scholarly journals Death domain-associated protein (DAXX) expression is associated with poor survival in metastatic high-grade serous carcinoma

2020 ◽  
Vol 477 (6) ◽  
pp. 857-864
Author(s):  
Ben Davidson ◽  
Erin McFadden ◽  
Arild Holth ◽  
Marta Brunetti ◽  
Vivi Ann Flørenes
Keyword(s):  
Cell Lines ◽  
Western Blotting ◽  
Serous Carcinoma ◽  
High Grade ◽  
Death Domain ◽  
Poor Overall Survival ◽  
Clinical Role ◽  
Entire Cohort ◽  
Clinicopathologic Parameters

AbstractThe objective of this study was to analyze the expression and clinical role of mitosis regulators α-thalassemia/mental retardation syndrome X-linked (ATRX) and death-domain-associated protein (DAXX) in metastatic high-grade serous carcinoma (HGSC). ATRX and DAXX protein expression by immunohistochemistry was analyzed in 400 HGSC effusions. DAXX expression was additionally studied in 15 cancer cell lines, including 4 ovarian carcinoma lines, and in 81 of the 400 HGSC effusions using Western blotting. ATRX and DAXX were expressed in HGSC cells in 386/400 (96%) and 348/400 (87%) effusions, respectively. Western blotting showed DAXX expression in all 15 cell lines and in 70/81 (86%) HGSC effusions. DAXX expression by immunohistochemistry was higher in pleural compared to peritoneal effusions (p = 0.006) and in post-chemotherapy compared to pre-chemotherapy effusions (p = 0.004), and its expression was significantly associated with poor overall survival in univariate of the entire cohort (p = 0.014), as well as analysis limited to chemo-naïve effusions tapped at diagnosis (p = 0.038). The former association retained its prognostic role in Cox multivariate survival analysis (p = 0.011). ATRX expression was unrelated to clinicopathologic parameters or survival. In conclusion, DAXX is associated with disease progression and could be a prognostic marker in metastatic HGSC. Silencing this molecule may have therapeutic relevance in this cancer.

Expression and clinical role of long non-coding RNA in high-grade serous carcinoma

2018 ◽  
Vol 148 (3) ◽  
pp. 559-566 ◽  
Author(s):  
Natalie Filippov-Levy ◽  
Hallel Cohen-Schussheim ◽  
Claes G. Tropé ◽  
Thea E. Hetland Falkenthal ◽  
Yoav Smith ◽  
...  
Keyword(s):  
Serous Carcinoma ◽  
High Grade ◽  
Clinical Role ◽  
Non Coding Rna ◽  
Long Non Coding Rna

scholarly journals Survival Analysis of 3 Different Age Groups and Prognostic Factors among 402 Patients with Skeletal High-Grade Osteosarcoma. Real World Data from a Single Tertiary Sarcoma Center

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 486
Author(s):  
Richard E. Evenhuis ◽  
Ibtissam Acem ◽  
Anja J. Rueten-Budde ◽  
Diederik S. A. Karis ◽  
Marta Fiocco ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Medical Center ◽  
Age Groups ◽  
High Grade ◽  
Real World Data ◽  
Poor Overall Survival ◽  
Histopathological Response ◽  
Curative Intent ◽  
Entire Cohort ◽  
High Grade Osteosarcoma

Age is a known prognostic factor for many sarcoma subtypes, however in the literature there are limited data on the different risk profiles of different age groups for osteosarcoma survival. This study aims to provide an overview of survival in patients with high-grade osteosarcoma in different age groups and prognostic variables for survival and local control among the entire cohort. In this single center retrospective cohort study, 402 patients with skeletal high-grade osteosarcoma were diagnosed and treated with curative intent between 1978 and 2017 at the Leiden University Medical Center (LUMC). Prognostic factors for survival were analyzed using a Cox proportional hazard model. In this study poor overall survival (OS) and event-free survival (EFS) were associated with increasing age. Age groups, tumor size, poor histopathological response, distant metastasis (DM) at presentation and local recurrence (LR) were important independent prognostic factors influencing OS and EFS. Differences in outcome among different age groups can be partially explained by patient and treatment characteristics.

P04.20 The role of YAP in Glioblastoma cell lines

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii22-ii23
Author(s):  
G Casati ◽  
L Giunti ◽  
A Iorio ◽  
A Marturano ◽  
I Sardi
Keyword(s):  
Cell Viability ◽  
Cell Lines ◽  
Western Blotting ◽  
Cytotoxic Effect ◽  
Target Genes ◽  
Hippo Pathway ◽  
Combined Treatment ◽  
Set Up ◽  
The Hippo Pathway

Abstract BACKGROUND Glioblastoma (GBM) is a primary human malignant brain tumor, the most common in adults. Several studies have highlighted the Hippo-pathway as a cancer signalling network. The Hippo pathway is an evolutionarily conserved signal cascade, which is involved in the control of organ growth. Dysregulations among this pathway have been found in lung, ovarian, liver and colorectal cancer. The key downstream effector of the Hippo-pathway is the Yes-associated protein (YAP); in the nucleus, its function as transcription co-activator is to interact with transcription factors, resulting in the expression of target genes involved in pro-proliferating and anti-apoptotic programs. MATERIAL AND METHODS Using western blotting analysis, we determined the nuclear expression of YAP on three GBM cell lines (U87MG, T98G and A172). To investigate which inhibitors against the Hippo-pathway were the most efficient, we performed a cytotoxic assay: we treated all the three cell lines with different inhibitors such as Verteporfin (VP), Cytochalasin D (CIT), Latrunculin A (LAT), Dobutamine (DOB) and Y27632. Afterwards, we performed a treatment using Doxorubicin (DOX) combined with the inhibitors, evaluating its cytotoxic effect on our cell lines, through cell viability experiments. More western blotting experiments were performed to investigate the oncogenic role of YAP at nucleus level. Furthermore, preliminary experiments have been conducted in order to investigate the apoptosis, senescence and autophagy modulation due to the Hippo-pathway. RESULTS We showed our cell lines express nuclear YAP. We assessed the efficiency of the main inhibitors against Hippo-pathway, proving that VP, LAT A and CIT show a strong cytostatic effect, linked to time increase; plus we saw a cytotoxic effect on T98G. The association of DOX with selected inhibitors is able to reduce cell viability and nuclear YAP expression rate in all three GBM lines. Finally, preliminary experiments were set up to assess how and if the mechanisms of apoptosis, autophagy and senescence were affected by the Hippo-pathway. The combination of DOX with inhibitors promotes resistance to apoptosis. CONCLUSION Our results show that nuclear YAP is present in all tumor lines, thus confirming that this molecular pathway is functioning in GBM lines. Nuclear YAP is more highly expressed after DOX administration. Moreover, the combined treatment (DOX with Hippo-pathway inhibitors) reduces both cell proliferation and viability, and increases the rate of apoptosis. Preliminary experiments on senescence and autophagy were used to determine the best Hippo-pathway inhibitor. These data demonstrate that the Hippo-pathway plays a crucial role in GBM proliferation and resistance to apoptosis. Inhibiting this pathway and in particular the transcription factor YAP, in association with DOX, might be an excellent therapeutic target.

scholarly journals Culprit or Bystander? The Role of the Fallopian Tube in “Ovarian” High-Grade Serous Carcinoma

2016 ◽  
Vol 6 (12) ◽  
pp. 1309-1311 ◽  
Author(s):  
Elizabeth M. Swisher ◽  
Rochelle L. Garcia ◽  
Mark R. Kilgore ◽  
Barbara M. Norquist
Keyword(s):  
Fallopian Tube ◽  
Serous Carcinoma ◽  
High Grade

scholarly journals The Biological and Clinical Role of the Long Non-Coding RNA LOC642852 in Ovarian Carcinoma

2020 ◽  
Vol 21 (15) ◽  
pp. 5237 ◽  
Author(s):  
Natalie Filippov-Levy ◽  
Reuven Reich ◽  
Ben Davidson
Keyword(s):  
Matrix Metalloproteinase ◽  
Cell Signaling ◽  
Ovarian Carcinoma ◽  
Serous Carcinoma ◽  
Spheroid Formation ◽  
Clinical Role ◽  
Cerna Network ◽  
Non Coding Rna ◽  
Long Non Coding Rna

The objective of the present study was to analyze the biological and clinical role of the long non-coding RNA LOC642852 in ovarian carcinoma (OC). LOC642852 expression was analyzed in seven OC cell lines (OVCAR-3, OVCAR-8, OVCA 433, OVCA 429, OC 238, DOV13, ES-2) and 139 high-grade serous carcinoma (HGSC) specimens (85 effusions, 54 surgical specimens). Following LOC642852 knockout (KO) using the CRISPR/Cas9 system, OVCAR-8 HGSC cells were analyzed for spheroid formation, migration, invasion, proliferation, matrix metalloproteinase (MMP) activity, and expression of cell signaling proteins. OVCAR-8 cells with LOC642852 KO were significantly less motile and less invasive compared to controls, with no differences in spheroid formation, proliferation, or matrix metalloproteinase (MMP) activity. Total Akt and Erk levels were comparable in controls and KO cells, but their phosphorylation was significantly increased in the latter. In clinical specimens, LOC642852 was overexpressed in ovarian tumors and omental/peritoneal metastases compared to effusion specimens (p = 0.013). A non-significant trend for shorter overall (p = 0.109) and progression-free (p = 0.056) survival was observed in patients with HGSC effusions with high LOC642852 levels. Bioinformatics analysis showed potential roles for LOC642852 as part of the TLE3/miR-221-3p ceRNA network and in relation to the FGFR3 protein. In conclusion, LOC642852 inactivation via CRISPR/Cas9 affects cell signaling, motility, and invasion in HGSC cells. LOC642852 is differentially expressed in HGSC cells at different anatomical sites. Its potential role in regulating the TLE3/miR-221-3p ceRNA network and FGFR3 merits further research.

Death-domain-associated protein (DAXX) is a novel prognostic factor in metastatic high-grade serous carcinoma

2020 ◽  
Vol 159 ◽  
pp. 92
Author(s):  
B. Davidson ◽  
M. Brunetti ◽  
E. McFadden ◽  
V.A. Flørenes ◽  
A. Holth
Keyword(s):  
Prognostic Factor ◽  
Serous Carcinoma ◽  
High Grade ◽  
Death Domain

The role of the glucocorticoid receptor (GR) in inhibiting chemotherapy-induced apoptosis in high-grade serous ovarian carcinoma (HGS-OvCa).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11101-11101
Author(s):  
Erica Michelle Stringer ◽  
Maxwell N. Skor ◽  
Gini F. Fleming ◽  
Suzanne D. Conzen
Keyword(s):  
Ovarian Cancer ◽  
Glucocorticoid Receptor ◽  
Tumor Cell ◽  
Cell Survival ◽  
Cell Lines ◽  
High Grade ◽  
Induced Apoptosis ◽  
Er Alpha ◽  
Ovca Cell

11101 Background: Ovarian cancer is the leading cause of death from gynecologic malignancies. High-grade serous ovarian cancer (HGS-OvCa) is often initially sensitive to platinum-based therapy, but relapse rates remain high. The TCGA recently found that HGS-OvCas have a gene expression and mutational profile similar to that of triple negative breast cancer (TNBC). Previously, our group demonstrated that dexamethasone treatment decreased chemotherapy-induced tumor cell apoptosis in TNBC and HGS-OvCa cell lines. We have also shown that glucocorticoid receptor (GR) activation induces expression of anti-apoptotic genes SGK1 and MKP1/DUSP1 in both HGS-OvCa and TNBC cell lines and in primary human ovarian and TNBC tumors. Methods: We examined glucocorticoid receptor (GR), estrogen receptor (ER), and progesterone receptor (PR) expression in a panel of HGS-OvCa cell lines by Western analysis and qRT-PCR. We also performed apoptosis assays with and without mifepristone, glucocorticoid and/or chemotherapy treatment using IncuCyte live-cell imaging technology in order to measure the effect of GR modulation of chemotherapy sensitivity. Results: HGS-OvCa cell lines (including CAOV3, HeyA8, SKOV3, Monty-1) all had detectable GR expression; HeyA8, SKOV3, and Monty-1 cell lines expressed very low levels of ER-alpha while all other HGS-OvCa cell lines did not express any detectable ER-alpha. Furthermore, none of the HGS-OvCa cell lines tested expressed PR.Apoptosis assays revealed that GR activation significantly inhibited gemcitabine/carboplatin-induced apoptosis in HGS-OvCa cell lines and that mifepristone could reverse this cell survival effect, presumably through GR antagonism. Conclusions: These results suggest that treatment with mifepristone, a GR antagonist, reverses GR-mediated cell survival signaling in HGS-OvCa and increases chemotherapy-induced tumor cell death. To further investigate the role of GR activity in HGS-OvCa, we are currently performing xenograft experiments with chemotherapy +/- mifepristone treatment.

scholarly journals Generation of Two Paclitaxel-Resistant High-Grade Serous Carcinoma Cell Lines With Increased Expression of P-Glycoprotein

2021 ◽  
Vol 11 ◽  
Author(s):  
Mariana Nunes ◽  
Patrícia M. A. Silva ◽  
Ricardo Coelho ◽  
Carla Pinto ◽  
Albina Resende ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Carcinoma Cell ◽  
Serous Carcinoma ◽  
Drug Efflux ◽  
High Grade ◽  
Intrinsic Resistance ◽  
Paclitaxel Resistance ◽  
Carcinoma Cell Lines ◽  
P Glycoprotein

Debulking surgery followed by chemotherapy are the standard of care for high-grade serous carcinoma. After an initial good response to treatment, the majority of patients relapse with a chemoresistant profile, leading to a poor overall survival. Chemotherapy regimens used in high-grade serous carcinomas are based in a combination of classical chemotherapeutic drugs, namely, Carboplatin and Paclitaxel. The mechanisms underlying drug resistance and new drug discovery are crucial to improve patients’ survival. To uncover the molecular mechanisms of chemoresistance and test drugs capable of overcoming this resistant profile, it is fundamental to use good cellular models capable of mimicking the chemoresistant disease. Herein, we established two high-grade serous carcinoma cell lines with intrinsic resistance to Carboplatin and induced Paclitaxel resistance (OVCAR8 PTX R C and OVCAR8 PTX R P) derived from the OVCAR8 cell line. These two chemoresistant cell line variants acquired an enhanced resistance to Paclitaxel-induced cell death by increasing the drug efflux capacity, and this resistance was stable in long-term culture and following freeze/thaw cycles. The mechanism underlying Paclitaxel resistance resides in a significant increase in P-glycoprotein expression and, when this drug efflux pump was blocked with Verapamil, cells re-acquired Paclitaxel sensitivity. We generated two high-grade serous carcinoma cell lines, with a double-chemoresistant (Carboplatin and Paclitaxel) phenotype that mimics the majority of tumor recurrences in ovarian cancer context. This robust tool is suitable for preliminary drug testing towards the development of therapeutic strategies to overcome chemoresistance.

scholarly journals 587 Prognostic role of chemotherapy response score system in tubo – ovarian high grade serous carcinoma

2021 ◽  
Author(s):  
A JS ◽  
S Sambasivan ◽  
PN Rema ◽  
S Ajeesh ◽  
S Ranjith J ◽  
...  
Keyword(s):  
Serous Carcinoma ◽  
Chemotherapy Response ◽  
High Grade ◽  
Prognostic Role ◽  
Score System ◽  
Response Score

scholarly journals Identification of ovarian high-grade serous carcinoma cell lines that show estrogen-sensitive growth as xenografts in immunocompromised mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Alexis De Haven Brandon ◽  
Gary Box ◽  
Albert Hallsworth ◽  
William Court ◽  
Nicoll Matthews ◽  
...  
Keyword(s):  
Cell Lines ◽  
Carcinoma Cell ◽  
Serous Carcinoma ◽  
High Grade ◽  
Carcinoma Cell Lines ◽  
Immunocompromised Mice
Sign in / Sign up

Export Citation Format

Share Document