs. These were expressed by immunopurified tumor endothelial cells and localized to tumor vasculature. Select TVMs were found to be specifically expressed in ovarian cancer and were absent in all normal tissues tested, including female reproductive tissues with physiologic angiogenesis. Many ovarian TVMs were expressed by a variety of other solid tumors. Finally, overexpression of any one of three ovarian TVMs by vascular cells was associated with decreased disease-free interval (all P < .005). We have identified for the first time the molecular profile of ovarian tumor vasculature. We demonstrate that TVMs may serve as potential biomarkers and molecular targets for ovarian cancer and a variety of other solid tumors.

  5. Trends in United States ovarian cancer mortality, 1979-1995.

    PubMed

    Oriel, K A; Hartenbach, E M; Remington, P L

    1999-01-01

    To describe the epidemiology of ovarian cancer mortality in the United States from 1979 to 1995. The mortality data of the Centers for Disease Control and Prevention were accessed using the Wide-ranging Online Data for Epidemiologic Research (WONDER). We selected all deaths among women with International Classification of Diseases, Ninth Revision (ICD-9) code 183.0 (ovarian malignant neoplasm). Mortality data for the years 1979-1995 were age-adjusted to the United States 1990 female population, and mortality rates for each year were calculated for females of all ages by age category, by race, and by geographic location. Trends were obtained for the periods 1979-1983 to 1991-1995, and the impact on the number of ovarian cancer deaths was calculated. Age-adjusted ovarian cancer mortality rates have changed little in the United States from 1979 to 1995, but rates are increasing in older women (65 years and older) and decreasing in younger women. Age-adjusted mortality rates are higher among whites than in blacks. Ovarian cancer mortality rates are higher in northern compared with southern states. The trends in ovarian cancer mortality among younger and older women parallel published changes in incidence and may be due to changes in risk factors, such as the use of oral contraceptives. The reasons for the higher ovarian cancer death rates in northern states are unknown. Better understanding of how modifiable risk factors and treatment methods affect ovarian cancer mortality trends is needed.

  6. Randomized Phase II trial of two high-dose chemotherapy regimens with stem cell transplantation for the treatment of advanced ovarian cancer in first remission or chemosensitive relapse: a Southwest Oncology Group study.

    PubMed

    Stiff, Patrick J; Shpall, Elizabeth J; Liu, P Y; Wilczynski, Sharon P; Callander, Natalie S; Scudder, Sidney A; Jazieh, Abdul-Rahman; Samlowski, Wolfram; McCoy, Jason; Alberts, David S

    2004-07-01

    To evaluate response rates, progression-free survival (PFS), overall survival (OS), and toxicity of two high-dose chemotherapy regimens with stem cell rescue used to treat patients with recurrent or persistent stage III/IV ovarian cancer, with the goal of taking one forward into a Phase III comparison with conventional therapy. Patients under 65 with clinically or pathologically persistent disease after initial chemotherapy or those relapsing >6 months after a complete remission (CR) were randomized to CMC carboplatin (1500 mg/m(2)), mitoxantrone (75 mg/m(2)), and cyclophosphamide (120 mg/kg)], or CTC: [cisplatin (165 mg/m(2)), thiotepa (600 mg/m(2)), and cyclophosphamide (5625 mg/m(2))] with stem cell rescue. Of 67 randomized, the 32 and 26 eligible in the CMC and CTC arms were matched including age (median 49), maximum tumor diameter, and disease status at transplant. Low-risk disease (maximum diameter disease

  7. Akt isoform specific effects in ovarian cancer progression

    PubMed Central

    Linnerth-Petrik, Nicolle M.; Santry, Lisa A.; Moorehead, Roger; Jücker, Manfred

    2016-01-01

    Ovarian cancer remains a significant therapeutic problem and novel, effective therapies are needed. Akt is a serine-threonine kinase that is overexpressed in numerous cancers, including ovarian. Mammalian cells express three Akt isoforms which are encoded by distinct genes. Although there are several Akt inhibitors in clinical trials, most indiscriminately target all isoforms. Current in vitro data and animal knockout experiments suggest that the Akt isoforms may have divergent roles. In this paper, we determined the isoform-specific functions of Akt in ovarian cancer cell proliferation in vitro and in ovarian cancer progression in vivo. For in vitro experiments, murine and human ovarian cancer cells were treated with Akt inhibitors and cell viability was assessed. We used two different in vivo approaches to identify the roles of Akt isoforms in ovarian cancer progression and their influence on the primary tumor and tumor microenvironment. In one experiment, wild-type C57Bl6 mice were orthotopically injected with ID8 cells with stable knockdown of Akt isoforms. In a separate experiment, mice null for Akt 1-3 were orthotopically injected with WT ID8 cells (Figure 1). Our data show that inhibition of Akt1 significantly reduced ovarian cancer cell proliferation and inhibited tumor progression in vivo. Conversely, disruption of Akt2 increased tumor growth. Inhibition of Akt3 had an intermediate phenotype, but also increased growth of ovarian cancer cells. These data suggest that there is minimal redundancy between the Akt isoforms in ovarian cancer progression. These findings have important implications in the design of Akt inhibitors for the effective treatment of ovarian cancer. PMID:27533079

  8. Surgery for advanced epithelial ovarian cancer.

    PubMed

    Hacker, Neville F; Rao, Archana

    2017-05-01

    Cytoreductive surgery for patients with advanced epithelial ovarian cancer has been practised since the pioneering work of Tom Griffiths in 1975. Further research has demonstrated the prognostic significance of the extent of metastatic disease pre-operatively, and of complete cytoreduction post-operatively. Patients with advanced epithelial ovarian cancer should be referred to high volume cancer units, and managed by multidisciplinary teams. The role of thoracoscopy and resection of intrathoracic disease is presently investigational. In recent years, there has been increasing use of neoadjuvant chemotherapy and interval cytoreductive surgery in patients with poor performance status, which is usually due to large volume ascites and/or large pleural effusions. Neoadjuvant chemotherapy reduces the post-operative morbidity, but if the tumour responds well to the chemotherapy, the inflammatory response makes the surgery more difficult. Post-operative morbidity is generally tolerable, but increases in older patients, and in those having multiple, aggressive surgical procedures, such as bowel resection or diaphragmatic stripping. Primary cytoreductive surgery should be regarded as the gold standard for most patients until a test is developed which would allow the prediction of platinum resistance pre-operatively. Copyright © 2016. Published by Elsevier Ltd.

  9. Pharmacoeconomics of amifostine in ovarian cancer.

    PubMed

    Calhoun, E A; Bennett, C L

    1999-04-01

    Physicians are frequently pressured to make therapeutic decisions within a cost-effective framework to demonstrate value to managed care. Because cancer is a chronic disease, health care costs are known to be expensive and physicians must use their resources as efficiently as possible. Historically, economic analyses in oncology have emphasized survival as their clinical end point. Today, both government groups and professional organizations are moving toward making quality of life the clinical end point in determining the economics of chemotherapy. This report evaluates the cost and efficacy of amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) use in the treatment of advanced ovarian cancer using two pharmacoeconomic analyses. A cost-utility analysis performed in the United States indicated that inclusion of amifostine therapy had both a favorable clinical and cost-utility profile compared with other medical therapies. A second cost-benefit analysis, conducted in Canada, suggested that use of amifostine in patients with advanced ovarian cancer would be cost saving. Amifostine is a novel agent that protects against both chemotherapy- and radiotherapy-induced toxicities, such as nephrotoxicity, neutropenia, thrombocytopenia, peripheral neuropathy, mucositis, and xerostomia. These toxicities are disturbing to both patients and physicians alike. The results of these studies support the use of amifostine as a valuable resource both economically and clinically.

  10. Highly expressed NRSN2 is related to malignant phenotype in ovarian cancer.

    PubMed

    Tang, Wenbin; Ren, Aimin; Xiao, Hongyang; Sun, Huizhen; Li, Bin

    2017-01-01

    Neurensin-2 (NRSN2) is a 24KD protein, which is reported located in the membrane, while its biological functions remain unknown, not to mention in the field of tumor biology. In current study, we aimed to analyze the functions of NRSN2 in ovarian cancer. We screened TCGA database and surprisingly found that its copy number and mRNA level are gained and heightened respectively in parts of serous ovarian cancer patients. In current study, both loss- and gain- function assays found that NRSN2 is associated with the malignant phenotype in ovarian cancer cells, because NRSN2 plays a remarkable role in anchorage-independent colony formation, subcutaneous tumor formation, cell invasion, and chemoresistance. Furthermore, we found that the level of NRSN2 was positively correlated with the expression of stem cell marker CD133. In addition, Wnt canonical signaling and Twist/Akt/Erk axis were also regulated by NRSN2. In conclusion, we found that a poorly studied protein, NRSN2, which is associated with the malignant phenotype of serous ovarian cancer and as a membrane protein; it could be a target for serous ovarian cancer treatment.

  11. Chromosome abnormalities in primary ovarian cancer

    SciTech Connect

    Yonescu, R.; Currie, J.; Griffin, C.A.

    1994-09-01

    Chromosome abnormalities that are specific and recurrent may occur in regions of the genome that are involved in the conversion of normal cells to those with tumorigenic potential. Ovarian cancer is the primary cause of death among patients with gynecological malignancies. We have performed cytogenetic analysis of 16 ovarian tumors from women age 28-82. Three tumors of low malignant potential and three granulosa cell tumors had normal karyotypes. To look for the presence of trisomy 12, which has been suggested to be a common aberration in this group of tumors, interphase fluorescence in situ hybridization was performed on direct preparations from three of these tumors using a probe for alpha satellite sequences of chromosome 12. In the 3 preparations, 92-98 percent of the cells contained two copies of chromosome 12, indicating that trisomy 12 is not a universal finding in low grade ovarian tumors. Endometrioid carcinoma of the ovary is histologically indistinguishable from endometial carcinoma of the uterus. We studied 10 endometrioid tumors to determine the degree of genetic similarity between these two carcinomas. Six out of ten endometrioid tumors showed a near-triploid modal number, and one presented with a tetraploid modal number. Eight of the ten contained structural chromosome abnormalities, of which the most frequent were 1p- (5 tumors), 19q+ (3 tumors), 6q- or ins(6) (4 tumors), 3q- or 3q+ (4 tumors). These cytogenetic results resemble those reported for papillary ovarian tumors and differ from those of endometrial carcinoma of the uterus. We conclude that despite the histologic similarities between the endometrioid and endometrial carcinomas, the genetic abnormalities in the genesis of these tumors differ significantly.

  12. Inhibitory Effect of Baicalin and Baicalein on Ovarian Cancer Cells

    PubMed Central

    Chen, Jianchu; Li, Zhaoliang; Chen, Allen Y.; Ye, Xingqian; Luo, Haitao; Rankin, Gary O.; Chen, Yi Charlie

    2013-01-01

    Ovarian cancer is one of the primary causes of death for women all through the Western world. Baicalin and baicalein are naturally occurring flavonoids that are found in the roots and leaves of some Chinese medicinal plants and are thought to have antioxidant activity and possible anti-angiogenic, anti-cancer, anxiolytic, anti-inflammatory and neuroprotective activities. Two kinds of ovarian cancer (OVCAR-3 and CP-70) cell lines and a normal ovarian cell line (IOSE-364) were selected to be investigated in the inhibitory effect of baicalin and baicalein on cancer cells. Largely, baicalin and baicalein inhibited ovarian cancer cell viability in both ovarian cancer cell lines with LD50 values in the range of 45–55 μM for baicalin and 25–40 μM for baicalein. On the other hand, both compounds had fewer inhibitory effects on normal ovarian cells viability with LD50 values of 177 μM for baicalin and 68 μM for baicalein. Baicalin decreased expression of VEGF (20 μM), cMyc (80 μM), and NFkB (20 μM); baicalein decreased expression of VEGF (10 μM), HIF-1α (20 μM), cMyc (20 μM), and NFkB (40 μM). Therefore baicalein is more effective in inhibiting cancer cell viability and expression of VEGF, HIF-1α, cMyc, and NFκB in both ovarian cancer cell lines. It seems that baicalein inhibited cancer cell viability through the inhibition of cancer promoting genes expression including VEGF, HIF-1α, cMyc, and NFκB. Overall, this study showed that baicalein and baicalin significantly inhibited the viability of ovarian cancer cells, while generally exerting less of an effect on normal cells. They have potential for chemoprevention and treatment of ovarian cancers. PMID:23502466

  13. Ovarian Stem Cells-the Pros and Cons.

    PubMed

    Evron, Ayelet; Blumenfeld, Zeev

    2013-03-20

    The potential for postnatal de novo oogenesis in mammals and in humans has become very controversial in the fields of reproductive science and biology. Historically, it has been thought that females of most mammalian species lose the ability to produce oocytes at birth. A contemporary understanding of stem cell biology together with novel experimental methods has challenged the model of a prenatal fixed ovarian primordial follicle pool that declines with age. Researchers have suggested replenishment of post-natal oocytes by germ-line stem cells (GSCs). According to this theory, GSCs produce oocytes and primordial follicles throughout the lifetime of the adult female. This review describes recent approaches supporting the revolutionary idea of de novo oogenesis in mammals and humans of reproductive-age and provides counter arguments from opponents of this novel and innovative concept.

  14. Trastuzumab Sensitizes Ovarian Cancer Cells to EGFR-targeted Therapeutics.

    PubMed

    Wilken, Jason A; Webster, Kristy T; Maihle, Nita J

    2010-03-27

    Early studies have demonstrated comparable levels of HER2/ErbB2 expression in both breast and ovarian cancer. Trastuzumab (Herceptin), a therapeutic monoclonal antibody directed against HER2, is FDA-approved for the treatment of both early and late stage breast cancer. However, clinical studies of trastuzumab in epithelial ovarian cancer (EOC) patients have not met the same level of success. Surprisingly, however, no reports have examined either the basis for primary trastuzumab resistance in ovarian cancer or potential ways of salvaging trastuzumab as a potential ovarian cancer therapeutic. An in vitro model of primary trastuzumab-resistant ovarian cancer was created by long-term culture of HER2-positive ovarian carcinoma-derived cell lines with trastuzumab. Trastuzumab treated vs. untreated parental cells were compared for HER receptor expression, trastuzumab sensitivity, and sensitivity to other HER-targeted therapeutics. In contrast to widely held assumptions, here we show that ovarian cancer cells that are not growth inhibited by trastuzumab are still responsive to trastuzumab. Specifically, we show that responsiveness to alternative HER-targeted inhibitors, such as gefitinib and cetuximab, is dramatically potentiated by long-term trastuzumab treatment of ovarian cancer cells. HER2-positive ovarian carcinoma-derived cells are, therefore, not "unresponsive" to trastuzumab as previously assumed, even when they not growth inhibited by this drug. Given the recent success of EGFR-targeted therapeutics for the treatment of other solid tumors, and the well-established safety profile of trastuzumab, results presented here provide a rationale for re-evaluation of trastuzumab as an experimental ovarian cancer therapeutic, either in concert with, or perhaps as a "primer" for EGFR-targeted therapeutics.

  15. MEIS and PBX homeobox proteins in ovarian cancer.

    PubMed

    Crijns, A P G; de Graeff, P; Geerts, D; Ten Hoor, K A; Hollema, H; van der Sluis, T; Hofstra, R M W; de Bock, G H; de Jong, S; van der Zee, A G J; de Vries, E G E

    2007-11-01

    Three amino-acid loop extension (TALE) homeobox proteins MEIS and PBX are cofactors for HOX-class homeobox proteins, which control growth and differentiation during embryogenesis and homeostasis. We showed that MEIS and PBX expression are related to cisplatin resistance in ovarian cancer cell lines. Therefore, MEIS1, MEIS2 and PBX expression were investigated immunohistochemically in a tissue microarray (N=232) of ovarian cancers and ovarian surface epithelium (N=15). Results were related to clinicopathologic characteristics and survival. All cancers expressed MEIS1, MEIS2 and PBX in nucleus and cytoplasm. MEIS1 and 2 only stained nuclear in surface epithelium. Nuclear MEIS2 was negatively related to stage, grade and overall survival in univariate analyses. Additionally, MEIS and PBX RNA expression in ovarian surface epithelium and other normal tissues and ovarian cancer versus other tumour types using public array data sets were studied. In ovarian cancer, MEIS1 is highly expressed compared to other cancer types. In conclusion, MEIS and PBX are extensively expressed in ovarian carcinomas and may play a role in ovarian carcinogenesis.

  16. Cancer Vaccines in Ovarian Cancer: How Can We Improve?

    PubMed Central

    Martin Lluesma, Silvia; Wolfer, Anita; Harari, Alexandre; Kandalaft, Lana E.

    2016-01-01

    Epithelial ovarian cancer (EOC) is one important cause of gynecologic cancer-related death. Currently, the mainstay of ovarian cancer treatment consists of cytoreductive surgery and platinum-based chemotherapy (introduced 30 years ago) but, as the disease is usually diagnosed at an advanced stage, its prognosis remains very poor. Clearly, there is a critical need for new treatment options, and immunotherapy is one attractive alternative. Prophylactic vaccines for prevention of infectious diseases have led to major achievements, yet therapeutic cancer vaccines have shown consistently low efficacy in the past. However, as they are associated with minimal side effects or invasive procedures, efforts directed to improve their efficacy are being deployed, with Dendritic Cell (DC) vaccination strategies standing as one of the more promising options. On the other hand, recent advances in our understanding of immunological mechanisms have led to the development of successful strategies for the treatment of different cancers, such as immune checkpoint blockade strategies. Combining these strategies with DC vaccination approaches and introducing novel combinatorial designs must also be considered and evaluated. In this review, we will analyze past vaccination methods used in ovarian cancer, and we will provide different suggestions aiming to improve their efficacy in future trials. PMID:28536377

  17. Update in Cancer Chemotherapy: Genitourinary Tract Cancer, Part 5: Ovarian Cancer

    PubMed Central

    Wright, Jane C.

    1988-01-01

    An update of the state of the art of cancer chemotherapeutic treatment of genitourinary tract cancer is described in this multi-part series: included are cancers of the kidney, bladder, prostate, testicle, ovary, uterus, vulva, and gestational trophoblastic neoplasms. Part 5 is a review of treatments for cancer of the ovary. Ovarian cancer is the leading cause of gynecologic cancer deaths and the fourth most frequent cause of death from cancer in women in the United States. Ovarian carcinoma is a classical “hidden” neoplasm of the abdomen and, as such, is insidious in its onset. Combination chemotherapy and cytoreductive surgery, however, have provided improved survival for patients with ovarian cancer. As dosage schedules and other refinements are made, the overall outlook for patients with ovarian cancer is promising. PMID:3047411

  18. Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium

    PubMed Central

    Pearce, C L; Near, A M; Van Den Berg, D J; Ramus, S J; Gentry-Maharaj, A; Menon, U; Gayther, S A; Anderson, A R; Edlund, C K; Wu, A H; Chen, X; Beesley, J; Webb, P M; Holt, S K; Chen, C; Doherty, J A; Rossing, M A; Whittemore, A S; McGuire, V; DiCioccio, R A; Goodman, M T; Lurie, G; Carney, M E; Wilkens, L R; Ness, R B; Moysich, K B; Edwards, R; Jennison, E; Kjaer, S K; Hogdall, E; Hogdall, C K; Goode, E L; Sellers, T A; Vierkant, R A; Cunningham, J C; Schildkraut, J M; Berchuck, A; Moorman, P G; Iversen, E S; Cramer, D W; Terry, K L; Vitonis, A F; Titus-Ernstoff, L; Song, H; Pharoah, P D P; Spurdle, A B; Anton-Culver, H; Ziogas, A; Brewster, W; Galitovskiy, V; Chenevix-Trench, G

    2009-01-01

    The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P⩽0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: ORhomozygous(hom)=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20–6.56, P=0.017, phet across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted. PMID:19127255

  19. Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

    PubMed

    Pearce, C L; Near, A M; Van Den Berg, D J; Ramus, S J; Gentry-Maharaj, A; Menon, U; Gayther, S A; Anderson, A R; Edlund, C K; Wu, A H; Chen, X; Beesley, J; Webb, P M; Holt, S K; Chen, C; Doherty, J A; Rossing, M A; Whittemore, A S; McGuire, V; DiCioccio, R A; Goodman, M T; Lurie, G; Carney, M E; Wilkens, L R; Ness, R B; Moysich, K B; Edwards, R; Jennison, E; Kjaer, S K; Hogdall, E; Hogdall, C K; Goode, E L; Sellers, T A; Vierkant, R A; Cunningham, J M; Cunningham, J C; Schildkraut, J M; Berchuck, A; Moorman, P G; Iversen, E S; Cramer, D W; Terry, K L; Vitonis, A F; Titus-Ernstoff, L; Song, H; Pharoah, P D P; Spurdle, A B; Anton-Culver, H; Ziogas, A; Brewster, W; Galitovskiy, V; Chenevix-Trench, G

    2009-01-27

    The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

  20. The detection, treatment, and biology of epithelial ovarian cancer

    PubMed Central

    2010-01-01

    Ovarian cancer is particularly insidious in nature. Its ability to go undetected until late stages coupled with its non-descript signs and symptoms make it the seventh leading cause of cancer related deaths in women. Additionally, the lack of sensitive diagnostic tools and resistance to widely accepted chemotherapy regimens make ovarian cancer devastating to patients and families and frustrating to medical practitioners and researchers. Here, we provide an in-depth review of the theories describing the origin of ovarian cancer, molecular factors that influence its growth and development, and standard methods for detection and treatment. Special emphasis is focused on interactions between ovarian tumors and the innate and adaptive immune system and attempts that are currently underway to devise novel immunotherapeutic approaches for the treatment of ovarian tumors. PMID:20350313

  1. Douching, Talc Use, and Risk of Ovarian Cancer

    PubMed Central

    Gonzalez, NL; O’Brien, KM; D’Aloisio, AA; Sandler, DP; Weinberg, CR

    2016-01-01

    Background Douching was recently reported to be associated with elevated levels of urinary metabolites of endocrine disrupting phthalates, but there is no literature on douching in relation to ovarian cancer. Numerous case-control studies of genital talc use have reported an increased risk of ovarian cancer, but prospective cohort studies have not uniformly confirmed this association. Behavioral correlation between talc use and douching could produce confounding. Methods The Sister Study (2003–2009) enrolled and followed 50,884 women in the US and Puerto Rico who had a sister diagnosed with breast cancer. At baseline participants were asked about douching and talc use during the previous 12 months. During follow-up (median of 6.6 years) 154 participants reported a diagnosis of ovarian cancer. We computed adjusted hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer risk using the Cox proportional hazards model. Results There was little association between baseline perineal talc use and subsequent ovarian cancer (HR: 0.73 CI: 0.44, 1.2). Douching was more common among talc users (OR: 2.1 CI: 2.0, 2.3), and douching at baseline was associated with increased subsequent risk of ovarian cancer (HR: 1.9 CI: 1.2, 2.8). Conclusions Douching but not talc use was associated with increased risk of ovarian cancer in the Sister Study. PMID:27327020

  2. Carboplatin and Paclitaxel With or Without Bevacizumab Compared to Docetaxel, Carboplatin, and Paclitaxel in Treating Patients With Stage II, Stage III, or Stage IV Ovarian Epithelial, Fallopian Tube, or Primary Peritoneal Cavity Carcinoma (Cancer)

    ClinicalTrials.gov

    2013-03-18

    Brenner Tumor; Fallopian Tube Cancer; Ovarian Carcinosarcoma; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Primary Peritoneal Cavity Cancer; Stage II Ovarian Epithelial Cancer; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

  3. Cancer risk awareness and concern among women with a family history of breast or ovarian cancer

    PubMed Central

    Andersen, M. Robyn; Thorpe, Jason; Buist, Diana SM; Beatty, J. David; Watabayashi, Kate; Hanson, Nancy; Resta, Robert; Chubak, Jessica; Urban, Nicole

    2015-01-01

    Women with a documented deleterious mutation in BRCA1 or BRCA2 are at substantially elevated risk for ovarian cancer. To understand what percentage of women with high risk family histories know their risk is elevated we surveyed 1,885 women with a high or moderate risk family history and no personal history of breast or ovarian cancer, and asked about their perceived risk of breast and ovarian cancer. Among high-risk women, fewer than 20% reported use of genetic counseling, and knowledge of elevated risk of ovarian cancer was low. Prior genetic counseling was associated with greater perceived risk for ovarian cancer. Results suggest that most high-risk women (> 75%) do not know their risk for ovarian cancer. Identification of potentially high-risk women for referral to genetic counseling may improve informed ovarian cancer risk management. PMID:25062114

  4. Cancer Risk Awareness and Concern among Women with a Family History of Breast or Ovarian Cancer.

    PubMed

    Andersen, M Robyn; Thorpe, Jason; Buist, Diana S M; Beatty, J David; Watabayashi, Kate; Hanson, Nancy; Resta, Robert; Chubak, Jessica; Urban, Nicole

    2016-01-01

    Women with a documented deleterious mutation in BRCA1 or BRCA2 are at substantially elevated risk for ovarian cancer. To understand what percentage of women with high-risk family histories know their risk is elevated we surveyed 1,885 women with a high- or moderate-risk family history and no personal history of breast or ovarian cancer, and asked about their perceived risk of breast and ovarian cancer. Among high-risk women, fewer than 20% reported use of genetic counseling, and knowledge of elevated risk of ovarian cancer was low. Prior genetic counseling was associated with greater perceived risk for ovarian cancer. Results suggest that most high-risk women (>75%) do not know their risk for ovarian cancer. Identification of potentially high-risk women for referral to genetic counseling may improve informed ovarian cancer risk management.

  5. Ovarian Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  6. Intraoperative radiation therapy in recurrent ovarian cancer

    SciTech Connect

    Yap, O.W. Stephanie . E-mail: stbeast@stanford.edu; Kapp, Daniel S.; Teng, Nelson N.H.; Husain, Amreen

    2005-11-15

    Purpose: To evaluate disease outcomes and complications in patients with recurrent ovarian cancer treated with cytoreductive surgery and intraoperative radiation therapy (IORT). Methods and Materials: A retrospective study of 24 consecutive patients with ovarian carcinoma who underwent secondary cytoreduction and intraoperative radiation therapy at our institution between 1994 and 2002 was conducted. After optimal cytoreductive surgery, IORT was delivered with orthovoltage X-rays (200 kVp) using individually sized and beveled cone applications. Outcomes measures were local control of disease, progression-free interval, overall survival, and treatment-related complications. Results: Of these 24 patients, 22 were available for follow-up analysis. Additional treatment at the time of and after IORT included whole abdominopelvic radiation, 9; pelvic or locoregional radiation, 5; chemotherapy, 6; and no adjuvant treatment, 2. IORT doses ranged from 9-14 Gy (median, 12 Gy). The anatomic sites treated were pelvis (sidewalls, vaginal cuff, presacral area, anterior pubis), para-aortic and paracaval lymph node beds, inguinal region, or porta hepatitis. At a median follow-up of 24 months, 5 patients remain free of disease, whereas 17 patients have recurred, of whom 4 are alive with disease and 13 died from disease. Five patients recurred within the radiation fields for a locoregional relapse rate of 32% and 12 patients recurred at distant sites with a median time to recurrence of 13.7 months. Five-year overall survival was 22% with a median survival of 26 months from time of IORT. Nine patients (41%) experienced Grade 3 toxicities from their treatments. Conclusion: In carefully selected patients with locally recurrent ovarian cancer, combined IORT and tumor reductive surgery is reasonably tolerated and may contribute to achieving local control and disease palliation.

  7. Carboplatin and Paclitaxel or Oxaliplatin and Capecitabine With or Without Bevacizumab as First-Line Therapy in Treating Patients With Newly Diagnosed Stage II-IV or Recurrent Stage I Epithelial Ovarian or Fallopian Tube Cancer

    ClinicalTrials.gov

    2017-04-05

    Borderline Ovarian Mucinous Tumor; Ovarian Mucinous Cystadenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Stage IA Fallopian Tube Cancer; Stage IA Ovarian Cancer; Stage IB Fallopian Tube Cancer; Stage IB Ovarian Cancer; Stage IC Fallopian Tube Cancer; Stage IC Ovarian Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer

  8. Elevated blood plasma concentrations of active ghrelin and obestatin in benign ovarian neoplasms and ovarian cancers.

    PubMed

    Markowska, A; Ziółkowska, A; Jaszczyńska-Nowinka, K; Madry, R; Malendowicz, L K

    2009-01-01

    Both ghrelin and obestatin are derived from preproghrelin by post-translational processing. The two peptides are secreted into the blood but circulating levels of these peptides have not been assessed in women with ovarian tumours. Therefore, the purpose of this study was to evaluate peripheral blood concentrations of active and total ghrelin and obestatin in patients with benign ovarian tumours and those with ovarian cancer. The studies were conducted on 22 patients operated due to benign ovarian tumours, and 31 patients operated due to ovarian cancer. A control group consisted of 32 women, 24 to 65 years of age. Both in women with benign ovarian tumours and those with ovarian cancer blood concentrations of active ghrelin and obestatin were higher than in the control group (active ghrelin: 90 +/- 4, 84 +/- 4 and 56 +/- 9 pg/ml, respectively, obestatin: 660 +/- 36; 630 +/- 30 and 538 +/- 31 ng/ml (x +/- SE), respectively). In contrast, total ghrelin concentrations in blood were similar in the studied groups. The alterations resulted in increased values of active to total ghrelin concentration ratio in the peripheral blood of patients with benign ovarian tumours or with ovarian cancer (0.79 +/- 0.02 and 0.93 +/- 0.05, respectively vs 0.58 +/- 0.02 in the control group). Due to the absence of any convincing proof for the presence of a functional GHS-R-1a receptor for ghrelin in human ovaries it did not seem probable that the observed elevated levels of active ghrelin and obestatin were directly linked to development of ovarian tumours.

  9. IL-36α suppresses proliferation of ovarian cancer cells.

    PubMed

    Chang, Lei; Guo, Ruixia; Yuan, Zhongfu

    2017-06-01

    Interleukin-36α (IL-36α), also formerly known as IL-1F6, is pertaining to IL-1 family members that has been shown to play an important pro-inflammatory role in chronic immune disorders. However, the role IL-36α in the setting of cancer remains unknown. Here, in our study, to investigate the clinical relevance of IL-36α in ovarian cancer, clinicopathological significance as well as expression level of IL-36α were analyzed in epithelial ovarian cancer clinical tissues and paired normal control. To explore the biological role of IL-36α in vitro in epithelial ovarian cancer cells, both overexpression and knockdown of IL-36α were performed. Based on the successful re-expression and silencing of IL-36α, proliferation, migration, and invasion were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, wound-healing, and Transwell assays, respectively. To further confirm the effect over proliferation in vivo, nude mice xenografted with epithelial ovarian cancer cells whose endogenous IL-36α was stably upregulated or downregulated were employed. It was found that IL-36α was shown to be markedly downregulated in epithelial ovarian cancer tissues relative to paired normal control and that reduced IL-36α expression was significantly associated with poor overall prognosis. In addition, IL-36α was observed to be able to suppress the growth of epithelial ovarian cancer cells both in vivo and in vitro. Taken together, IL-36α was displayed to be able to suppress the growth of epithelial ovarian cancer cells in our setting, which is suggestive of its druggable potential in curing the epithelial ovarian cancer and that upregulation of IL-36α was found to be capable of inhibiting the growth of epithelial ovarian cancer cells.

  10. Selection of suitable reference genes for gene expression studies in normal human ovarian tissues, borderline ovarian tumours and ovarian cancer.

    PubMed

    Ofinran, Olumide; Bose, Ujjal; Hay, Daniel; Abdul, Summi; Tufatelli, Cristina; Khan, Raheela

    2016-12-01

    The use of reference genes is the most common method of controlling the variation in mRNA expression during quantitative polymerase chain reaction, although the use of traditional reference genes, such as β‑actin, glyceraldehyde‑3‑phosphate dehydrogenase or 18S ribosomal RNA, without validation occasionally leads to unreliable results. Therefore, the present study aimed to evaluate a set of five commonly used reference genes to determine the most suitable for gene expression studies in normal ovarian tissues, borderline ovarian and ovarian cancer tissues. The expression stabilities of these genes were ranked using two gene stability algorithms, geNorm and NormFinder. Using geNorm, the two best reference genes in ovarian cancer were β‑glucuronidase and β‑actin. Hypoxanthine phosphoribosyltransferase‑1 and β‑glucuronidase were the most stable in ovarian borderline tumours, and hypoxanthine phosphoribosyltransferase‑1 and glyceraldehyde‑3‑phosphate dehydrogenase were the most stable in normal ovarian tissues. NormFinder ranked β‑actin the most stable in ovarian cancer, and the best combination of two genes was β‑glucuronidase and β‑actin. In borderline tumours, hypoxanthine phosphoribosyltransferase‑1 was identified as the most stable, and the best combination was hypoxanthine phosphoribosyltransferase‑1 and β‑glucuronidase. In normal ovarian tissues, β‑glucuronidase was recommended as the optimum reference gene, and the most optimum pair of reference genes was hypoxanthine phosphoribosyltransferase‑1 and β‑actin. To the best of our knowledge, this is the first study to investigate the selection of a set of reference genes for normalisation in quantitative polymerase chain reactions in different ovarian tissues, and therefore it is recommended that β‑glucuronidase, β‑actin and hypoxanthine phosphoribosyltransferase‑1 are the most suitable reference genes for such analyses.

  11. Markers of Ovarian Cancer Using a Glycoprotein/Antibody Array

    DTIC Science & Technology

    2014-05-01

    ovarian cancer are desperately needed. In addition, a number of benign conditions, including pregnancy , endometriosis, normal menstruation, and pelvic...CBG is a plasma glycoprotein that binds steroid hormones such as progesterone and cortisol, which have been implicated in the progression of ovarian...Welander, C. E. The effects of estrogen, progesterone , and tamoxifen alone and in combination with cytotoxic agents against human ovarian carcinoma in

  12. Imminent ovarian failure in childhood cancer survivors.

    PubMed

    Lantinga, G M; Simons, A H M; Kamps, W A; Postma, A

    2006-07-01

    The aim of this study was to investigate reproductive history and the prevalence of imminent ovarian failure (IOF) in female childhood cancer survivors. Reproductive history and ovarian function were evaluated by questionnaires (n=124) and by measurement of follicle stimulating hormone (FSH) and oestradiol (E2) levels (n=93). IOF was defined as FSH>10 IU/l or E2>0.28 nmol/l on day 3 of the menstrual cycle, or FSH>12.4 IU/l on day 7 of the pill-free interval. IOF was demonstrated in 22.6% of the participants and correlated with age at diagnosis (P<0.005) and age at study (P=0.036). IOF correlated inversely with methotrexate (P=0.046). The incidence of miscarriages (22.7%) and recurrent miscarriages (7.3%) was increased. The male/female (M/F) ratio of the offspring was decreased. In conclusion, female childhood cancer survivors are at risk for IOF. If pregnant, the risk of (recurrent) miscarriages is increased. The M/F ratio in the offspring is decreased.

  13. Epidemiology of ovarian cancer: a review

    PubMed Central

    Reid, Brett M.; Permuth, Jennifer B.; Sellers, Thomas A.

    2017-01-01

    Ovarian cancer (OC) is the seventh most commonly diagnosed cancer among women in the world and the tenth most common in China. Epithelial OC is the most predominant pathologic subtype, with five major histotypes that differ in origination, pathogenesis, molecular alterations, risk factors, and prognosis. Genetic susceptibility is manifested by rare inherited mutations with high to moderate penetrance. Genome-wide association studies have additionally identified 29 common susceptibility alleles for OC, including 14 subtype-specific alleles. Several reproductive and hormonal factors may lower risk, including parity, oral contraceptive use, and lactation, while others such as older age at menopause and hormone replacement therapy confer increased risks. These associations differ by histotype, especially for mucinous OC, likely reflecting differences in etiology. Endometrioid and clear cell OC share a similar, unique pattern of associations with increased risks among women with endometriosis and decreased risks associated with tubal ligation. OC risks associated with other gynecological conditions and procedures, such as hysterectomy, pelvic inflammatory disease, and polycystic ovarian syndrome, are less clear. Other possible risk factors include environmental and lifestyle factors such as asbestos and talc powder exposures, and cigarette smoking. The epidemiology provides clues on etiology, primary prevention, early detection, and possibly even therapeutic strategies. PMID:28443200

  14. Epidemiology of ovarian cancer: a review.

    PubMed

    Reid, Brett M; Permuth, Jennifer B; Sellers, Thomas A

    2017-02-01

    Ovarian cancer (OC) is the seventh most commonly diagnosed cancer among women in the world and the tenth most common in China. Epithelial OC is the most predominant pathologic subtype, with five major histotypes that differ in origination, pathogenesis, molecular alterations, risk factors, and prognosis. Genetic susceptibility is manifested by rare inherited mutations with high to moderate penetrance. Genome-wide association studies have additionally identified 29 common susceptibility alleles for OC, including 14 subtype-specific alleles. Several reproductive and hormonal factors may lower risk, including parity, oral contraceptive use, and lactation, while others such as older age at menopause and hormone replacement therapy confer increased risks. These associations differ by histotype, especially for mucinous OC, likely reflecting differences in etiology. Endometrioid and clear cell OC share a similar, unique pattern of associations with increased risks among women with endometriosis and decreased risks associated with tubal ligation. OC risks associated with other gynecological conditions and procedures, such as hysterectomy, pelvic inflammatory disease, and polycystic ovarian syndrome, are less clear. Other possible risk factors include environmental and lifestyle factors such as asbestos and talc powder exposures, and cigarette smoking. The epidemiology provides clues on etiology, primary prevention, early detection, and possibly even therapeutic strategies.

  15. Laparoscopic Cytoreduction for Primary Advanced Ovarian Cancer

    PubMed Central

    Hojat, Rod; Johnson, Jil; Fenton, Bradford

    2010-01-01

    Introduction: We evaluated the feasibility of laparoscopic cytoreduction for primary advanced ovarian cancer. Methods: All patients with presumed stage 3/4 primary ovarian cancer underwent attempted laparoscopic cytoreduction. All patients had CT evidence of omental metastasis and ascites. A 5-port (5-mm) transperitoneal approach was used. A bilateral salpingo-oophorectomy, supracervical hysterectomy, and omentectomy were performed with PlasmaKinetic (PK) cutting forceps. A laparoscopic 5-mm Argon-Beam Coagulator was used to coagulate tumor in the pelvis, abdominal peritoneum, intestinal mesentery, and diaphragm. Results: Nine of 11 cases (82%) were successfully de-bulked laparoscopically without conversion to laparotomy. Median operative time was 2.5 hours, and median blood loss was 275 mL. All tumors were debulked to <2 cm and 45% had no residual disease. Stages were 1–3B, 7–3C, and 1–4. Median length of stay was one day. Median VAS pain score was 4 (discomforting). Two of 11 patients (18%) had postoperative complications. Conclusion: Laparoscopic cytoreduction was successful and resulted in minimal morbidity. Because of our small sample size, additional studies are needed. PMID:20529532

  16. Laparoscopic cytoreduction for primary advanced ovarian cancer.

    PubMed

    Fanning, James; Hojat, Rod; Johnson, Jil; Fenton, Bradford

    2010-01-01

    We evaluated the feasibility of laparoscopic cytoreduction for primary advanced ovarian cancer. All patients with presumed stage 3/4 primary ovarian cancer underwent attempted laparoscopic cytoreduction. All patients had CT evidence of omental metastasis and ascites. A 5-port (5-mm) transperitoneal approach was used. A bilateral salpingo-oophorectomy, supracervical hysterectomy, and omentectomy were performed with PlasmaKinetic (PK) cutting forceps. A laparoscopic 5-mm Argon-Beam Coagulator was used to coagulate tumor in the pelvis, abdominal peritoneum, intestinal mesentery, and diaphragm. Nine of 11 cases (82%) were successfully debulked laparoscopically without conversion to laparotomy. Median operative time was 2.5 hours, and median blood loss was 275 mL. All tumors were debulked to <2 cm and 45% had no residual disease. Stages were 1-3B, 7-3C, and 1-4. Median length of stay was one day. Median VAS pain score was 4 (discomforting). Two of 11 patients (18%) had postoperative complications. Laparoscopic cytoreduction was successful and resulted in minimal morbidity. Because of our small sample size, additional studies are needed.

  17. Interleukin-6 as a therapeutic target in human ovarian cancer

    PubMed Central

    Coward, Jermaine; Kulbe, Hagen; Chakravarty, Probir; Leader, David; Vassileva, Vessela; Leinster, D. Andrew; Thompson, Richard; Schioppa, Tiziana; Nemeth, Jeffery; Vermeulen, Jessica; Singh, Naveena; Avril, Norbert; Cummings, Jeff; Rexhepaj, Elton; Jirström, Karin; Gallagher, William M; Brennan, Donal J.; McNeish, Iain A.; Balkwill, Fran

    2011-01-01

    Purpose We investigated whether inhibition of IL-6 has therapeutic activity in ovarian cancer via abrogation of a tumor-promoting cytokine network. Experimental Design We combined pre-clinical and in silico experiments with a phase II clinical trial of the anti-IL-6 antibody siltuximab in patients with platinum-resistant ovarian cancer. Results Automated immunohistochemistry on tissue microarrays from 221 ovarian cancer cases demonstrated that intensity of IL-6 staining in malignant cells significantly associated with poor prognosis. Treatment of ovarian cancer cells with siltuximab reduced constitutive cytokine and chemokine production and also inhibited IL-6 signalling, tumor growth, the tumor-associated macrophage infiltrate and angiogenesis in IL-6-producing intraperitoneal ovarian cancer xenografts. In the clinical trial, the primary endpoint was response rate as assessed by combined RECIST and CA125 criteria. One patient of eighteen evaluable had a partial response, whilst seven others had periods of disease stabilization. In patients treated for six months, there was a significant decline in plasma levels of IL-6-regulated CCL2, CXCL12 and VEGF. Gene expression levels of factors that were reduced by siltuximab treatment in the patients significantly correlated with high IL-6 pathway gene expression and macrophage markers in microarray analyses of ovarian cancer biopsies. Conclusions IL-6 stimulates inflammatory cytokine production, tumor angiogenesis and the tumor macrophage infiltrate in ovarian cancer and these actions can be inhibited by a neutralising anti-IL-6 antibody in pre-clinical and clinical studies. PMID:21795409

  18. Interleukin-6 as a therapeutic target in human ovarian cancer.

    PubMed

    Coward, Jermaine; Kulbe, Hagen; Chakravarty, Probir; Leader, David; Vassileva, Vessela; Leinster, D Andrew; Thompson, Richard; Schioppa, Tiziana; Nemeth, Jeffery; Vermeulen, Jessica; Singh, Naveena; Avril, Norbert; Cummings, Jeff; Rexhepaj, Elton; Jirström, Karin; Gallagher, William M; Brennan, Donal J; McNeish, Iain A; Balkwill, Frances R

    2011-09-15

    We investigated whether inhibition of interleukin 6 (IL-6) has therapeutic activity in ovarian cancer via abrogation of a tumor-promoting cytokine network. We combined preclinical and in silico experiments with a phase 2 clinical trial of the anti-IL-6 antibody siltuximab in patients with platinum-resistant ovarian cancer. Automated immunohistochemistry on tissue microarrays from 221 ovarian cancer cases showed that intensity of IL-6 staining in malignant cells significantly associated with poor prognosis. Treatment of ovarian cancer cells with siltuximab reduced constitutive cytokine and chemokine production and also inhibited IL-6 signaling, tumor growth, the tumor-associated macrophage infiltrate and angiogenesis in IL-6-producing intraperitoneal ovarian cancer xenografts. In the clinical trial, the primary endpoint was response rate as assessed by combined RECIST and CA125 criteria. One patient of eighteen evaluable had a partial response, while seven others had periods of disease stabilization. In patients treated for 6 months, there was a significant decline in plasma levels of IL-6-regulated CCL2, CXCL12, and VEGF. Gene expression levels of factors that were reduced by siltuximab treatment in the patients significantly correlated with high IL-6 pathway gene expression and macrophage markers in microarray analyses of ovarian cancer biopsies. IL-6 stimulates inflammatory cytokine production, tumor angiogenesis, and the tumor macrophage infiltrate in ovarian cancer and these actions can be inhibited by a neutralizing anti-IL-6 antibody in preclinical and clinical studies. ©2011 AACR.

  19. Hormonal aspects of epithelial ovarian cancer: review of epidemiological evidence.

    PubMed

    Riman, T; Persson, I; Nilsson, S

    1998-12-01

    Epithelial ovarian cancer is fairly common with high rates in Scandinavia, intermediate rates in western Europe and North America and low rates in the developing countries and in Japan. The 5-year survival rate is less than 40%. Increasing parity consistently gives a strong protection against epithelial ovarian cancer. A lesser degree of protection is probably derived from incomplete pregnancies and lactation. Ages at menarche and menopause are most probably weak predictors of epithelial ovarian cancer risk. Ever users of oral contraceptives (OC) have 30% lower risk compared to never users. The protection increases with duration of OC use, being about 50% after 5 years. The reduced risk among past OC users persists for at least 10 years after cessation of use. Results concerning hormone replacement therapy (HRT) and epithelial ovarian cancer risk are conflicting, but most data point to a weak or no association, but as an increasing number of women use HRT it still seems important to resolve any potential effect. Infertility adds to epithelial ovarian cancer risk in nulliparous women, while temporary fertility problems in parous women do not appear to increase risk. A possible independent risk effect of fertility drug use has not been easy to assess and remains unresolved. It has been particularly difficult to separate the effects of fertility drugs from those of infertility. Tubal ligation and hysterectomy convey protection against epithelial ovarian cancer, possibly through a suppressed ovarian hormone production. The causes of epithelial ovarian cancer are poorly understood, but reproductive hormones are thought to be involved in the aetiology. For a long time the 'incessant' and 'gonadotrophin' hypotheses have been promoted in relation to carcinogenesis. Both hypotheses find support in ovarian cancer epidemiology, and recent progress in molecular biology adds to the understanding of possible aetiological mechanisms. Another hypothesis focuses on the retrograde

  20. Isolation and Characterization of Tumor Cells from the Ascites of Ovarian Cancer Patients: Molecular Phenotype of Chemoresistant Ovarian Tumors

    PubMed Central

    Latifi, Ardian; Luwor, Rodney B.; Bilandzic, Maree; Nazaretian, Simon; Stenvers, Kaye; Pyman, Jan; Zhu, Hongjian; Thompson, Erik W.; Quinn, Michael A.; Findlay, Jock K.; Ahmed, Nuzhat

    2012-01-01

    Tumor cells in ascites are a major source of disease recurrence in ovarian cancer patients. In an attempt to identify and profile the population of ascites cells obtained from ovarian cancer patients, a novel method was developed to separate adherent (AD) and non-adherent (NAD) cells in culture. Twenty-five patients were recruited to this study; 11 chemonaive (CN) and 14 chemoresistant (CR). AD cells from both CN and CR patients exhibited mesenchymal morphology with an antigen profile of mesenchymal stem cells and fibroblasts. Conversely, NAD cells had an epithelial morphology with enhanced expression of cancer antigen 125 (CA125), epithelial cell adhesion molecule (EpCAM) and cytokeratin 7. NAD cells developed infiltrating tumors and ascites within 12–14 weeks after intraperitoneal (i.p.) injections into nude mice, whereas AD cells remained non-tumorigenic for up to 20 weeks. Subsequent comparison of selective epithelial, mesenchymal and cancer stem cell (CSC) markers between AD and NAD populations of CN and CR patients demonstrated an enhanced trend in mRNA expression of E-cadherin, EpCAM, STAT3 and Oct4 in the NAD population of CR patients. A similar trend of enhanced mRNA expression of CD44, MMP9 and Oct4 was observed in the AD population of CR patients. Hence, using a novel purification method we demonstrate for the first time a distinct separation of ascites cells into epithelial tumorigenic and mesenchymal non-tumorigenic populations. We also demonstrate that cells from the ascites of CR patients are predominantly epithelial and show a trend towards increased mRNA expression of genes associated with CSCs, compared to cells isolated from the ascites of CN patients. As the tumor cells in the ascites of ovarian cancer patients play a dominant role in disease recurrence, a thorough understanding of the biology of the ascites microenvironment from CR and CN patients is essential for effective therapeutic interventions. PMID:23056490

  1. Pro-lipogenic Action of Lysophosphatidic Acid in Ovarian Cancer

    DTIC Science & Technology

    2014-04-01

    driven lipogenesis is required for proliferation of ovarian cancer cells, our results together establish a dual role for lipid metabolism ( anabolism ...proliferation of ovarian cancer cells, our results together establish a dual role for lipid metabolism ( anabolism and catabolism) in maintenance of the...Conclusion: LPA is causally linked to the aberrant lipogenesis in cancer. Significance: This study offers a new strategy to inhibit lipid anabolism in a

  2. E-cadherin Expression in Ovarian Cancer in the Laying Hen, Gallus Domesticus, compared to Human Ovarian Cancer

    PubMed Central

    Ansenberger, Kristine; Zhuge, Yan; Lagman, Jo Ann J.; Richards, Cassandra; Barua, Animesh; Bahr, Janice M.; Hales, Dale Buchanan

    2010-01-01

    Objective Epithelial ovarian carcinoma (EOC) is a leading cause of cancer deaths in women. Until recently, a significant lack of an appropriate animal model has hindered the discovery of early detection markers for ovarian cancer. The aging hen serves as an animal model because it spontaneously develops ovarian adenocarcinomas similar in histological appearance to the human disease. E-cadherin is an adherens protein that is down-regulated in many cancers, but has been shown to be up-regulated in primary human ovarian cancer. Our objective was to evaluate E-cadherin expression in the hen ovary and compare its expression to human ovarian cancer. Methods White Leghorn hens aged 185 weeks (cancerous and normal) were used for sample collection. A human ovarian tumor tissue array was used for comparison to the human disease. E-cadherin mRNA and protein expression were analyzed in cancerous and normal hen ovaries by immunohistochemistry (IHC), Western blot, and quantitative real-time PCR (qRT-PCR). Tissue fixed in neutral buffered formalin was used for IHC. Protein from tissue frozen in liquid nitrogen was analyzed by Western blot. RNA was extracted from tissue preserved in RNAlater and analyzed by qRT-PCR. The human ovarian tumor tissue array was used for IHC. Results E-cadherin mRNA and protein expression were significantly increased in cancerous hen ovaries as compared to ovaries of normal hens by qRT-PCR and Western blot. Similar expression of E-cadherin was observed by IHC in both human and hen ovarian cancer tissues. Similar E-cadherin expression was also observed in primary ovarian tumor and peritoneal metastatic tissue from cancerous hens. Conclusions Our findings suggest that the up-regulation of E-cadherin is an early defining event in ovarian cancer and may play a significant role in the initial development of the primary ovarian tumor. E-cadherin also appears to be important in the development of secondary tumors within the peritoneal cavity. Our data suggest

  3. Carboplatin, Paclitaxel, Bevacizumab, and Veliparib in Treating Patients With Newly Diagnosed Stage II-IV Ovarian Epithelial, Fallopian Tube, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2017-09-04

    Fallopian Tube Carcinosarcoma; Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Serous Neoplasm; Fallopian Tube Transitional Cell Carcinoma; Ovarian Brenner Tumor; Ovarian Carcinosarcoma; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Seromucinous Tumor; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma

  4. Long-term mortality among women with epithelial ovarian cancer.

    PubMed

    Dinkelspiel, Helen E; Champer, Miriam; Hou, June; Tergas, Ana; Burke, William M; Huang, Yongmei; Neugut, Alfred I; Ananth, Cande V; Hershman, Dawn L; Wright, Jason D

    2015-08-01

    Patients with solid tumors are at greatest risk for dying from their cancers in the five years following diagnosis. For most malignancies, deaths from other chronic diseases begin to exceed those from cancer at some point. As little is known about the causes of death among long-term survivors of ovarian cancer, we examined causes of death by years from diagnosis. The Surveillance, Epidemiology, and End Results (SEER) database was used to identify women diagnosed with ovarian cancer between 1988 and 2012. We compared causes of death by stage, age, and interval time after diagnosis. A total of 67,385 women were identified. For stage I neoplasms, 13.6% (CI, 13.0-14.2%) died from ovarian cancer, 4.2% (CI, 3.8-4.5%) from cardiovascular disease, 3.6% (CI, 3.3-3.9%) from other causes and 2.6% (CI, 2.4-2.9%) from other tumors; ovarian cancer was the leading cause of death until 7 years after diagnosis after which time deaths are more frequently due to other causes. For those with stage III-IV tumors, 67.8% (CI, 67.3-68.2%) died from ovarian cancer, 2.8% (CI, 2.6-2.9%) from other causes, 2.3% (CI, 2.2-2.4%) from cardiovascular disease and 1.9% (CI, 1.7-2.0%) from other cancers; ovarian cancer was the most frequent cause of death in years 1-15 after which time deaths were more commonly due to other causes. The probability of dying from ovarian cancer decreases with time. Ovarian cancer remains the most common cause of death for 15 years after diagnosis in women with stage III-IV tumors. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Other Gynecologic Cancers: endometrial, ovarian, vulvar and vaginal cancers

    PubMed Central

    Duarte-Franco, Eliane; Franco, Eduardo L

    2004-01-01

    Health issue In Canada, cancers of the endometrium, ovaries, vulva, vagina, placenta and adnexa account for 11% of all malignant neoplasms in women and 81% of all genital cancers. Although the incidence and mortality from vulvar and vaginal cancers are very low, endometrium and ovarian cancer are important public health problems. Key findings In Canada, there has been no appreciable improvement in survival for women with advanced endometrial (EC) or ovarian cancer (OC) over the past 30 years. The prognosis of EC is good for most patients because diagnosis is made at early stages. However, survival of OC is poor; more than 70% of cases are diagnosed at late stages. Up to 10% of OCs is linked to familial aggregation. Cancers of the vulva and of the vagina are very rare. The survival experience for women with the latter is worse than for those with the former. Both share many risk factors with cervical cancer and the recent developments in the study of HPV infection should be applicable to these diseases as well. Of particular interest will be the advent of vaccines for the primary prevention of HPV infection. Data gaps and recommendations At present, the best available means to diagnose gynecologic malignancies is a detailed clinical examination, considering the totality of information on potential and proven risk factors, such as age, reproductive health, sexual practices, use unopposed estrogens or of oral contraceptives or tubal ligation, obesity, diet, smoking, and the familial clustering of some of these cancers. PMID:15345077

  6. [Assessment and impact of intrathoracic disease in advanced ovarian cancer].

    PubMed

    Cohen-Mouly, S; Badia, A; Bats, A-S; Barthes, F; Bensaïd, C; Huchon, C; Riquet, M; Lécuru, F

    2010-05-01

    As seventy-five percent of patients with ovarian cancer are diagnosed at an advanced stage (FIGO stage III/IV), optimal surgery is then difficult to perform. The aim of our study is to assess the interest of thoracoscopy in the management of ovarian carcinoma with pleural effusion.

  7. Role of Fallopian Tubes in the Development of Ovarian Cancer.

    PubMed

    Corzo, Camila; Iniesta, Maria D; Patrono, Maria Guadalupe; Lu, Karen H; Ramirez, Pedro T

    2017-02-01

    Ovarian cancer is the leading cause of death from gynecologic malignancy and the fifth cause of cancer death in women in the United States. The most common and lethal histologic subtype of epithelial ovarian cancer is high-grade serous carcinoma (HGSC), which generally presents at an advanced stage. HGSC may be associated with BRCA1 and BRCA2 mutations. Historically, HGSC was believed to originate from the ovarian epithelial cells. However, more recent evidence supports the idea that most ovarian cancers originate in the fallopian tube epithelium in both high-risk women and in the general population. Serous tubal intraepithelial carcinomas may ultimately evolve into ovarian or peritoneal cancer. As a result, prophylactic salpingectomy with conservation of the ovaries has become an increasingly more common practice for premenopausal women undergoing risk-reducing surgery. Because the fallopian tube is now recognized as the most common potential site of origin of ovarian carcinoma, there is ongoing research to explore molecular and genetic factors that may be critical in the development of this disease. Further research is needed to identify novel opportunities for early detection and screening of ovarian cancer with the ultimate goal of increasing overall survival. Copyright © 2016 AAGL. Published by Elsevier Inc. All rights reserved.

  8. Evolving Paradigms in Research and Care in Ovarian Cancers.

    PubMed

    Karlan, Beth Y; Alvarez, Ronald D; Strauss, Jerome F

    2016-10-01

    The National Academies of Sciences, Engineering, and Medicine convened an expert committee to examine and summarize the state of the science in ovarian cancer research. An Executive Summary of the recently released report describing the key findings and specific recommendations to reduce the incidence of and morbidity and mortality from ovarian cancers is presented. Highlights include the recognition that ovarian cancer is not just one disease, but rather a constellation of distinct cancer types, some of which originate outside of the ovary. Furthermore, it was noted that our incomplete understanding of the basic biology of each subtype of ovarian cancer is an impediment to advances in prevention, screening, early detection, diagnosis, treatment, and supportive care.

  9. Dysregulated Expression of Long Noncoding RNAs in Ovarian Cancer

    PubMed Central

    Zhong, Yancheng; Gao, Dan; He, Shiwei; Shuai, Cijun; Peng, Shuping

    2016-01-01

    Abstract Ovarian cancer is the leading cause of death among women with gynecologic malignancies. The development and progression of ovarian cancer are complex and a multiple-step process. New biomarker molecules for diagnostic and prognostic are essential for novel therapeutic targets and to extend the survival time of patients with ovarian cancer. Long noncoding RNAs (lncRNAs) are non–protein-coding transcripts longer than 200 nucleotides that have recently been found as key regulators of various biological processes and to be involved in the development and progression of many diseases including cancers. In this review, we summarized the expression pattern of several dysregulated lncRNAs (HOTAIR, H19, XIST, and HOST2) and the functional molecular mechanism of these lncRNAs on the initiation and progression of ovarian cancer. The lncRNAs as biomarkers may be used for current and future clinical diagnosis, therapeutics, and prognosis. PMID:27603915

  10. Recent Progress in the Diagnosis and Treatment of Ovarian Cancer

    PubMed Central

    Jelovac, Danijela; Armstrong, Deborah K.

    2013-01-01

    Epithelial ovarian cancer is the most lethal of the gynecologic malignancies, largely due to the advanced stage at diagnosis in most patients. Screening strategies using ultrasound and the cancer antigen (CA) 125 tumor marker are currently under study and may lower stage at diagnosis but have not yet been shown to improve survival. Women who have inherited a deleterious mutation in the BRCA1 or BRCA2 gene and those with the Lynch syndrome (hereditary nonpolyposis colorectal cancer) have the highest risk of developing ovarian cancer but account for only approximately 10% of those with the disease. Other less common and less well-defined genetic syndromes may increase the risk of ovarian cancer, but their contribution to genetic risk is small. A clear etiology for sporadic ovarian cancer has not been identified, but risk is affected by reproductive and hormonal factors. Surgery has a unique role in ovarian cancer, as it is used not only for diagnosis and staging but also therapeutically, even in patients with widely disseminated, advanced disease. Ovarian cancer is highly sensitive to chemotherapy drugs, particularly the platinum agents, and most patients will attain a remission with initial treatment. Recent advances in the delivery of chemotherapy using the intraperitoneal route have further improved survival after initial therapy. Although the majority of ovarian cancer patients will respond to initial chemotherapy, most will ultimately develop disease recurrence. Chemotherapy for recurrent disease includes platinum-based, multiagent regimens for women whose disease recurs more than 6 to 12 months after the completion of initial therapy and sequential single agents for those whose disease recurs earlier. New targeted biologic agents, particularly those involved with the vascular endothelial growth factor pathway and those targeting the poly (ADP-ribose) polymerase (PARP) enzyme, hold great promise for improving the outcome of ovarian cancer. PMID:21521830

  11. Antigen-specific immunotherapy of cervical and ovarian cancer

    PubMed Central

    Hung, Chien-fu; Wu, TC; Monie, Archana; Roden, Richard

    2009-01-01

    Summary We contrast the efforts to treat ovarian cancer and cervical cancer through vaccination because of their different pathobiology. A plethora of approaches have been developed for therapeutic vaccination against cancer, many of which target defined tumor-associated antigens (TAAs). Persistent infection with oncogenic human papillomavirus (HPV) types is necessary cause of cervical cancer. Furthermore, cervical cancer patients frequently mount both humoral and T cell immune responses to the HPV E6 and E7 oncoproteins, whose expression is required for the transformed phenotype. Numerous vaccine studies target these viral TAAs, including recent trials that may enhance clearance of pre-malignant disease. By contrast little is known about the etiology of epithelial ovarian cancer. Although it is clear that p53 mutation or loss is a critical early event in the development of epithelial ovarian cancer, no precursor lesion has been described for the most common serous histotype, and even the location of its origin is debated. These issues have complicated the selection of appropriate ovarian TAAs and the design of vaccines. Here we focus on mesothelin as a promising ovarian TAA because it is overexpressed and immunogenic at high frequency in patients, is displayed on the cell surface and potentially contributes to ovarian cancer biology. PMID:18363994

  12. Breast Cancer Stem Cells

    PubMed Central

    Velasco-Velázquez, Marco A.; Homsi, Nora; De La Fuente, Marisol; Pestell, Richard G.

    2012-01-01

    Breast cancer stem cells (BCSCs) constitute a subpopulation of tumor cells that express stem cell-associated markers and have a high capacity for tumor generation in vivo. Identification of BCSCs from tumor samples or breast cancer cell lines has been based mainly on CD44+/CD24−/low or ALDH+ phenotypes. BCSCs isolation has allowed the analysis of the molecular mechanisms involved in their origin, self-renewal, differentiation into tumor cells, resistance to radiation therapy and chemotherapy, and invasiveness and metastatic ability. Molecular genetic analysis using knockout animals and inducible transgenics have identified NF-κB, c-Jun, p21CIP1, and Forkhead-like-protein Dach1 in BCSC expansion and fate. Clinical analyses of BCSCs in breast tumors have found a correlation between the proportion of BCSCs and poor prognosis. Therefore, new therapies that specifically target BCSCs are an urgent need. We summarize recent evidence that partially explain the biological characteristics of BCSCs. PMID:22249027

  13. Occupational exposure and ovarian cancer risk.

    PubMed

    Le, Nhu D; Leung, Andy; Brooks-Wilson, Angela; Gallagher, Richard P; Swenerton, Kenneth D; Demers, Paul A; Cook, Linda S

    2014-07-01

    Relatively little work has been done concerning occupational risk factors in ovarian cancer. Although studies conducted in occupational settings have reported positive associations, their usefulness is generally limited by the lack of information on important confounders. In a population-based case-control study, we assessed risk for developing epithelial ovarian cancer (EOC) associated with occupational exposure while accounting for important confounders. Participants were identified through provincial population-based registries. Lifetime occupational history and information on potential confounding factors were obtained through a self-administered questionnaire. Unconditional logistic regression and the likelihood ratio test were used to assess EOC risk with each occupation (or industry), relative to all other occupations (or industries), adjusting for potential confounders including body mass index, oral contraceptive use, menopausal hormone therapy, parity, age at first childbirth, age at menarche, age at menopause, family history of breast and ovarian cancer in mother and sister(s), tubal ligation, partial oophorectomy, and hysterectomy. Occupations and industries were coded according to the Canadian Standard Occupational Classification (SOC) and Standard Industrial Classification (SIC). Significant excess risk was observed for several groups of teaching occupations, including SOC 27, teaching and related (adjusted OR 1.77, 95% CI 1.15-2.81) and SOC 279, other teaching and related (adjusted OR 3.11, 95% CI 1.35-8.49). Significant excess was also seen for a four-digit occupational group SOC 4131, bookkeepers and accounting clerks (adjusted OR 2.80, 95% CI 1.30-6.80). Industrial sub-groups showing significant excess risk included SIC 65, other retail stores (adjusted OR 2.19, 95 % CI 1.16-4.38); SIC 85, educational service (adjusted OR 1.45, 95% CI 1.00-2.13); and SIC 863, non-institutional health services (adjusted OR 2.54, 95% CI 1.13-6.52). Our study found

  14. Mutational heterogeneity in non-serous ovarian cancers.

    PubMed

    Teer, Jamie K; Yoder, Sean; Gjyshi, Anxhela; Nicosia, Santo V; Zhang, Chaomei; Monteiro, Alvaro N A

    2017-08-29

    Epithelial ovarian cancer is a leading cause of death in gynecological cancers. While several systematic studies have revealed the mutation landscape of serous epithelial ovarian cancer, other non-serous subtypes of the disease have not been explored as extensively. Here we conduct exome sequencing of nine non-serous epithelial ovarian tumors (six endometrioid and three mucinous) and their corresponding normal DNA as well as a tumor-only granulosa cell sample. We integrated the exome data with targeted gene sequencing for 1,321 genes selected for their involvement in cancer from additional 28 non-serous ovarian tumors and compared our results to TCGA ovarian serous cystadenocarcinoma and uterine corpus endometrial carcinomas. Prevalence of TP53 mutations in non-serous was much lower than in serous epithelial OC, whereas the prevalence of PIK3CA, PIK3R1, PTEN, CTNNB1, ARID1A, and KRAS was higher. We confirmed the high prevalence of FOXL2 and KRAS mutations in granulosa cell tumors and in mucinous tumors, respectively. We also identified POLE proofreading domain mutations in three endometrioid ovarian tumors. These results highlight mutational differences between serous and non-serous ovarian cancers, and further distinguish different non-serous subtypes.

  15. Safety assessment of ovarian cryopreservation and transplantation in nude mice bearing human epithelial ovarian cancer.

    PubMed

    Zhu, Gen-Hai; Wang, Sheng-Tan; Yang, Zhao-Xin; Cai, Jun-Hong; Chen, Chun-Ying; Yao, Mao-Zhong; Hong, Lan; He, Guo-Li; Yang, Shu-Ying

    2012-01-01

    Nude mice with orthotopic transplantation of human ovarian epithelial cancer were used to investigate screening criteria for paraneoplastic normal ovarian tissue and the security of the freezing and thawing for ovarian tissue transplantation. Expression of CK-7, CA125, P53, survivin, MMP-2/TIMP- 2 in paraneoplastic normal ovarian tissues were detected by RT-PCR as well as immunohistochemistry. The tissues of the groups with all negative indicators of RT-PCR, all negative indicators of immunohistochemistry, negative expression of CK-7, CA125 and survivin, positive expression of CK-7, CA125 and survivin, cancer tissues and normal ovarian tissues of nude mice were used for freezing and thawing transplantation, to analyze overt and occult carcinogenesis rates after transplantation. When all indicators or the main indicators, CK-7, CA125 and survivin, were negative, tumorigenesis did not occur after transplantation. In addition the occult carcinogenesis rate was lower than in the group with positive expression of CK-7, CA125 and survivin (P<0.01). After subcutaneous and orthotopic transplantation of ovarian tissues, rates did not change (P>0.05). There was no statistical significance among rates after transplantation of ovarian tissues which were obtained under different severity conditions (P>0.05). Negative expression of CK-7, CA125 and survivin can be treated as screening criteria for security of ovarian tissues for transplantation. Immunohistochemical methods can be used as the primary detection approach. Both subcutaneous and orthotopic transplantation are safe. The initial severity does not affect the carcinogenesis rate after tissue transplantation. Freezing and thawing ovarian tissue transplantation in nude mice with human epithelial ovarian carcinoma is feasible and safe.

  16. Immune physiology and oogenesis in fetal and adult humans, ovarian infertility, and totipotency of adult ovarian stem cells.

    PubMed

    Bukovsky, Antonin; Caudle, Michael R; Virant-Klun, Irma; Gupta, Satish K; Dominguez, Roberto; Svetlikova, Marta; Xu, Fei

    2009-03-01

    It is still widely believed that while oocytes in invertebrates and lower vertebrates are periodically renewed throughout life, oocytes in humans and higher vertebrates are formed only during the fetal/perinatal period. However, this dogma is questioned, and clashes with Darwinian evolutionary theory. Studies of oogenesis and follicular renewal from ovarian stem cells (OSCs) in adult human ovaries, and of the role of third-party bone marrow-derived cells (monocyte-derived tissue macrophages and T lymphocytes) could help provide a better understanding of the causes of ovarian infertility, its prevention, and potential treatment. We have reported differentiation of distinct cell types from OSC and the production of new eggs in cultures derived from premenopausal and postmenopausal human ovaries. OSCs are also capable of producing neural/neuronal cells in vitro after sequential stimulation with sex steroid combinations. Hence, OSC represent a unique type of totipotent adult stem cells, which could be utilized for autologous treatment of premature ovarian failure and also for autologous stem cell therapy of neurodegenerative diseases without use of allogeneic embryonic stem cells or somatic cell nuclear transfer. The in vivo application of sex steroid combinations may augment the proliferation of existing neural stem cells and their differentiation into mature neuronal cells (systemic regenerative therapy). Such treatment may also stimulate the transdifferentiation of autologous neural stem cell precursors into neural stem cells useful for topical or systemic regenerative treatment.

  17. Current strategies for prevention, detection, and treatment of ovarian cancer.

    PubMed

    Shepherd, J E

    2000-01-01

    To review the prevalence, etiology, risk factors, diagnosis, and treatment of ovarian cancer. English-language journal articles retrieved from a MEDLINE search from 1990 to the present, and selected references retrieved from the bibliographies of those articles. Clinical trials and pertinent review articles that discussed the detection, prevention, and clinical management of ovarian cancer. Although relatively uncommon, ovarian cancer is the leading cause of mortality from gynecologic cancer. Because most ovarian cancers are not detected until the disease has metastasized beyond the ovary, the 5-year survival rate for all cases is only 50%. Pharmacists can educate women about strategies that can reduce ovarian cancer risk, especially the use of oral contraceptives. To aid in earlier detection, pharmacists also should be aware of the nonspecific symptoms that can be associated with the disease, and refer women with suggestive symptoms to their physicians for further evaluation. Treatment usually consists of hysterectomy with debulking surgery to remove as much tumor as possible, followed by chemotherapy, for which the current gold standard is cisplatin and paclitaxel. Pharmacist-provided education can help women reduce their risk of ovarian cancer. As integral members of the health care team, pharmacists also can optimize the efficacy and tolerability of chemotherapeutic regimens; assist with palliative care for nausea, vomiting, and pain; and serve as a resource for patient information and support.

  18. Municipal distribution of ovarian cancer mortality in Spain

    PubMed Central

    Lope, Virginia; Pollán, Marina; Pérez-Gómez, Beatriz; Aragonés, Nuria; Vidal, Enrique; Gómez-Barroso, Diana; Ramis, Rebeca; García-Pérez, Javier; Cabanes, Anna; López-Abente, Gonzalo

    2008-01-01

    Background Spain was the country that registered the greatest increases in ovarian cancer mortality in Europe. This study describes the municipal distribution of ovarian cancer mortality in Spain using spatial models for small-area analysis. Methods Smoothed relative risks of ovarian cancer mortality were obtained, using the Besag, York and Molliè autoregressive spatial model. Standardised mortality ratios, smoothed relative risks, and distribution of the posterior probability of relative risks being greater than 1 were depicted on municipal maps. Results During the study period (1989–1998), 13,869 ovarian cancer deaths were registered in 2,718 Spanish towns, accounting for 4% of all cancer-related deaths among women. The highest relative risks were mainly concentrated in three areas, i.e., the interior of Barcelona and Gerona (north-east Spain), the north of Lugo and Asturias (north-west Spain) and along the Seville-Huelva boundary (in the south-west). Eivissa (Balearic Islands) and El Hierro (Canary Islands) also registered increased risks. Conclusion Well established ovarian cancer risk factors might not contribute significantly to the municipal distribution of ovarian cancer mortality. Environmental and occupational exposures possibly linked to this pattern and prevalent in specific regions, are discussed in this paper. Small-area geographical studies are effective instruments for detecting risk areas that may otherwise remain concealed on a more reduced scale. PMID:18789142

  19. Recurrence season impacts the survival of epithelial ovarian cancer patients.

    PubMed

    Liu, Xiao-Hui; Man, Ya-Nan; Wu, Xiong-Zhi

    2014-01-01

    Several studies indicated that the diagnosis season affects the prognosis of some cancers, such as examples in the prostate, colon and breast This retrospective study aimed to investigate whether the diagnosis and recurrent season impacts the prognosis of epithelial ovarian cancer patients. From January 2005 to August 2010, 161 epithelial ovarian cancer patients were analyzed and followed up until August 2013. Kaplan- Meier survival curves and the log-rank test were used to make the survival analysis. Multivariate analysis was conducted to identify independent prognostic factors. The prognostic factors of overall survival in epithelial ovarian cancer patients included age, clinical stage, pathological type, histological grade, residual disease after primary surgery, recurrent season and adjuvant chemotherapy cycles. Moreover, clinical stage, histological grade, residual disease after primary surgery, recurrent season and adjuvant chemotherapy cycles also impacted the progression-free survival of epithelial ovarian cancer patients. The diagnosis season did not have a significantly relationship with the survival of operable epithelial ovarian cancer patients. Median overall survival of patients with recurrent month from April to November was 47 months, which was longer (P < 0.001) than that of patients with recurrence month from December to March (19 months). Median progression-free survival of patients with recurrence month from April to November and December to March was 20 and 8 months, respectively (P < 0.001). The recurrence season impacts the survival of epithelial ovarian cancer patients. However, the diagnosed season does not appear to exert a significant influence.

  20. Discovery – BRCA Connection to Breast and Ovarian Cancer

    Cancer.gov

    NCI-funded research helped identify inherited BRCA1 and BRCA2 genetic mutations and their connection to breast and ovarian cancer. From this research, a screening test was also developed to help patients make informed decisions about their health.

  1. What Will Happen After Treatment for Ovarian Cancer?

    MedlinePlus

    ... careful general physical exam and blood tests for tumor markers that help recognize recurrence. For epithelial ovarian cancer, ... life with your doctor. The choice of which tumor marker blood tests to check depends on the type ...

  2. BRCA mutation in ovarian cancer: testing, implications and treatment considerations.

    PubMed

    Neff, Robert T; Senter, Leigha; Salani, Ritu

    2017-08-01

    Ovarian cancer is a heterogeneous disease that encompasses a number of different cellular subtypes, the most common of which is high-grade serous ovarian cancer (HGSOC). Still today, ovarian cancer is primarily treated with chemotherapy and surgery. Recent advances in the hereditary understanding of this disease have shown a significant role for the BRCA gene. While only a minority of patients with HGSOC will have a germline BRCA mutation, many others may have tumor genetic aberrations within BRCA or other homologous recombination proteins. Genetic screening for these BRCA mutations has allowed improved preventative measures and therapeutic development. This review focuses on the understanding of BRCA mutations and their relationship with ovarian cancer development, as well as future therapeutic targets.

  3. Defining Therapy for Recurrent Platinum-sensitive Ovarian Cancer

    Cancer.gov

    In this phase III clinical trial, women with platinum-sensitive, recurrent ovarian epithelial, fallopian tube, or primary peritoneal cancer will be randomly assigned to undergo secondary cytoreductive surgery, if they are candidates for such surgery, and

  4. EGFR/HER-targeted therapeutics in ovarian cancer.

    PubMed

    Wilken, Jason A; Badri, Tayf; Cross, Sarah; Raji, Rhoda; Santin, Alessandro D; Schwartz, Peter; Branscum, Adam J; Baron, Andre T; Sakhitab, Adam I; Maihle, Nita J

    2012-03-01

    Despite decades of research and evolving treatment modalities, survival among patients with epithelial ovarian cancer has improved only incrementally. During this same period, the development of biologically targeted therapeutics has improved survival for patients with diverse malignancies. Many of these new drugs target the human epidermal growth factor receptor (EGFR/HER/ErbB) family of tyrosine kinases, which play a major role in the etiology and progression of many carcinomas, including epithelial ovarian cancer. While several HER-targeted therapeutics are US FDA approved for the treatment of various malignancies, none have gained approval for the treatment of ovarian cancer. Here, we review the published literature on HER-targeted therapeutics for the treatment of ovarian cancer, including novel HER-targeted therapeutics in various stages of clinical development, as well as the challenges that have limited the use of these inhibitors in clinical settings.

  5. Combining Chemotherapy with Bevacizumab Improves Outcomes for Ovarian Cancer Patients

    Cancer.gov

    Results from two phase III randomized clinical trials suggest that, at least for some patients with ovarian cancer, adding the antiangiogenesis agent bevacizumab to chemotherapy increases the time to disease progression and may improve survival.

  6. [Long-term survival metastatic ovarian cancer elderly patient].

    PubMed

    Amoroso, L; De Iuliis, F; Taglieri, L; Vendittozzi, S; Salerno, G; Blasi, L; Lanza, R

    Ovarian cancer is the sixth diagnosed cancer among women worldwide, it has a high mortality and in most cases it's diagnosed in advanced stage (stage III-IV). Combination platinum-paclitaxel chemotherapy administered every 3 weeks is considered the gold standard for first-line treatment of patients with advanced ovarian cancer. Elderly patients with ovarian cancer represents a subgroup with poor prognosis because they are often treated less radically for comorbidities and age. In the present article, we report a case of a 85 year old woman who was diagnosed with stage IV ovarian carcinoma for the presence of peritoneal carcinomatosis ab initio, not radically debulked and then treated with weekly schedule platinum-based and paclitaxel. Despite not being able to complete the chemotherapy, the patient achieved excellent results and represents a case of long survival.

  7. Surgery and Chemotherapy With or Without Chemotherapy After Surgery in Treating Patients With Ovarian, Fallopian Tube, Uterine, or Peritoneal Cancer

    ClinicalTrials.gov

    2016-10-18

    Recurrent Uterine Corpus Cancer; Recurrent Fallopian Tube Cancer; Recurrent Ovarian Cancer; Recurrent Primary Peritoneal Cancer; Stage IIIA Uterine Corpus Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cavity Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cavity Cancer; Stage IIIC Uterine Corpus Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cavity Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cavity Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer

  8. Ovarian steroids, stem cells and uterine leiomyoma: therapeutic implications

    PubMed Central

    Moravek, Molly B.; Yin, Ping; Ono, Masanori; Coon V, John S.; Dyson, Matthew T.; Navarro, Antonia; Marsh, Erica E.; Chakravarti, Debabrata; Kim, J. Julie; Wei, Jian-Jun; Bulun, Serdar E.

    2015-01-01

    BACKGROUND Uterine leiomyoma is the most common benign tumor in women and is thought to arise from the clonal expansion of a single myometrial smooth muscle cell transformed by a cellular insult. Leiomyomas cause a variety of symptoms, including abnormal uterine bleeding, pelvic pain, bladder or bowel dysfunction, and recurrent pregnancy loss, and are the most common indication for hysterectomy in the USA. A slow rate of cell proliferation, combined with the production of copious amounts of extracellular matrix, accounts for tumor expansion. A common salient feature of leiomyomas is their responsiveness to steroid hormones, thus providing an opportunity for intervention. METHODS A comprehensive search of PUBMED was conducted to identify peer-reviewed literature published since 1980 pertinent to the roles of steroid hormones and somatic stem cells in leiomyoma, including literature on therapeutics that target steroid hormone action in leiomyoma. Reviewed articles were restricted to English language only. Studies in both animals and humans were reviewed for the manuscript. RESULTS Estrogen stimulates the growth of leiomyomas, which are exposed to this hormone not only through ovarian steroidogenesis, but also through local conversion of androgens by aromatase within the tumors themselves. The primary action of estrogen, together with its receptor estrogen receptor α (ERα), is likely mediated via induction of progesterone receptor (PR) expression, thereby allowing leiomyoma responsiveness to progesterone. Progesterone has been shown to stimulate the growth of leiomyoma through a set of key genes that regulate both apoptosis and proliferation. Given these findings, aromatase inhibitors and antiprogestins have been developed for the treatment of leiomyoma, but neither treatment results in complete regression of leiomyoma, and tumors recur after treatment is stopped. Recently, distinct cell populations were discovered in leiomyomas; a small population showed stem

  9. Progesterone Signaling Mediated Through Progesterone Receptor Membrane Component-1 in Ovarian Cells with Special Emphasis on Ovarian Cancer

    PubMed Central

    Peluso, John J.

    2011-01-01

    Various ovarian cell types including granulosa cells and ovarian surface epithelial cells express the progesterone (P4) binding protein, Progesterone Receptor Membrane Component-1 (PGRMC1). PGRMC1 is also expressed in ovarian tumors. PGRMC1 plays an essential role in promoting the survival of both normal and cancerous ovarian cell in vitro. Given the clinical significance of factors that regulate the viability of ovarian cancer, this review will focus on the role of PGRMC1 in ovarian cancer, while drawing insights into the mechanism of PGRMC1’s action from cell lines derived from healthy ovaries as well as ovarian tumors. Studies using PGRMC1 siRNA demonstrated that P4’s ability to inhibit ovarian cells from undergoing apoptosis in vitro is dependent on PGRMC1. To confirm the importance of PGRMC1, the ability of PGRMC1-deplete ovarian cancer cell lines to form tumors in intact nude mice was assessed. Compared to PGRMC1-expressing ovarian cancer cells, PGRMC1-deplete ovarian cancer cells formed tumors in fewer mice (80% compared to 100% for controls). Moreover, the number of tumors derived from PGRMC1-deplete ovarian cancer cells was 50% of that observed in controls. Finally, the tumors that formed from PGRMC1-deplete ovarian cancer cells were about a fourth the size of tumors derived from ovarian cancer cells with normal levels of PGRMC1. One reason for PGRMC1-deplete tumors being smaller is that they had a poorly developed microvasculature system. How PGRMC1 regulates cell viability and in turn tumor growth is not known but part of the mechanism likely involves the regulation of genes that promote cell survival and inhibit apoptosis. PMID:21371489

  10. Ovarian cancer in Lynch syndrome; a systematic review.

    PubMed

    Helder-Woolderink, J M; Blok, E A; Vasen, H F A; Hollema, H; Mourits, M J; De Bock, G H

    2016-03-01

    The aim was to systematically review the characteristics of ovarian cancer in women with Lynch syndrome (LS) and evaluate the role of surveillance in detection of ovarian cancer in LS. All studies between 1979 and 2015 of women with ovarian cancer and LS or at 50% risk of LS were evaluated. Two reviewers independently evaluated eligible studies and extracted data on age at diagnosis, histological type, FIGO stage, and way of detection according to pre-specified criteria. The studies were assessed for quality using the Newcastle-Ottawa quality assessment scales. The quality score of the 49 identified studies was at least 6 out of 8 and provide clinical information on 747 LS women with ovarian cancer. The mean age at diagnosis was 45.3 (range 19-82) years. Most frequent mutations were MSH2 (47%) and MLH1 (38%). Histopathological data were available for 445 women. The most frequently reported histological type was mixed type (mucinous/endometrioid/clear cell carcinomas) (n = 136; 31%). Most tumours (281, 65%) were diagnosed at an early stage (FIGO I/II). Six studies evaluating the effect of surveillance of ovarian cancer, reported that seven of 22 (32%) ovarian cancers were found during surveillance, 6/7 (86%) were detected at an early stage. This systematic review describes that ovarian cancer in women with LS has a wide age-range of onset, is often diagnosed at an early stage with frequently endometrioid/clear cell histology. Data about the role of surveillance in detection of ovarian cancer in women with LS are scarce however detection at an early stage seems possible. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Perineal use of talc and risk of ovarian cancer.

    PubMed

    Langseth, H; Hankinson, S E; Siemiatycki, J; Weiderpass, E

    2008-04-01

    Ovarian cancer is one of the most common gynaecological neoplasms, especially in industrialised countries. The aetiology of the disease is not well understood, except that inherited mutations in the breast cancer genes BRCA-1 and BRCA-2 account for up to 10% of all cases, and child-bearing, oral contraceptive use and breast-feeding reduce the risk. Some environmental exposures, notably talc and asbestos, have been suspected as ovarian carcinogens.

  12. Profile of olaparib in the treatment of advanced ovarian cancer.

    PubMed

    Chase, Dana M; Patel, Shreya; Shields, Kristin

    2016-01-01

    Olaparib is a poly(ADP-ribose) polymerase inhibitor that received accelerated approval from the US Food and Drug Administration as monotherapy for patients with germline BRCA mutations and ovarian cancer treated with three or more prior lines of chemotherapy. This article summarizes the mechanism of poly(ADP-ribose) polymerase inhibition, therapeutic profile and uses of olaparib, and current and ongoing literature pertaining to olaparib in advanced ovarian cancer.

  13. Location of recurrent asymptomatic ovarian cancer through endoscopic ultrasound.

    PubMed

    Carvalho, Joaquim; Formighieri, Beatriz; Filippi, Sheila; Rossini, Lucio

    2015-01-01

    Ovarian cancer is frequent and recurrence happens in about 75% of patients. As it presents high rates of relapse, the exams for this diagnosis are widely discussed. Beside this, there have been discussions about benefits for early anatomic diagnosis and whether endoscopic ultrasound (EUS) can be used to track the relapse of the disease. We present a case, in which anatomic location and histological definition of an asymptomatic recurrence of the ovarian cancer was misdiagnosed with conventional methods, but was possible through EUS.

  14. Therapeutic Strategies against Cyclin E1-Amplified Ovarian Cancers

    DTIC Science & Technology

    2016-10-01

    strategy for targeting CCNE1 amplified tumors. In the next funding period, we plan to perform studies of miRNA mimics with additional PARP-inhibitors and...AWARD NUMBER: W81XWH-15-1-0564 TITLE: Therapeutic Strategies against Cyclin E1-Amplified Ovarian Cancers PRINCIPAL INVESTIGATOR: Panagiotis A...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Therapeutic Strategies against Cyclin E1-Amplified Ovarian Cancers 5b. GRANT NUMBER W81XWH-15-1-0564 5c

  15. Paclitaxel, Bevacizumab And Adjuvant Intraperitoneal Carboplatin in Treating Patients Who Had Initial Debulking Surgery for Stage II, Stage III, or Stage IV Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2014-06-18

    Brenner Tumor; Fallopian Tube Cancer; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Primary Peritoneal Cavity Cancer; Stage II Ovarian Epithelial Cancer; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

  16. Ovarian cancer: a molecularly insidious disease.

    PubMed

    Mezzanzanica, Delia

    2015-01-01

    In this issue of the Chinese Journal of Cancer, European, American, and Chinese experts review the current management and future perspectives of epithelial ovarian cancer (EOC), the leading cause of gynecological cancer deaths. Although major advances have been made in understanding the cellular and molecular biology of this highly heterogeneous malignancy, the survival rate of women with EOC has changed little since the introduction of platinum-based treatment as a front-line therapy. The papers describe the progress in deciphering the molecular complexity of this disease and the newly available molecular-driven therapies, which have been applied by shifting trial designs toward restricting eligibility to specific subgroups of patients rather than testing agents in unselected populations. These new trial designs provide potential opportunities for improved efficacy in targeted populations. Given the molecular complexity of this disease, patient survival may be increased by searching for new molecular prognostic/predictive signatures as well as by translating the recent insight of microRNA involvement in EOC progression into new, targeted therapies. Particular attention has been given to the issue of fertility sparing for women affected by curable diseases.

  17. Proteomics of ovarian cancer: functional insights and clinical applications

    SciTech Connect

    Elzek, Mohamed A.; Rodland, Karin D.

    2015-03-04

    In the past decade, there has been an increasing interest in applying proteomics to assist in understanding the pathogenesis of ovarian cancer, elucidating the mechanism of drug resistance, and in the development of biomarkers for early detection of ovarian cancer. Although ovarian cancer is a spectrum of different diseases, the strategies for diagnosis and treatment with surgery and adjuvant therapy are similar across ovarian cancer types, increasing the general applicability of discoveries made through proteomics research. While proteomic experiments face many difficulties which slow the pace of clinical applications, recent advances in proteomic technology contribute significantly to the identification of aberrant proteins and networks which can serve as targets for biomarker development and individualized therapies. This review provides a summary of the literature on proteomics’ contributions to ovarian cancer research and highlights the current issues, future directions, and challenges. In conclusion, we propose that protein-level characterization of primary lesion in ovarian cancer can decipher the mystery of this disease, improve diagnostic tools, and lead to more effective screening programs.

  18. Classifications of ovarian cancer tissues by proteomic patterns.

    PubMed

    Zhu, Yi; Wu, Rong; Sangha, Navneet; Yoo, Chul; Cho, Kathleen R; Shedden, Kerby A; Katabuchi, Hidetaka; Lubman, David M

    2006-11-01

    Ovarian cancer is a morphologically and biologically heterogeneous disease. The identification of type-specific protein markers for ovarian cancer would provide the basis for more tailored treatments, as well as clues for understanding the molecular mechanisms governing cancer progression. In the present study, we used a novel approach to classify 24 ovarian cancer tissue samples based on the proteomic pattern of each sample. The method involved fractionation according to pI using chromatofocusing with analytical columns in the first dimension followed by separation of the proteins in each pI fraction using nonporous RP HPLC, which was coupled to an ESI-TOF mass analyzer for molecular weight (MW) analysis. A 2-D mass map of the protein content of each type of ovarian cancer tissue samples based upon pI versus intact protein MW was generated. Using this method, the clear cell and serous ovarian carcinoma samples were histologically distinguished by principal component analysis and clustering analysis based on their protein expression profiles and subtype-specific biomarker candidates of ovarian cancers were identified, which could be further investigated for future clinical study.

  19. Proteomics of ovarian cancer: functional insights and clinical applications

    DOE PAGES

    Elzek, Mohamed A.; Rodland, Karin D.

    2015-03-04

    In the past decade, there has been an increasing interest in applying proteomics to assist in understanding the pathogenesis of ovarian cancer, elucidating the mechanism of drug resistance, and in the development of biomarkers for early detection of ovarian cancer. Although ovarian cancer is a spectrum of different diseases, the strategies for diagnosis and treatment with surgery and adjuvant therapy are similar across ovarian cancer types, increasing the general applicability of discoveries made through proteomics research. While proteomic experiments face many difficulties which slow the pace of clinical applications, recent advances in proteomic technology contribute significantly to the identification ofmore » aberrant proteins and networks which can serve as targets for biomarker development and individualized therapies. This review provides a summary of the literature on proteomics’ contributions to ovarian cancer research and highlights the current issues, future directions, and challenges. In conclusion, we propose that protein-level characterization of primary lesion in ovarian cancer can decipher the mystery of this disease, improve diagnostic tools, and lead to more effective screening programs.« less

  20. PTN signaling: Components and mechanistic insights in human ovarian cancer.

    PubMed

    Sethi, Geetika; Kwon, Youngjoo; Burkhalter, Rebecca J; Pathak, Harsh B; Madan, Rashna; McHugh, Sarah; Atay, Safinur; Murthy, Smruthi; Tawfik, Ossama W; Godwin, Andrew K

    2015-12-01

    Molecular vulnerabilities represent promising candidates for the development of targeted therapies that hold the promise to overcome the challenges encountered with non-targeted chemotherapy for the treatment of ovarian cancer. Through a synthetic lethality screen, we previously identified pleiotrophin (PTN) as a molecular vulnerability in ovarian cancer and showed that siRNA-mediated PTN knockdown induced apoptotic cell death in epithelial ovarian cancer (EOC) cells. Although, it is well known that PTN elicits its pro-tumorigenic effects through its receptor, protein tyrosine phosphatase receptor Z1 (PTPRZ1), little is known about the potential importance of this pathway in the pathogenesis of ovarian cancer. In this study, we show that PTN is expressed, produced, and secreted in a panel of EOC cell lines. PTN levels in serous ovarian tumor tissues are on average 3.5-fold higher relative to normal tissue and PTN is detectable in serum samples of patients with EOC. PTPRZ1 is also expressed and produced by EOC cells and is found to be up-regulated in serous ovarian tumor tissue relative to normal ovarian surface epithelial tissue (P < 0.05). Gene silencing of PTPRZ1 in EOC cell lines using siRNA-mediated knockdown shows that PTPRZ1 is essential for viability and results in significant apoptosis with no effect on the cell cycle phase distribution. In order to determine how PTN mediates survival, we silenced the gene using siRNA mediated knockdown and performed expression profiling of 36 survival-related genes. Through computational mapping of the differentially expressed genes, members of the MAPK (mitogen-activated protein kinase) family were found to be likely effectors of PTN signaling in EOC cells. Our results provide the first experimental evidence that PTN and its signaling components may be of significance in the pathogenesis of epithelial ovarian cancer and provide a rationale for clinical evaluation of MAPK inhibitors in PTN and/or PTPRZ1 expressing ovarian

  1. PTN Signaling: Components and Mechanistic Insights in Human Ovarian Cancer

    PubMed Central

    Sethi, Geetika; Kwon, Youngjoo; Burkhalter, Rebecca J; Pathak, Harsh B.; Madan, Rashna; McHugh, Sarah; Atay, Safinur; Murthy, Smruthi; Tawfik, Ossama W.; Godwin, Andrew K.

    2015-01-01

    Molecular vulnerabilities represent promising candidates for the development of targeted therapies that hold the promise to overcome the challenges encountered with non-targeted chemotherapy for the treatment of ovarian cancer. Through a synthetic lethality screen, we previously identified pleiotrophin (PTN) as a molecular vulnerability in ovarian cancer and showed that siRNA mediated PTN knockdown induced apoptotic cell death in epithelial ovarian cancer (EOC) cells. Although it is well known that PTN elicits its pro-tumorigenic effects through its receptor, protein tyrosine phosphatase receptor Z1 (PTPRZ1), little is known about the potential importance of this pathway in the pathogenesis of ovarian cancer. In this study we show that PTN is expressed, produced, and secreted in a panel of EOC cell lines. PTN levels in serous ovarian tumor tissues are on average 3.5-fold higher relative to normal tissue and PTN is detectable in serum samples of patients with EOC. PTPRZ1 is also expressed and produced by EOC cells and is found to be up-regulated in serous ovarian tumor tissue relative to normal ovarian surface epithelial tissue (p<0.05). Gene silencing of PTPRZ1 in EOC cell lines using siRNA mediated knockdown shows that PTPRZ1 is essential for viability and results in significant apoptosis with no effect on the cell cycle phase distribution. In order to determine how PTN mediates survival, we silenced the gene using siRNA mediated knockdown and performed expression profiling of 36 survival-related genes. Through computational mapping of the differentially expressed genes, members of the MAPK (mitogen-activated protein kinase) family were found to be likely effectors of PTN signaling in EOC cells. Our results provide the first experimental evidence that PTN and its signaling components may be of significance in the pathogenesis of epithelial ovarian cancer and provide a rationale for clinical evaluation of MAPK inhibitors in PTN and/or PTPRZ1 expressing ovarian

  2. Hedgehog signaling pathway as a therapeutic target for ovarian cancer.

    PubMed

    Li, Haixia; Li, Jinghua; Feng, Limin

    2016-02-01

    Ovarian cancer is the most lethal cause of death among gynecological malignancies. Despite advancements in surgery and chemotherapy treatment strategies, the prognosis of ovarian cancer patients remains poor; a majority of patients relapse and eventually succumb to this disease. Therefore, novel therapeutic approaches to improve patient outcome are urgently needed. The hedgehog signaling pathway is vital for embryonic development and tissue homeostasis, and its deregulation is implicated in cancer cell growth, survival, differentiation, and metastasis. The critical role of hedgehog signaling in multiple biologic processes raises concerns about its potential therapeutic use in cancer. Consequently, many studies are focusing on hedgehog signaling as an attractive target in cancer treatment. In this review, we present an overview of the hedgehog pathway and its pathological aberrations in ovarian cancer. We also discuss inhibitors of the hedgehog signaling pathway that are currently being investigated in the laboratory and in early clinical trials; as well as the clinical challenges these inhibitors face.

  3. Drugs Approved for Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for ovarian cancer. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters. The drug names link to NCI's Cancer Drug Information summaries.

  4. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

    PubMed

    Ramus, Susan J; Antoniou, Antonis C; Kuchenbaecker, Karoline B; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Sinilnikova, Olga M; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A; Liljegren, Annelie; Lindblom, Annika; Olsson, Håkan; Kristoffersson, Ulf; Stenmark-Askmalm, Marie; Melin, Beatrice; Domchek, Susan M; Nathanson, Katherine L; Rebbeck, Timothy R; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Złowocka, Elżbieta; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Toloczko-Grabarek, Aleksandra; Osorio, Ana; Benitez, Javier; Duran, Mercedes; Tejada, Maria-Isabel; Hamann, Ute; Rookus, Matti; van Leeuwen, Flora E; Aalfs, Cora M; Meijers-Heijboer, Hanne E J; van Asperen, Christi J; van Roozendaal, K E P; Hoogerbrugge, Nicoline; Collée, J Margriet; Kriege, Mieke; van der Luijt, Rob B; Peock, Susan; Frost, Debra; Ellis, Steve D; Platte, Radka; Fineberg, Elena; Evans, D Gareth; Lalloo, Fiona; Jacobs, Chris; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Paterson, Joan; Douglas, Fiona; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J; Walker, Lisa; Porteous, Mary E; Kennedy, M John; Pathak, Harsh; Godwin, Andrew K; Stoppa-Lyonnet, Dominique; Caux-Moncoutier, Virginie; de Pauw, Antoine; Gauthier-Villars, Marion; Mazoyer, Sylvie; Léoné, Mélanie; Calender, Alain; Lasset, Christine; Bonadona, Valérie; Hardouin, Agnès; Berthet, Pascaline; Bignon, Yves-Jean; Uhrhammer, Nancy; Faivre, Laurence; Loustalot, Catherine; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy K; John, Esther M; Southey, Melissa; Goldgar, David; Singer, Christian F; Tea, Muy-Kheng; Pfeiler, Georg; Fink-Retter, Anneliese; Hansen, Thomas v O; Ejlertsen, Bent; Johannsson, Oskar Th; Offit, Kenneth; Kirchhoff, Tomas; Gaudet, Mia M; Vijai, Joseph; Robson, Mark; Piedmonte, Marion; Phillips, Kelly-Anne; Van Le, Linda; Hoffman, James S; Ewart Toland, Amanda; Montagna, Marco; Tognazzo, Silvia; Imyanitov, Evgeny; Issacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Iganacio; Tornero, Eva; Navarro, Matilde; Moysich, Kirsten B; Karlan, Beth Y; Gross, Jenny; Olah, Edith; Vaszko, Tibor; Teo, Soo-Hwang; Ganz, Patricia A; Beattie, Mary S; Dorfling, Cecelia M; van Rensburg, Elizabeth J; Diez, Orland; Kwong, Ava; Schmutzler, Rita K; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Heidemann, Simone; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Fiebig, Britta; Schäfer, Dieter; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Plante, Marie; Spurdle, Amanda B; Neuhausen, Susan L; Ding, Yuan Chun; Wang, Xianshu; Lindor, Noralane; Fredericksen, Zachary; Pankratz, V Shane; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Bonanni, Bernardo; Bernard, Loris; Dolcetti, Riccardo; Papi, Laura; Ottini, Laura; Radice, Paolo; Greene, Mark H; Mai, Phuong L; Andrulis, Irene L; Glendon, Gord; Ozcelik, Hilmi; Pharoah, Paul D P; Gayther, Simon A; Simard, Jacques; Easton, Douglas F; Couch, Fergus J; Chenevix-Trench, Georgia

    2012-04-01

    Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer. © 2012 Wiley Periodicals, Inc.

  5. Secretion of annexin A3 from ovarian cancer cells and its association with platinum resistance in ovarian cancer patients

    PubMed Central

    Yin, Jie; Yan, Xuedong; Yao, Xin; Zhang, Yongli; Shan, Ying; Mao, Ning; Yang, Yili; Pan, Lingya

    2012-01-01

    Abstract Early detection of resistance to platinum-based therapy is critical for improving the treatment of ovarian cancers. We have previously found that increased expression of annexin A3 is a mechanism for platinum resistance in ovarian cancer cells. Here we demonstrate that annexin A3 can be detected in the culture medium of ovarian cancer cells, particularly these cells that express high levels of annexin A3. Levels of annexin A3 were then determined in sera from ovarian cancer patients using an enzyme-linked immunosorbent assay. Compared with those from normal donors, sera from ovarian cancer patients contain significantly higher levels of annexin A3. Furthermore, serum levels of annexin A3 were significantly higher in platinum-resistant patients than in platinum-sensitive patients. To gain insight into the mechanism of secretion, the ovarian cancer cell lines were examined using both transmission electron microscopy and immunoelectron microscopy. Compared with parent cells, there are significantly more vesicles in the cytoplasm of ovarian cancer cells that express high levels of annexin A3, and at least some vesicles are annexin A3-positive. Moreover, some vesicles appear to be fused with the cell membrane, suggesting that annexin A3 secretion may be associated with exocytosis and the release of exosomes. This is supported by our observation that ovarian cancer cells expressing higher levels of annexin A3 released increased numbers of exosomes. Furthermore, annexin A3 can be detected in exosomes released from cisplatin-resistant cells (SKOV3/Cis) by immunoblotting and immunoelectron microscopy. PMID:21435174

  6. Task Force Reaffirms Recommendation against Ovarian Cancer Screening | Division of Cancer Prevention

    Cancer.gov

    Women at average risk of ovarian cancer should not be screened for the disease, the U.S. Preventive Services Task Force (USPSTF) has reaffirmed. Published in the Annals of Internal Medicine on September 11, the latest USPSTF clinical guideline does not apply to women who have symptoms of ovarian cancer or who have genetic mutations that increase their risk of ovarian cancer. |

  7. Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer

    PubMed Central

    Pagani, Olivia; Regan, Meredith M.; Walley, Barbara A.; Fleming, Gini F.; Colleoni, Marco; Láng, István; Gomez, Henry L.; Tondini, Carlo; Burstein, Harold J.; Perez, Edith A.; Ciruelos, Eva; Stearns, Vered; Bonnefoi, Hervé R.; Martino, Silvana; Geyer, Charles E.; Pinotti, Graziella; Puglisi, Fabio; Crivellari, Diana; Ruhstaller, Thomas; Winer, Eric P.; Rabaglio-Poretti, Manuela; Maibach, Rudolf; Ruepp, Barbara; Giobbie-Hurder, Anita; Price, Karen N.; Bernhard, Jürg; Luo, Weixiu; Ribi, Karin; Viale, Giuseppe; Coates, Alan S.; Gelber, Richard D.; Goldhirsch, Aron; Francis, Prudence A.

    2014-01-01

    BACKGROUND Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor–positive breast cancer. METHODS In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor–positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials. RESULTS After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane–ovarian suppression group and 87.3% in the tamoxifen–ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane–ovarian suppression group, as compared with 88.8% in the tamoxifen–ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane–ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P = 0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane–ovarian suppression group and 29.4% of those in the tamoxifen–ovarian suppression group, with profiles similar to those for postmenopausal women. CONCLUSIONS In premenopausal women with hormone-receptor–positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT Clinical

  8. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer.

    PubMed

    Pagani, Olivia; Regan, Meredith M; Walley, Barbara A; Fleming, Gini F; Colleoni, Marco; Láng, István; Gomez, Henry L; Tondini, Carlo; Burstein, Harold J; Perez, Edith A; Ciruelos, Eva; Stearns, Vered; Bonnefoi, Hervé R; Martino, Silvana; Geyer, Charles E; Pinotti, Graziella; Puglisi, Fabio; Crivellari, Diana; Ruhstaller, Thomas; Winer, Eric P; Rabaglio-Poretti, Manuela; Maibach, Rudolf; Ruepp, Barbara; Giobbie-Hurder, Anita; Price, Karen N; Bernhard, Jürg; Luo, Weixiu; Ribi, Karin; Viale, Giuseppe; Coates, Alan S; Gelber, Richard D; Goldhirsch, Aron; Francis, Prudence A

    2014-07-10

    Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor-positive breast cancer. In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor-positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials. After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane-ovarian suppression group and 87.3% in the tamoxifen-ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane-ovarian suppression group, as compared with 88.8% in the tamoxifen-ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane-ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P=0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane-ovarian suppression group and 29.4% of those in the tamoxifen-ovarian suppression group, with profiles similar to those for postmenopausal women. In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT ClinicalTrials.gov numbers, NCT00066703 and NCT00066690, respectively.).

  9. Complications from Surgeries Related to Ovarian Cancer Screening

    PubMed Central

    Baldwin, Lauren A.; Pavlik, Edward J.; Ueland, Emma; Brown, Hannah E.; Ladd, Kelsey M.; Huang, Bin; DeSimone, Christopher P.; van Nagell, John R.; Ueland, Frederick R.; Miller, Rachel W.

    2017-01-01

    The aim of this study was to evaluate complications of surgical intervention for participants in the Kentucky Ovarian Cancer Screening Program and compare results to those of the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial. A retrospective database review included 657 patients who underwent surgery for a positive screen in the Kentucky Ovarian Cancer Screening Program from 1988–2014. Data were abstracted from operative reports, discharge summaries, and office notes for 406 patients. Another 142 patients with incomplete records were interviewed by phone. Complete information was available for 548 patients. Complications were graded using the Clavien–Dindo (C–D) Classification of Surgical Complications and considered minor if assigned Grade I (any deviation from normal course, minor medications) or Grade II (other pharmacological treatment, blood transfusion). C–D Grade III complications (those requiring surgical, endoscopic, or radiologic intervention) and C–D Grade IV complications (those which are life threatening) were considered “major”. Statistical analysis was performed using SAS 9.4 software. Complications were documented in 54/548 (10%) subjects. For women with malignancy, 17/90 (19%) had complications compared to 37/458 (8%) with benign pathology (p < 0.003). For non-cancer surgery, obesity was associated with increased complications (p = 0.0028). Fifty patients had minor complications classified as C–D Grade II or less. Three of 4 patients with Grade IV complications had malignancy (p < 0.0004). In the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial, 212 women had surgery for ovarian malignancy, and 95 had at least one complication (45%). Of the 1080 women with non-cancer surgery, 163 had at least one complication (15%). Compared to the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial, the Kentucky Ovarian Cancer Screening Program had significantly fewer complications from both cancer and non-cancer

  10. Complications from Surgeries Related to Ovarian Cancer Screening.

    PubMed

    Baldwin, Lauren A; Pavlik, Edward J; Ueland, Emma; Brown, Hannah E; Ladd, Kelsey M; Huang, Bin; DeSimone, Christopher P; van Nagell, John R; Ueland, Frederick R; Miller, Rachel W

    2017-03-08

    The aim of this study was to evaluate complications of surgical intervention for participants in the Kentucky Ovarian Cancer Screening Program and compare results to those of the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial. A retrospective database review included 657 patients who underwent surgery for a positive screen in the Kentucky Ovarian Cancer Screening Program from 1988-2014. Data were abstracted from operative reports, discharge summaries, and office notes for 406 patients. Another 142 patients with incomplete records were interviewed by phone. Complete information was available for 548 patients. Complications were graded using the Clavien-Dindo (C-D) Classification of Surgical Complications and considered minor if assigned Grade I (any deviation from normal course, minor medications) or Grade II (other pharmacological treatment, blood transfusion). C-D Grade III complications (those requiring surgical, endoscopic, or radiologic intervention) and C-D Grade IV complications (those which are life threatening) were considered "major". Statistical analysis was performed using SAS 9.4 software. Complications were documented in 54/548 (10%) subjects. For women with malignancy, 17/90 (19%) had complications compared to 37/458 (8%) with benign pathology (p < 0.003). For non-cancer surgery, obesity was associated with increased complications (p = 0.0028). Fifty patients had minor complications classified as C-D Grade II or less. Three of 4 patients with Grade IV complications had malignancy (p < 0.0004). In the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial, 212 women had surgery for ovarian malignancy, and 95 had at least one complication (45%). Of the 1080 women with non-cancer surgery, 163 had at least one complication (15%). Compared to the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial, the Kentucky Ovarian Cancer Screening Program had significantly fewer complications from both cancer and non-cancer surgery (p

  11. Opportunities and challenges in ovarian cancer research, a perspective from the 11th Ovarian cancer action/HHMT Forum, Lake Como, March 2007.

    PubMed

    Ashworth, Alan; Balkwill, Frances; Bast, Robert C; Berek, Jonathan S; Kaye, Allyson; Boyd, Jeffrey A; Mills, Gordon; Weinstein, John N; Woolley, Katie; Workman, Paul

    2008-03-01

    Advances in surgery and chemotherapy have improved the 5-year survival for patients with epithelial ovarian cancer, but have not impacted on the ultimate rate of cure in a disease that is diagnosed in late stage and that recurs in the majority of patients. "Omic" technologies promise to define genetically driven aberrant signaling pathways in malignant cells, provided that bioinformatic expertise can be focused on a cancer that is neither common nor rare. Molecular therapeutics must be linked to molecular diagnostics to permit individualized therapy. Not only epithelial cancer cells but also stroma, vasculature and the immune response must be targeted. Closer collaboration between academic institutions, biotech and pharma will be required to facilitate this process and to interest the private sector in an orphan disease. New preclinical models may permit more efficient development of drugs and siRNA that can target dormant drug resistant stem cells. Strategies must be developed to deal with the heterogeneity of different grades and histotypes. Identification of women at increased risk will facilitate prevention and early detection in subsets of patients. BRCA1/2 might be sequenced in all ovarian cancer patients to identify new kindreds. Epidemiologic algorithms are being developed and validated. Awareness must be raised that oral contraceptives can reduce risk of developing ovarian cancer by 50%. Early detection is likely to require panels of complementary biomarkers, analyzed by sophisticated statistical techniques, to improve sensitivity while maintaining extremely high specificity. As ovarian cancer becomes a chronic disease, greater emphasis will be placed on the challenges facing survivors.

  12. Reliable in vitro studies require appropriate ovarian cancer cell lines

    PubMed Central

    2014-01-01

    Ovarian cancer is the fifth most common cause of cancer death in women and the leading cause of death from gynaecological malignancies. Of the 75% women diagnosed with locally advanced or disseminated disease, only 30% will survive five years following treatment. This poor prognosis is due to the following reasons: limited understanding of the tumor origin, unclear initiating events and early developmental stages of ovarian cancer, lack of reliable ovarian cancer-specific biomarkers, and drug resistance in advanced cases. In the past, in vitro studies using cell line models have been an invaluable tool for basic, discovery-driven cancer research. However, numerous issues including misidentification and cross-contamination of cell lines have hindered research efforts. In this study we examined all ovarian cancer cell lines available from cell banks. Hereby, we identified inconsistencies in the reporting, difficulties in the identification of cell origin or clinical data of the donor patients, restricted ethnic and histological type representation, and a lack of tubal and peritoneal cancer cell lines. We recommend that all cell lines should be distributed via official cell banks only with strict guidelines regarding the minimal available information required to improve the quality of ovarian cancer research in future. PMID:24936210

  13. Estrogen signaling crosstalk: implications for endocrine resistance in ovarian cancer

    PubMed Central

    Ribeiro, Jennifer R.; Freiman, Richard N.

    2014-01-01

    Resistance to anti-estrogen therapies is a prominent challenge in the treatment of ovarian cancer. Tumors develop endocrine resistance by acquiring adaptations that help them rely on alternative oncogenic signaling cascades, which crosstalk with estrogen signaling pathways. An understanding of estrogen signaling crosstalk with these growth promoting cascades is essential in order to maximize efficacy of anti-estrogen treatments in ovarian cancer. Herein, we provide an overview of estrogen signaling in ovarian cancer and discuss the major challenges associated with anti-estrogen therapies. We also review what is currently known about how genomic and non-genomic estrogen signaling pathways crosstalk with several major oncogenic signaling cascades. The insights provided here illustrate existing strategies for targeting endocrine resistant ovarian tumors and may help identify new strategies to improve the treatment of this disease. PMID:24565562

  14. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group.

    PubMed

    Whittemore, A S; Harris, R; Itnyre, J

    1992-11-15

    Data collected from 2,197 white ovarian cancer patients and 8,893 white controls in 12 US case-control studies conducted in the period 1956-1986 were used to evaluate the relation of invasive epithelial ovarian cancer to reproductive and menstrual characteristics, exogenous estrogen use, and prior pelvic surgeries. Clear trends of decreasing risk were evident with increasing number of pregnancies (regardless of outcome) and increasing duration of breast feeding and oral contraceptive use. Ovarian dysfunction leading to both infertility and malignancy is an unlikely explanation for these trends for several reasons: 1) The trends were evident even among the highly parous; 2) risk among nulliparous women did not vary by marital status or gravidity; and 3) risk among ever-married women showed little relation to length of longest pregnancy attempt or history of clinically diagnosed infertility. Risk was increased among women who had used fertility drugs and among women with long total duration of premenopausal sexual activity without birth control; these associations were particularly strong among the nulligravid. No consistent trends in risk were seen with age at menarche, age at menopause, or duration of estrogen replacement therapy. A history of tubal ligation or of hysterectomy with ovarian conservation was associated with reduced ovarian cancer risk. These observations suggest that pregnancy, breast feeding, and oral contraceptive use induce biological changes that protect against ovarian malignancy, that, at most, a small fraction of the excess ovarian cancer risk among nulliparous women is due to infertility, and that any increased risk associated with infertility may be due to the use of fertility drugs.

  15. Apoptotic effects of salinomycin on human ovarian cancer cell line (OVCAR-3).

    PubMed

    Kaplan, Fuat; Teksen, Fulya

    2016-03-01

    In this study, we studied the apoptotic and cytotoxic effects of salinomycin on human ovarian cancer cell line (OVCAR-3) as salinomycin is known as a selectively cancer stem cell killer agent. We used immortal human ovarian epithelial cell line (IHOEC) as control group. Ovarian cancer cells and ovarian epithelial cells were treated by different concentrations of salinomycin such as 0.1, 1, and 40 μM and incubated for 24, 48, and 72 h. Dimethylthiazol (MTT) cell viability assay was performed to determine cell viability and toxicity. On the other hand, the expression levels of some of the apoptosis-related genes, namely anti-apoptotic Bcl-2, apoptotic Bax, and Caspase-3 were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, Caspase-3 protein level was also determined. As a result, we concluded that incubation of human OVCAR-3 by 0.1 μM concentration of salinomycin for 24 h killed 40 % of the cancer cells by activating apoptosis but had no effect on normal cells. The apoptotic Bax gene expression was upregulated but anti-apoptotic Bcl-2 gene expression was downregulated. Active Caspase-3 protein level was increased significantly (p < 0.05).

  16. Ruxolitinib Phosphate, Paclitaxel, and Carboplatin in Treating Patients With Stage III-IV Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2017-01-20

    Fallopian Tube Carcinosarcoma; Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Serous Neoplasm; High Grade Ovarian Serous Adenocarcinoma; Ovarian Carcinosarcoma; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Primary Peritoneal Serous Adenocarcinoma; Stage III Fallopian Tube Cancer; Stage III Ovarian Cancer; Stage III Primary Peritoneal Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  17. Glycomics Laboratory for the Early Detection of Epithelial Ovarian Cancer | Division of Cancer Prevention

    Cancer.gov

    DESCRIPTION (provided by applicant): Ovarian cancer is a silent killer with few early symptoms and advanced disease present at the time of diagnosis. This cancer is the most lethal of all gynecologic malignancies with over 20,000 new cases diagnosed each year. The 5 year survival rates for ovarian cancer dramatically improve when the disease is diagnosed at an early stage. |

  18. Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: Results from three US population-based case-control studies of ovarian cancer

    SciTech Connect

    Whittemore, A.S.; Gong, G.; Itnyre, J.

    1997-03-01

    We investigate the familial risks of cancers of the breast and ovary, using data pooled from three population-based case-control studies of ovarian cancer that were conducted in the United States. We base estimates of the frequency of mutations of BRCA1 (and possibly other genes) on the reported occurrence of breast cancer and ovarian cancer in the mothers and sisters of 922 women with incident ovarian cancer (cases) and in 922 women with no history of ovarian cancer (controls). Segregation analysis and goodness-of-fit testing of genetic models suggest that rare mutations (frequency .0014; 95% confidence interval .0002-.011) account for all the observed aggregation of breast cancer and ovarian cancer in these families. The estimated risk of breast cancer by age 80 years is 73.5% in mutation carriers and 6.8% in noncarriers. The corresponding estimates for ovarian cancer are 27.8% in carriers and 1.8% in noncarriers. For cancer risk in carriers, these estimates are lower than those obtained from families selected for high cancer prevalence. The estimated proportion of all U.S. cancer diagnoses, by age 80 years, that are due to germ-line BRCA1 mutations is 3.0% for breast cancer and 4.4% for ovarian cancer. Aggregation of breast cancer and ovarian cancer was less evident in the families of 169 cases with borderline ovarian cancers than in the families of cases with invasive cancers. Familial aggregation did not differ by the ethnicity of the probands, although the number of non-White and Hispanic cases (N = 99) was sparse. 14 refs., 3 figs., 6 tabs.

  19. Ovarian Cancer Proteomic, Phosphoproteomic, and Glycoproteomic Data Released - Office of Cancer Clinical Proteomics Research

    Cancer.gov

    National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC) scientists have just released a comprehensive dataset of the proteomic analysis of high grade serous ovarian tumor samples,

  20. Suppression of ABHD2, identified through a functional genomics screen, causes anoikis resistance, chemoresistance and poor prognosis in ovarian cancer

    PubMed Central

    Yamanoi, Koji; Matsumura, Noriomi; Murphy, Susan K.; Baba, Tsukasa; Abiko, Kaoru; Hamanishi, Junzo; Yamaguchi, Ken; Koshiyama, Masafumi; Konishi, Ikuo; Mandai, Masaki

    2016-01-01

    Anoikis resistance is a hallmark of cancer, and relates to malignant phenotypes, including chemoresistance, cancer stem like phenotypes and dissemination. The aim of this study was to identify key factors contributing to anoikis resistance in ovarian cancer using a functional genomics screen. A library of 81 000 shRNAs targeting 15 000 genes was transduced into OVCA420 cells, followed by incubation in soft agar and colony selection. We found shRNAs directed to ABHD2, ELAC2 and CYB5R3 caused reproducible anoikis resistance. These three genes are deleted in many serous ovarian cancers according to The Cancer Genome Atlas data. Suppression of ABHD2 in OVCA420 cells increased phosphorylated p38 and ERK, platinum resistance, and side population cells (p<0.01, respectively). Conversely, overexpression of ABHD2 decreased resistance to anoikis (p<0.05) and the amount of phosphorylated p38 and ERK in OVCA420 and SKOV3 cells. In clinical serous ovarian cancer specimens, low expression of ABHD2 was associated with platinum resistance and poor prognosis (p<0.05, respectively). In conclusion, we found three novel genes relevant to anoikis resistance in ovarian cancer using a functional genomics screen. Suppression of ABHD2 may promote a malignant phenotype and poor prognosis for women with serous ovarian cancer. PMID:27323405

  1. 3 CFR 8853 - Proclamation 8853 of August 31, 2012. National Ovarian Cancer Awareness Month, 2012

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... family history of ovarian or breast cancer, or who have had certain cancers in the past are at increased... Ovarian Cancer Awareness Month, 2012 8853 Proclamation 8853 Presidential Documents Proclamations Proclamation 8853 of August 31, 2012 Proc. 8853 National Ovarian Cancer Awareness Month, 2012By the...

  2. 3 CFR 8551 - Proclamation 8551 of August 31, 2010. National Ovarian Cancer Awareness Month, 2010

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... history of ovarian cancer or breast cancer, and those over age 55—to protect their health by understanding... Ovarian Cancer Awareness Month, 2010 8551 Proclamation 8551 Presidential Documents Proclamations Proclamation 8551 of August 31, 2010 Proc. 8551 National Ovarian Cancer Awareness Month, 2010By the...

  3. Ovarian cancer: density equalizing mapping of the global research architecture.

    PubMed

    Brüggmann, Dörthe; Pulch, Katharina; Klingelhöfer, Doris; Pearce, Celeste Leigh; Groneberg, David A

    2017-01-13

    Despite its impact on female health worldwide, no efforts have been made to depict the global architecture of ovarian cancer research and to understand the trends in the related literature. Hence, it was the objective of this study to assess the global scientific performance chronologically, geographically and in regards to economic benchmarks using bibliometric tools and density equalizing map projections. The NewQIS platform was employed to identify all ovarian cancer related articles published in the Web of Science since 1900. The items were analyzed regarding quantitative aspects (e.g. publication date, country of origin) and parameters describing the recognition of the work by the scientific community (e.g. citation rates). 23,378 articles on ovarian cancer were analyzed. The USA had the highest activity of ovarian cancer research with a total of n = 9312 ovarian cancer-specific publications, followed by the UK (n = 1900), China (n = 1813), Germany (n = 1717) and Japan (n = 1673). Ovarian cancer-specific country h-index also showed a leading position of the USA with an h-index (HI) of 207, followed by the UK (HI = 122), Canada (HI = 99), Italy (HI = 97), Germany (HI = 84), and Japan (HI = 81). In the socio-economic analysis, the USA were ranked first with an average of 175.6 ovarian cancer-related publications per GDP per capita in 1000 US-$, followed by Italy with an index level of 46.85, the UK with 45.48, and Japan with 43.3. Overall, the USA and Western European nations, China and Japan constituted the scientific power players publishing the majority of highly cited ovarian cancer-related articles and dominated international collaborative efforts. African, Asian and South American countries played almost no visible role in the scientific community. The quantity and scientific recognition of publications related to ovarian cancer are continuously increasing. The research endeavors in the field are concentrated in high-income countries

  4. Epigenetics in cancer stem cells.

    PubMed

    Toh, Tan Boon; Lim, Jhin Jieh; Chow, Edward Kai-Hua

    2017-02-01

    Compelling evidence have demonstrated that bulk tumors can arise from a unique subset of cells commonly termed "cancer stem cells" that has been proposed to be a strong driving force of tumorigenesis and a key mechanism of therapeutic resistance. Recent advances in epigenomics have illuminated key mechanisms by which epigenetic regulation contribute to cancer progression. In this review, we present a discussion of how deregulation of various epigenetic pathways can contribute to cancer initiation and tumorigenesis, particularly with respect to maintenance and survival of cancer stem cells. This information, together with several promising clinical and preclinical trials of epigenetic modulating drugs, offer new possibilities for targeting cancer stem cells as well as improving cancer therapy overall.

  5. Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study

    PubMed Central

    Lee, Alice W.; Tyrer, Jonathan P.; Doherty, Jennifer A.; Stram, Douglas A.; Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Spiewankiewicz, Beata; Myers, Emily J.; Chenevix-Trench, Georgia; Fasching, Peter A.; Beckmann, Matthias W.; Ekici, Arif B.; Hein, Alexander; Vergote, Ignace; Van Nieuwenhuysen, Els; Lambrechts, Diether; Wicklund, Kristine G.; Eilber, Ursula; Wang-Gohrke, Shan; Chang-Claude, Jenny; Rudolph, Anja; Sucheston-Campbell, Lara; Odunsi, Kunle; Moysich, Kirsten B.; Shvetsov, Yurii B.; Thompson, Pamela J.; Goodman, Marc T.; Wilkens, Lynne R.; Dörk, Thilo; Hillemanns, Peter; Dürst, Matthias; Runnebaum, Ingo B.; Bogdanova, Natalia; Pelttari, Liisa M.; Nevanlinna, Heli; Leminen, Arto; Edwards, Robert P.; Kelley, Joseph L.; Harter, Philipp; Schwaab, Ira; Heitz, Florian; du Bois, Andreas; Orsulic, Sandra; Lester, Jenny; Walsh, Christine; Karlan, Beth Y.; Hogdall, Estrid; Kjaer, Susanne K.; Jensen, Allan; Vierkant, Robert A.; Cunningham, Julie M.; Goode, Ellen L.; Fridley, Brooke L.; Southey, Melissa C.; Giles, Graham G.; Bruinsma, Fiona; Wu, Xifeng; Hildebrandt, Michelle A.T.; Lu, Karen; Liang, Dong; Bisogna, Maria; Levine, Douglas A.; Weber, Rachel Palmieri; Schildkraut, Joellen M.; Iversen, Edwin S.; Berchuck, Andrew; Terry, Kathryn L.; Cramer, Daniel W.; Tworoger, Shelley S.; Poole, Elizabeth M.; Olson, Sara H.; Orlow, Irene; Bandera, Elisa V.; Bjorge, Line; Tangen, Ingvild L.; Salvesen, Helga B.; Krakstad, Camilla; Massuger, Leon F.A.G.; Kiemeney, Lambertus A.; Aben, Katja K.H.; van Altena, Anne M.; Bean, Yukie; Pejovic, Tanja; Kellar, Melissa; Le, Nhu D.; Cook, Linda S.; Kelemen, Linda E.; Brooks-Wilson, Angela; Lubinski, Jan; Gronwald, Jacek; Cybulski, Cezary; Jakubowska, Anna; Wentzensen, Nicolas; Brinton, Louise A.; Lissowska, Jolanta; Yang, Hannah; Nedergaard, Lotte; Lundvall, Lene; Hogdall, Claus; Song, Honglin; Campbell, Ian G.; Eccles, Diana; Glasspool, Rosalind; Siddiqui, Nadeem; Carty, Karen; Paul, James; McNeish, Iain A.; Sieh, Weiva; McGuire, Valerie; Rothstein, Joseph H.; Whittemore, Alice S.; McLaughlin, John R.; Risch, Harvey A.; Phelan, Catherine M.; Anton-Culver, Hoda; Ziogas, Argyrios; Menon, Usha; Ramus, Susan J.; Gentry-Maharaj, Aleksandra; Harrington, Patricia; Pike, Malcolm C.; Modugno, Francesmary; Rossing, Mary Anne; Ness, Roberta B.; Pharoah, Paul D.P.; Stram, Daniel O.; Wu, Anna H.; Pearce, Celeste Leigh

    2016-01-01

    Objective Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. Methods Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. Results We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p = 0.045, mucinous), LHCGR (p = 0.046, high-grade serous), GNRH (p = 0.041, high-grade serous), and FSHB (p = 0.036, overall invasive). There was also suggestive evidence for INHA (p = 0.060, overall invasive). Conclusions Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available. PMID:25528498

  6. Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study.

    PubMed

    Lee, Alice W; Tyrer, Jonathan P; Doherty, Jennifer A; Stram, Douglas A; Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Spiewankiewicz, Beata; Myers, Emily J; Chenevix-Trench, Georgia; Fasching, Peter A; Beckmann, Matthias W; Ekici, Arif B; Hein, Alexander; Vergote, Ignace; Van Nieuwenhuysen, Els; Lambrechts, Diether; Wicklund, Kristine G; Eilber, Ursula; Wang-Gohrke, Shan; Chang-Claude, Jenny; Rudolph, Anja; Sucheston-Campbell, Lara; Odunsi, Kunle; Moysich, Kirsten B; Shvetsov, Yurii B; Thompson, Pamela J; Goodman, Marc T; Wilkens, Lynne R; Dörk, Thilo; Hillemanns, Peter; Dürst, Matthias; Runnebaum, Ingo B; Bogdanova, Natalia; Pelttari, Liisa M; Nevanlinna, Heli; Leminen, Arto; Edwards, Robert P; Kelley, Joseph L; Harter, Philipp; Schwaab, Ira; Heitz, Florian; du Bois, Andreas; Orsulic, Sandra; Lester, Jenny; Walsh, Christine; Karlan, Beth Y; Hogdall, Estrid; Kjaer, Susanne K; Jensen, Allan; Vierkant, Robert A; Cunningham, Julie M; Goode, Ellen L; Fridley, Brooke L; Southey, Melissa C; Giles, Graham G; Bruinsma, Fiona; Wu, Xifeng; Hildebrandt, Michelle A T; Lu, Karen; Liang, Dong; Bisogna, Maria; Levine, Douglas A; Weber, Rachel Palmieri; Schildkraut, Joellen M; Iversen, Edwin S; Berchuck, Andrew; Terry, Kathryn L; Cramer, Daniel W; Tworoger, Shelley S; Poole, Elizabeth M; Olson, Sara H; Orlow, Irene; Bandera, Elisa V; Bjorge, Line; Tangen, Ingvild L; Salvesen, Helga B; Krakstad, Camilla; Massuger, Leon F A G; Kiemeney, Lambertus A; Aben, Katja K H; van Altena, Anne M; Bean, Yukie; Pejovic, Tanja; Kellar, Melissa; Le, Nhu D; Cook, Linda S; Kelemen, Linda E; Brooks-Wilson, Angela; Lubinski, Jan; Gronwald, Jacek; Cybulski, Cezary; Jakubowska, Anna; Wentzensen, Nicolas; Brinton, Louise A; Lissowska, Jolanta; Yang, Hannah; Nedergaard, Lotte; Lundvall, Lene; Hogdall, Claus; Song, Honglin; Campbell, Ian G; Eccles, Diana; Glasspool, Rosalind; Siddiqui, Nadeem; Carty, Karen; Paul, James; McNeish, Iain A; Sieh, Weiva; McGuire, Valerie; Rothstein, Joseph H; Whittemore, Alice S; McLaughlin, John R; Risch, Harvey A; Phelan, Catherine M; Anton-Culver, Hoda; Ziogas, Argyrios; Menon, Usha; Ramus, Susan J; Gentry-Maharaj, Aleksandra; Harrington, Patricia; Pike, Malcolm C; Modugno, Francesmary; Rossing, Mary Anne; Ness, Roberta B; Pharoah, Paul D P; Stram, Daniel O; Wu, Anna H; Pearce, Celeste Leigh

    2015-03-01

    Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive). Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Cellular therapy for ovarian cancer: experimental and clinical perspectives.

    PubMed

    Ingersoll, Susan B; Ahmad, Sarfraz; Finkler, Neil J; Edwards, John R; Holloway, Robert W

    2012-01-01

    Ovarian cancer is the leading cause of death among gynecologic malignancies and the 5th leading cause of cancer deaths for women in the United States. Two-thirds of patients present with advanced-stage disease (Stage III and IV) and the majority will suffer recurrence of disease, require ongoing treatment, and eventually succumb to chemotherapy-resistant disease. To potentially circumvent chemo-resistance in recurrent ovarian cancer, immunotherapy is being explored as a novel treatment option. Our laboratory findings demonstrate that immune effector cells from healthy donors elicit a significant cytotoxic response in the presence of IL-2 and IFN alpha- 2b against ovarian cancer in vitro; however, peripheral blood mononuclear cells (PBMC) isolated from ovarian cancer patients fail to elicit a similar response. A major obstacle to immunotherapy is the immunosuppressive environment supported by tumors, which limits the immune system's ability to fight the tumor. Myeloid-derived suppressor cells are an immature population of myeloid cells, which have recently been implicated to play a major role in immunosuppression and tumor evasion. In addition to novel immunotherapies, new diagnostic and prognostic markers are being identified through applying molecular tools/approaches in clinical and pathological analyses of this malignancy, which will provide additional therapeutic targets. To test these experimental therapeutic options, pre-clinical murine models of ovarian cancer are being developed. Ultimately, treatment of ovarian cancer will benefit from the careful alignment of appropriate target, drug, patient, and trial design. This article provides an objective overview of cellular therapy (the use of immune cells to elicit an anti-tumor response) for ovarian cancer highlighting both experimental and clinical perspectives.

  8. Targeting glutamine metabolism and the focal adhesion kinase additively inhibits the mammalian target of the rapamycin pathway in spheroid cancer stem-like properties of ovarian clear cell carcinoma in vitro.

    PubMed

    Sato, Masakazu; Kawana, Kei; Adachi, Katsuyuki; Fujimoto, Asaha; Yoshida, Mitsuyo; Nakamura, Hiroe; Nishida, Haruka; Inoue, Tomoko; Taguchi, Ayumi; Ogishima, Juri; Eguchi, Satoko; Yamashita, Aki; Tomio, Kensuke; Wada-Hiraike, Osamu; Oda, Katsutoshi; Nagamatsu, Takeshi; Osuga, Yutaka; Fujii, Tomoyuki

    2017-04-01

    Ovarian cancer is one of the leading causes of death in the world, which is linked to its resistance to chemotherapy. Strategies to overcome chemoresistance have been keenly investigated. Culturing cancer cells in suspension, which results in formation of spheroids, is a more accurate reflection of clinical cancer behavior in vitro than conventional adherent cultures. By performing RNA-seq analysis, we found that the focal adhesion pathway was essential in spheroids. The phosphorylation of focal adhesion kinase (FAK) was increased in spheroids compared to adherent cells, and inhibition of FAK in spheroids resulted in inhibition of the downstream mammalian target of the rapamycin (mTOR) pathway in ovarian clear cell carcinomas. This result also suggested that only using a FAK inhibitor might have limitations because the phosphorylation level of FAK could not be reduced to the level in adherent cells, and it appeared that some combination therapies might be necessary. We previously reported that glutamine and glutamate concentrations were higher in spheroids than adherent cells, and we investigated a synergistic effect targeting glutamine metabolism with FAK inhibition on the mTOR pathway. The combination of AOA, a pan-transaminase inhibitor, and PF 573228, a FAK inhibitor, additively inhibited the mTOR pathway in spheroids from ovarian clear cell carcinomas. Our in vitro study proposed a rationale for the positive and negative effects of using FAK inhibitors in ovarian clear cell carcinomas and suggested that targeting glutamine metabolism could overcome the limitation of FAK inhibitors by additively inhibiting the mTOR pathway.

  9. Low-grade serous ovarian cancer: A review.

    PubMed

    Kaldawy, Anis; Segev, Yakir; Lavie, Ofer; Auslender, Ron; Sopik, Victoria; Narod, Steven A

    2016-11-01

    Epithelial ovarian cancers can be divided into the more common, aggressive type II cancers and the less common, slow-growing type I cancers. Under this model, serous ovarian carcinomas can be subdivided into high-grade (type II) and low-grade (type I) tumours. The two-tier system for grading serous ovarian carcinomas is superior to more detailed grading systems in terms of predicting survival. Low-grade serous carcinomas typically present in young women and have a relatively good prognosis, despite being resistant to chemotherapy. Low-grade serous cancers have a high prevalence of KRAS and BRAF mutations, but a low prevalence of TP53 mutations (which are characteristic of high-grade serous cancers). Among women with low-grade serous ovarian cancer, the presence of a KRAS/BRAF mutation is a favorable prognostic factor. Studies of the mitogen-activated protein kinase (MAPK) inhibitor in low-grade serous ovarian cancer suggest that identifying MAPK mutations might eventually be useful in guiding treatment.

  10. Senescent peritoneal mesothelium creates a niche for ovarian cancer metastases

    PubMed Central

    Mikuła-Pietrasik, Justyna; Uruski, Paweł; Sosińska, Patrycja; Maksin, Konstantin; Piotrowska-Kempisty, Hanna; Kucińska, Małgorzata; Murias, Marek; Szubert, Sebastian; Woźniak, Aldona; Szpurek, Dariusz; Sajdak, Stefan; Piwocka, Katarzyna; Tykarski, Andrzej; Książek, Krzysztof

    2016-01-01

    Although both incidence and aggressiveness of ovarian malignancy rise with age, the exact reason for this tendency, in particular the contribution of senescent cells, remains elusive. In this project we found that the patient's age determines the frequency of intraperitoneal metastases of ovarian cancer. Moreover, we documented that senescent human peritoneal mesothelial cells (HPMCs) stimulate proliferation, migration and invasion of ovarian cancer cells in vitro, and that this effect is related to both the activity of soluble agents released to the environment by these cells and direct cell-cell contact. The panel of mediators of the pro-cancerous activity of senescent HPMCs appeared to be cancer cell line-specific. The growth of tumors in a mouse peritoneal cavity was intensified when the cancer cells were co-injected together with senescent HPMCs. This effect was reversible when the senescence of HPMCs was slowed down by the neutralization of p38 MAPK. The analysis of lesions excised from the peritoneum of patients with ovarian cancer showed the abundance of senescent HPMCs in close proximity to the cancerous tissue. Collectively, our findings indicate that senescent HPMCs which accumulate in the peritoneum in vivo may create a metastatic niche facilitating intraperitoneal expansion of ovarian malignancy. PMID:28032864

  11. Geranylgeranylacetone inhibits ovarian cancer progression in vitro and in vivo

    SciTech Connect

    Hashimoto, Kae; Morishige, Ken-ichirou . E-mail: mken@gyne.med.osaka-u.ac.jp; Sawada, Kenjiro; Ogata, Seiji; Tahara, Masahiro; Shimizu, Shoko; Sakata, Masahiro; Tasaka, Keiichi; Kimura, Tadashi

    2007-04-27

    Geranylgeranylacetone (GGA), an isoprenoid compound, is an anti-ulcer drug developed in Japan. In our previous study, GGA was shown to inhibit ovarian cancer invasion by attenuating Rho activation [K. Hashimoto, K. Morishige, K. Sawada, M. Tahara, S. Shimizu, M. Sakata, K. Tasaka, Y. Murata, Geranylgeranylacetone inhibits lysophosphatidic acid-induced invasion of human ovarian carcinoma cells in vitro. Cancer 103 (2005) 1529-1536.]. In the present study, GGA treatment inhibited ovarian cancer progression in vitro and suppressed the tumor growth and ascites in the in vivo ovarian cancer model. In vitro analysis, treatment of cancer cells by GGA resulted in the inhibition of cancer cell proliferation, the inactivation of Ras, and the suppression of tyrosine phosphorylation of mitogen-activated protein kinase (MAPK). In conclusion, this is the first report that GGA inhibited ovarian cancer progression and the anti-tumor effect by GGA is, at least in part, derived not only from the suppression of Rho activation but also Ras-MAPK activation.

  12. Geranylgeranylacetone inhibits ovarian cancer progression in vitro and in vivo.

    PubMed

    Hashimoto, Kae; Morishige, Ken-ichirou; Sawada, Kenjiro; Ogata, Seiji; Tahara, Masahiro; Shimizu, Shoko; Sakata, Masahiro; Tasaka, Keiichi; Kimura, Tadashi

    2007-04-27

    Geranylgeranylacetone (GGA), an isoprenoid compound, is an anti-ulcer drug developed in Japan. In our previous study, GGA was shown to inhibit ovarian cancer invasion by attenuating Rho activation [K. Hashimoto, K. Morishige, K. Sawada, M. Tahara, S. Shimizu, M. Sakata, K. Tasaka, Y. Murata, Geranylgeranylacetone inhibits lysophosphatidic acid-induced invasion of human ovarian carcinoma cells in vitro. Cancer 103 (2005) 1529-1536.]. In the present study, GGA treatment inhibited ovarian cancer progression in vitro and suppressed the tumor growth and ascites in the in vivo ovarian cancer model. In vitro analysis, treatment of cancer cells by GGA resulted in the inhibition of cancer cell proliferation, the inactivation of Ras, and the suppression of tyrosine phosphorylation of mitogen-activated protein kinase (MAPK). In conclusion, this is the first report that GGA inhibited ovarian cancer progression and the anti-tumor effect by GGA is, at least in part, derived not only from the suppression of Rho activation but also Ras-MAPK activation.

  13. Targeting c-MYC in Platinum-Resistant Ovarian Cancer.

    PubMed

    Reyes-González, Jeyshka M; Armaiz-Peña, Guillermo N; Mangala, Lingegowda S; Valiyeva, Fatma; Ivan, Cristina; Pradeep, Sunila; Echevarría-Vargas, Ileabett M; Rivera-Reyes, Adrian; Sood, Anil K; Vivas-Mejía, Pablo E

    2015-10-01

    The purpose of this study was to investigate the molecular and therapeutic effects of siRNA-mediated c-MYC silencing in cisplatin-resistant ovarian cancer. Statistical analysis of patient's data extracted from The Cancer Genome Atlas (TCGA) portal showed that the disease-free (DFS) and the overall (OS) survival were decreased in ovarian cancer patients with high c-MYC mRNA levels. Furthermore, analysis of a panel of ovarian cancer cell lines showed that c-MYC protein levels were higher in cisplatin-resistant cells when compared with their cisplatin-sensitive counterparts. In vitro cell viability, growth, cell-cycle progression, and apoptosis, as well as in vivo therapeutic effectiveness in murine xenograft models, were also assessed following siRNA-mediated c-MYC silencing in cisplatin-resistant ovarian cancer cells. Significant inhibition of cell growth and viability, cell-cycle arrest, and activation of apoptosis were observed upon siRNA-mediated c-MYC depletion. In addition, single weekly doses of c-MYC-siRNA incorporated into 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG-2000)-based nanoliposomes resulted in significant reduction in tumor growth. These findings identify c-MYC as a potential therapeutic target for ovarian cancers expressing high levels of this oncoprotein. ©2015 American Association for Cancer Research.

  14. Vaccine Therapy With Sargramostim (GM-CSF) in Treating Patients With Her-2 Positive Stage III-IV Breast Cancer or Ovarian Cancer

    ClinicalTrials.gov

    2016-05-02

    HER2-positive Breast Cancer; Stage III Ovarian Epithelial Cancer; Stage III Ovarian Germ Cell Tumor; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor

  15. Regulatory considerations on endpoints in ovarian cancer drug development.

    PubMed

    Balasubramaniam, Sanjeeve; Kim, Geoffrey S; McKee, Amy E; Pazdur, Richard

    2017-07-15

    Ovarian cancer remains a disease entity that is responsible for considerable morbidity and mortality among women worldwide. Modern drug research pipelines and accelerated drug development timelines applied to other disease entities have begun to make an impact on treatment options for patients with advanced ovarian cancer, as exemplified by the recent accelerated approval of 2 agents for this disease as the forerunners of a growing number of registrational trials. Regulatory flexibility for this serious and life-threatening condition spurs the consideration of intermediate endpoints for regulatory trial design, including potential applications in the development of newer therapeutic classes such as targeted therapies and immunotherapies for patients with advanced ovarian cancer. Cancer 2017;123:2604-8. © 2017 American Cancer Society. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

  16. Targeting prostate cancer stem cells.

    PubMed

    Crea, Francesco; Mathews, Lesley A; Farrar, William L; Hurt, Elaine M

    2009-12-01

    Cancer stem cells are the sub-population of cells present within tumors responsible for tumorigenesis. These cells have unique biological properties including self-renewal and the ability to differentiate. Furthermore, it is thought that these cells are more resistant to conventional chemotherapy and, as a result, are responsible for patient relapse. We will discuss the identification of prostate cancer stem cells, their unique properties and how these cells may be targeted for more efficacious therapies.

  17. Carboplatin and Gemcitabine Hydrochloride With or Without ATR Kinase Inhibitor VX-970 in Treating Patients With Recurrent and Metastatic Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2017-01-31

    High Grade Ovarian Serous Adenocarcinoma; Ovarian Endometrioid Tumor; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  18. The stem-cell profile of ovarian surface epithelium is reproduced in the oviductal fimbriae, with increased stem-cell marker density in distal parts of the fimbriae.

    PubMed

    Auersperg, Nelly

    2013-09-01

    High-grade serous ovarian carcinomas are the most common and most lethal ovarian cancers, but their histologic origin is still controversial. Current evidence suggests that they may originate in the ovarian surface epithelium (OSE) and/or epithelium of oviductal fimbriae (FE). To further investigate this question we compared the stem-cell profiles of these epithelia. Formalin-fixed sections of normal FE (N=21) and ovaries (N=21) were stained immunohistochemically for the stem-cell markers NANOG, SFRP1, LHX9, ALDH1A1, and ALDH1A2. All markers were detected in both OSE and FE. A total of 75% to 100% of surface OSE expressed all markers except ALDH1A1, which occurred in about 25% of cells. Among epithelial inclusion cysts with flat-to-cuboidal epithelium, resembling OSE, ALDH1A1 was significantly increased, whereas SFRP1 was reduced compared with surface OSE, suggesting an increased trend towards malignant transformation. Similarly, among cysts lined by columnar cells resembling FE, SFRP1 expression was low, whereas ALDH1A1 approached 100% of the cysts. FE exhibited considerable variation between and within specimens. In about half of the samples, SFRP1 and NANOG were detected in ≤25% FE. The most widespread markers were ALDH1A1 and ALDH1A2. The highest proportion of all markers occurred in the distal parts of the FE, the site of the putative ovarian cancer precursors. Marker expression in tubal ampullae was low or absent except for ALDH1A1 and ALDH1A2. The results provide an explanation for the characteristic distal location of fimbrial high-grade serous ovarian carcinoma precursor lesions, and indicate that both OSE and FE have the capacity to undergo neoplastic transformation.

  19. IKK inhibition increases bortezomib effectiveness in ovarian cancer

    PubMed Central

    Singha, Bipradeb; Gatla, Himavanth Reddy; Phyo, Sai; Patel, Atish; Chen, Zhe-Sheng; Vancurova, Ivana

    2015-01-01

    Ovarian cancer is associated with increased expression of the pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8), which induces tumor cell proliferation, angiogenesis, and metastasis. Even though bortezomib (BZ) has shown remarkable anti-tumor activity in hematological malignancies, it has been less effective in ovarian cancer; however, the mechanisms are not understood. We have recently shown that BZ unexpectedly induces the expression of IL-8 in ovarian cancer cells in vitro, by IκB kinase (IKK)-dependent mechanism. Here, we tested the hypothesis that IKK inhibition reduces the IL-8 production and increases BZ effectiveness in reducing ovarian tumor growth in vivo. Our results demonstrate that the combination of BZ and the IKK inhibitor Bay 117085 significantly reduces the growth of ovarian tumor xenografts in nude mice when compared to either drug alone. Mice treated with the BZ/Bay 117085 combination ex