scholarly journals Cellular senescence is a central response to cytotoxic chemotherapy in high-grade serous ovarian cancer

2018 ◽  
Author(s):  
L. Calvo ◽  
S. Cheng ◽  
M. Skulimowski ◽  
I. Clément ◽  
L. Portelance ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Cell Fate ◽  
Cellular Senescence ◽  
Response To Treatment ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Cell Fate Decisions ◽  
Response To Chemotherapy

AbstractHigh-grade serous ovarian cancer (HGSOC) commonly responds to initial therapy, but this response is rarely durable. Understanding cell fate decisions taken by HGSOC cells in response to treatment could guide new therapeutic opportunities. Here we find that primary HGSOC cultures undergo therapy-induced senescence (TIS) in response to DNA damage induced by chemotherapy. HGSOC-TIS displays most senescence hallmarks including persistent DNA damage, senescence-associated inflammatory secretome, and selective sensitivity to senolytic Bcl-2 family inhibitors, suggesting avenues for preferential synergistic clearance of these cells. Comparison of pre- and post-chemotherapy HGSOC patient tissue samples revealed changes in senescence biomarkers suggestive of post-treatment “in patient” TIS, and a stronger TIS response in post-chemotherapy tissues correlated with better 5-year survival rates for patients. Together, these data suggest that the induction of cellular senescence in HGSOC cells accounts at least in part for beneficial cellular responses to treatment in patients providing a new therapeutic target.One Sentence SummaryCellular senescence is a central beneficial response to chemotherapy in high-grade serous ovarian cancer bothin vitroand in patient.

scholarly journals Primary high-grade serous ovarian cancer cells are sensitive to senescence induced by carboplatin and paclitaxel in vitro

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Paweł Uruski ◽  
Agnieszka Sepetowska ◽  
Corinna Konieczna ◽  
Martyna Pakuła ◽  
Michał Wyrwa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Telomere Length ◽  
Telomerase Activity ◽  
Ovarian Cancer Cells ◽  
High Grade ◽  
Serous Ovarian Cancer

Abstract Background Various types of normal and cancer cells undergo senescence in response to carboplatin and paclitaxel, which are considered the gold standard treatments in ovarian cancer management. Surprisingly, the effect of these drugs on ovarian cancer cell senescence remained unknown. Methods The experiments were conducted on primary high-grade serous ovarian cancer cells. Molecular markers of senescence were evaluated using cytochemistry and immunofluorescence. Cell cycle distribution was analyzed using flow cytometry. Expression of cyclins and signaling pathways was tested using western blot. Telomere length and telomerase activity were measured using qPCR, and the colocalization of telomeres with DNA damage foci using immuno-FISH. Oxidative stress-related parameters were quantified using appropriate fluorescence probes. Production of cancerogenic agents was analyzed using qPCR and ELISA. Results Carboplatin applied with paclitaxel induces senescence of ovarian cancer cells in vitro. This activity was reflected by permanent G2/M growth arrest, a high fraction of cells expressing senescence biomarkers (SA-β-Gal and γ-H2A.X), upregulated expression of p16, p21, and p53 cell cycle inhibitors, and decreased expression of cyclin B1. Neither telomere length nor telomerase activity changed in the senescent cells, and the majority of DNA damage was localized outside telomeres. Moreover, drug-treated cancer cells exhibited increased production of STAT3 protein, overproduced superoxide and peroxides, and increased mitochondrial mass. They were also characterized by upregulated ANG1, CCL11, IL-6, PDGF-D, TIMP-3, TSP-1, and TGF-β1 at the mRNA and/or protein level. Conclusions Our findings imply that conventional chemotherapy may elicit senescence in ovarian cancer cells, which may translate to the development of a cancer-promoting phenotype, despite the inability of these cells to divide.

scholarly journals Promoter Methylation of the MGRN1 Gene Predicts Prognosis and Response to Chemotherapy of High-Grade Serous Ovarian Cancer Patients

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiao-fei Li ◽  
Hai-yan Sun ◽  
Tian Hua ◽  
Hai-bo Zhang ◽  
Yun-jie Tian ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mrna Expression ◽  
Promoter Region ◽  
Upstream Region ◽  
Platinum Resistance ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Kaplan Meier ◽  
Response To Chemotherapy ◽  
Low Expression

Aberrant DNA methylation is considered to play a critical role in the chemoresistance of epithelial ovarian cancer (EOC). In this study, we explored the relationship between hypermethylation of the Mahogunin Ring Finger 1 (MGRN1) gene promoter and primary chemoresistance and clinical outcomes in high-grade serous ovarian cancer (HGSOC) patients. The MALDI-TOF mass spectrometry assays revealed a strong association between hypermethylation of the MGRN1 upstream region and platinum resistance in HGSOC patients. Spearman’s correlation analysis revealed a significantly negative connection between the methylation level of MGRN1 and its expression in HGSOC. In vitro analysis demonstrated that knockdown of MGRN1 reduced the sensitivity of cells to cisplatin and that expression of EGR1 was significantly decreased in SKOV3 cells with low levels of MGRN1 expression. Similarly, EGR1 mRNA expression was lower in platinum-resistant HGSOC patients and was positively correlated with MGRN1 mRNA expression. Kaplan-Meier analyses showed that high methylation of the MGRN1 promoter region and low expression of MGRN1 were associated with worse survival of HGSOC patients. In multivariable models, low MGRN1 expression was an independent factor predicting poor outcome. Furthermore, low expression of EGR1 was also been confirmed to be significantly related to the poor prognosis of HGSOC patients by Kaplan-Meier. The hypermethylation of the MGRN1 promoter region and low expression of MGRN1 were associated with platinum resistance and poor outcomes in HGSOC patients, probably by altering EGR1 expression.

scholarly journals Building in vitro 3D human multicellular models of high-grade serous ovarian cancer

2022 ◽  
Vol 3 (1) ◽  
pp. 101086
Author(s):  
Beatrice Malacrida ◽  
Oliver M.T. Pearce ◽  
Frances R. Balkwill
Keyword(s):  
Ovarian Cancer ◽  
High Grade ◽  
Serous Ovarian Cancer

scholarly journals KLF7: a new candidate biomarker and therapeutic target for high-grade serous ovarian cancer

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Marta De Donato ◽  
Gabriele Babini ◽  
Simona Mozzetti ◽  
Marianna Buttarelli ◽  
Alessandra Ciucci ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Prognostic Marker ◽  
Late Stage ◽  
Therapeutic Target ◽  
Family Members ◽  
High Grade ◽  
Serous Ovarian Cancer

Abstract Background In spite of great progress in the surgical and clinical management, until now no significant improvement in overall survival of High-Grade Serous Ovarian Cancer (HGSOC) patients has been achieved. Important aspects for disease control remain unresolved, including unclear pathogenesis, high heterogeneity and relapse resistance after chemotherapy. Therefore, further research on molecular mechanisms involved in cancer progression are needed to find new targets for disease management. The Krüppel-like factors (KLFs) are a family of transcriptional regulators controlling several basic cellular processes, including proliferation, differentiation and migration. They have been shown to play a role in various cancer-relevant processes, in a context-dependent way. Methods To investigate a possible role of KLF family members as prognostic biomarkers, we carried out a bioinformatic meta-analysis of ovarian transcriptome datasets in different cohorts of late-stage HGSOC patients. In vitro cellular models of HGSOC were used for functional studies exploring the role of KLF7 in disease development and progression. Finally, molecular modelling and virtual screening were performed to identify putative KLF7 inhibitors. Results Bioinformatic analysis highlighted KLF7 as the most significant prognostic gene, among the 17 family members. Univariate and multivariate analyses identified KLF7 as an unfavourable prognostic marker for overall survival in late-stage TCGA-OV and GSE26712 HGSOC cohorts. Functional in vitro studies demonstrated that KLF7 can play a role as oncogene, driving tumour growth and dissemination. Mechanistic targets of KLF7 included genes involved in epithelial to mesenchymal transition, and in maintaining pluripotency and self-renewal characteristics of cancer stem cells. Finally, in silico analysis provided reliable information for drug-target interaction prediction. Conclusions Results from the present study provide the first evidence for an oncogenic role of KLF7 in HGSOC, suggesting it as a promising prognostic marker and therapeutic target.

scholarly journals Clinical Value of lncRNA MEG3 in High-Grade Serous Ovarian Cancer

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 966 ◽  
Author(s):  
Marianna Buttarelli ◽  
Marta De Donato ◽  
Giuseppina Raspaglio ◽  
Gabriele Babini ◽  
Alessandra Ciucci ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Biology ◽  
Tissue Level ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Clinical Value ◽  
Pre Treatment ◽  
Phosphatase And Tensin Homologue

Long non-coding RNAs (lncRNAs) are emerging as regulators in cancer development and progression, and aberrant lncRNA profiles have been reported in several cancers. Here, we evaluated the potential of using the maternally expressed gene 3 (MEG3) tissue level as a prognostic marker in high-grade serous ovarian cancer (HGSOC), the most common and deadliest gynecologic malignancy. To the aim of the study, we measured MEG3 transcript levels in 90 pre-treatment peritoneal biopsies. We also investigated MEG3 function in ovarian cancer biology. We found that high MEG3 expression was independently associated with better progression-free (p = 0.002) and overall survival (p = 0.01). In vitro and in vivo preclinical studies supported a role for MEG3 as a tumor suppressor in HGSOC, possibly through modulation of the phosphatase and tensin homologue (PTEN) network. Overall, results from this study demonstrated that decreased MEG3 is a hallmark for malignancy and tumor progression in HGSOC.

Effect of therapeutic GAS6/AXL inhibition of tumor and stromal cells on DNA damage and response to chemotherapy in ovarian cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14676-e14676 ◽  
Author(s):  
Mary M Mullen ◽  
Elena Lomonosova ◽  
Hollie M Noia ◽  
Lei Guo ◽  
Lindsay Midori Kuroki ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Neoadjuvant Chemotherapy ◽  
Cell Viability ◽  
Mouse Models ◽  
Stromal Cells ◽  
Predictive Biomarker ◽  
Response To Chemotherapy

e14676 Background: Ovarian cancer is the leading cause of death due to gynecologic malignancy. Biomarkers to predict chemoresponse and novel therapies to target these proteins would be practice changing. We aim to establish serum and tissue GAS6 as a predictive biomarker of chemoresponse and to determine if AXL inhibition through sequestration of its ligand, GAS6, with AVB-S6-500 (AVB) can improve chemoresponse. Methods: AVB was supplied by Aravive Biologics. High grade serous ovarian cancer (HGSOC) tumor samples were obtained pre- and post-neoadjuvant chemotherapy. AXL and GAS6 expression were evaluated by immunohistochemistry and serum concentration. In vitro viability and clonogenic assays were performed on chemoresistant tumor (OVCAR8, OVCAR5, COV62, and POV71-hTERT) and stromal cells (CAF86) treated with chemotherapy +/- AVB. Mouse models (OVCAR8, PDX, OVCAR5) were used to determine if the combination of chemotherapy + AVB reduced tumor burden. Immunofluorescent assays targeting ɣH2AX were used to evaluate DNA damage. Results: Patients with high pretreatment tumor GAS6 expression ( > 85%, n = 7) or serum GAS6 concentrations ( > 25ng/mL, n = 13) were more likely to be resistant to neoadjuvant chemotherapy than those with low tumor GAS6 expression ( < 45%, n = 4) (P = 0.010) or low serum GAS6 concentrations ( < 15ng/mL, n = 5) (P = 0.002). Carboplatin plus AVB (2µM, 5µM) and paclitaxel plus AVB (1µM) resulted in decreased cell viability and clonogenic growth compared to chemotherapy alone (p < 0.05) in all tumor and stromal cell lines. Synergism was seen between carboplatin+AVB and paclitaxel+AVB with a weighted combination index < 1. In vivo tumor mouse models treated with chemotherapy+AVB had significantly smaller subcutaneous and intraperitoneal (IP) tumors than those treated with chemotherapy alone (3.1mg vs 64mg, P = 0.003 OVCAR8; 62mg vs 157mg, P = 0.0108 PDX subcutaneous model; 0.05mg vs 0.3669mg, P < 0.001 OVCAR5 IP model). Increased DNA damage was noted in tumor and stromal cells treated with carboplatin+AVB compared to carboplatin alone (OVCAR8, COV362, CAF86 P < 0.001). Conclusions: High GAS6 is associated with lack of neoadjuvant chemoresponse in HGSOC patients. The combination of chemotherapy with AVB decreases tumor cell viability, tumor growth, and an increase in DNA damage response.

Genomic characterization of brain metastases (BM) in high-grade serous ovarian cancer (HGSOC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13580-e13580
Author(s):  
Renata Duchnowska ◽  
Anna Maria Supernat ◽  
Rafał Pęksa ◽  
Marta Łukasiewicz ◽  
Tomasz Stokowy ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Somatic Mutations ◽  
Dna Damage Repair ◽  
Genetic Alterations ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Primary Tumors ◽  
Tp53 Mutations ◽  
Damage Repair

e13580 Background: BM are a rare occurrence in ovarian cancer (OC) and their molecular characteristics is virtually unknown. DNA damage repair (DDR) deficiency is prevalent in OC, and co-mutated TP53 and any DDR denotes high tumor mutation burden (TMB). We genetically characterized a unique series of high-grade serous ovarian cancer (HGSOC) patients who developed BM to identify alterations of potential clinical relevance. Methods: Whole-exome sequencing (2x150bp, SureSelectXT Library Prep Kit, Illumina’s NovaSeq platform) was performed in matched BM, primary tumors (PT) and normal tissue. DNA was extracted from FFPE samples using QIAamp DNA FFPE Tissue Kit (Qiagen, Germany). All mutations were checked with Catalogue of Somatic Mutations in Cancer (COSMIC) and Integrative Genomics Viewer (IGV). Results: Study group included 10 HGSOC patients (International Federation of Gynecology and Obstetrics classification (FIGO) II-IV, mean age at diagnosis 48 years, range 35-59). Median time from primary HGSOC diagnosis to BM was 38 months (range, 18 to 149). TP53 somatic mutations were found in both primary tumor (PT) and BM in 8 patients. The other 2 cases harbored TP53 mutations not reported in COSMIC catalogue: p.S60L and intronic TP53 mutation preceding p.I322 (IGV). In 9 cases TP53 mutations coexisted with germline or somatic DNA damage repair deficiency. Four cases contained BRCA1 mutations (all germline), and none harbored germline BRCA2 mutation. Other mutated genes included MLH1 (2 somatic, 2 germline), ATR (4 germline, 1 somatic), AMT (1 somatic), RAD50 (1 somatic), ERCC4 (1 somatic), FANCD2 (1 somatic) and RPA1 (1 germline). Three mutation signatures defined in the COSMIC database were indentified in BM: 6, 20 and 30. In 6 cases these mutations were shared in PT, and in another 4 their presence in PT could not be determined due to technical reasons. Median survival from BM was 31 months (range, 5 to 184). Conclusions: Genomic analysis of BM provides an opportunity to identify potentially clinically informative alterations. Mutational profiles in PT are generally reflected in BM. Detected genetic alterations suggest their potential sensitivity to PARP inhibitors and immunotherapy.

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