Building in vitro 3D human multicellular models of 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.

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

Cancers ◽

10.3390/cancers12040966 ◽

2020 ◽

Vol 12 (4) ◽

pp. 966 ◽

Cited By ~ 2

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.

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A Unique Pattern of Mesothelial-Mesenchymal Transition Induced in the Normal Peritoneal Mesothelium by High-Grade Serous Ovarian Cancer

Cancers ◽

10.3390/cancers11050662 ◽

2019 ◽

Vol 11 (5) ◽

pp. 662 ◽

Cited By ~ 3

Author(s):

Martyna Pakuła ◽

Paweł Uruski ◽

Arkadiusz Niklas ◽

Aldona Woźniak ◽

Dariusz Szpurek ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Specific Pattern ◽

Laboratory Animals ◽

Ovarian Cancer Cells ◽

High Grade ◽

Serous Ovarian Cancer ◽

Mesenchymal Transition

The study was designed to establish whether high aggressiveness of high-grade serous ovarian cancer cells (HGSOCs), which display rapid growth, advanced stage at diagnosis and the highest mortality among all epithelial ovarian cancer histotypes, may be linked with a specific pattern of mesothelial-mesenchymal transition (MMT) elicited by these cells in normal peritoneal mesothelial cells (PMCs). Experiments were performed on primary PMCs, stable and primary ovarian cancer cells, tumors from patients with ovarian cancer, and laboratory animals. Results of in vitro and in vivo tests showed that MMT triggered by HGSOCs (primary cells and OVCAR-3 line) is far more pronounced than the process evoked by cells representing less aggressive ovarian cancer histotypes (A2780, SKOV-3). Mechanistically, HGSOCs induce MMT via Smad 2/3, ILK, TGF-β1, HGF, and IGF-1, whereas A2780 and SKOV-3 cells via exclusively Smad 2/3 and HGF. The conditioned medium from PMCs undergoing MMT promoted the progression of cancer cells and the effects exerted by the cells triggered to undergo MMT by the HGSOCs were significantly stronger than those related to the activity of their less aggressive counterparts. Our findings indicate that MMT in PMCs provoked by HGSOCs is stronger, proceeds via different mechanisms and has more procancerous characteristics than MMT provoked by less aggressive cancer histotypes, which may at least partly explain high aggressiveness of HGSOCs.

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Cytotoxic capacity of a novel glycosylated antitumor ether lipid in chemotherapy-resistant high grade serous ovarian cancer in vitro and in vivo

Translational Oncology ◽

10.1016/j.tranon.2021.101203 ◽

2021 ◽

Vol 14 (11) ◽

pp. 101203

Author(s):

Mark W Nachtigal ◽

Paris Musaphir ◽

Shiv Dhiman ◽

Alon D Altman ◽

Frank Schweizer ◽

...

Keyword(s):

Ovarian Cancer ◽

Ether Lipid ◽

High Grade ◽

Serous Ovarian Cancer

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Beclin-1 expression is retained in high-grade serous ovarian cancer yet is not essential for autophagy induction in vitro

Journal of Ovarian Research ◽

10.1186/s13048-015-0182-y ◽

2015 ◽

Vol 8 (1) ◽

Cited By ~ 14

Author(s):

Rohann J. M. Correa ◽

Yudith Ramos Valdes ◽

Trevor G. Shepherd ◽

Gabriel E. DiMattia

Keyword(s):

Ovarian Cancer ◽

Beclin 1 ◽

High Grade ◽

Serous Ovarian Cancer ◽

Autophagy Induction

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Abstract 323: High grade serous ovarian cancer cells spontaneously self-organize in vitro into multicellular irregular aggregates and highly organized spheroids.

10.1158/1538-7445.am2013-323 ◽

2013 ◽

Author(s):

Alicia A. Goyeneche

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Ovarian Cancer Cells ◽

High Grade ◽

Serous Ovarian Cancer

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Reduced Gonadotrophin Receptor Expression Is Associated with a More Aggressive Ovarian Cancer Phenotype

International Journal of Molecular Sciences ◽

10.3390/ijms22010071 ◽

2020 ◽

Vol 22 (1) ◽

pp. 71

Author(s):

Janelle Cheung ◽

Noor A. Lokman ◽

Riya D. Abraham ◽

Anne M. Macpherson ◽

Eunice Lee ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Progression Free Survival ◽

Receptor Expression ◽

Ovarian Cancer Cells ◽

High Grade ◽

Serous Ovarian Cancer ◽

Cancer Phenotype

Follicle-stimulating hormone (FSH) and luteinising hormone (LH) play important roles in regulating cell growth and proliferation in the ovary. However, few studies have explored the expression of FSH and LH receptors (FSHR and LHCGR) in ovarian cancer, and their functional roles in cancer progression remain inconclusive. This study investigated the potential impact of both mRNA (FSHR, LHCGR) and protein (FSHR, LHCGR) expression on ovarian cancer progression using publicly available online databases, qRT-PCR (high grade serous ovarian cancers, HGSOC, n = 29 and benign ovarian tumors, n = 17) and immunohistochemistry (HGSOC, n = 144). In addition, we investigated the effect of FSHR and LHCGR siRNA knockdown on the pro-metastatic behavior of serous ovarian cancer cells in vitro. High FSHR or high LHCGR expression in patients with all subtypes of high-grade ovarian cancer was significantly associated with longer progression-free survival (PFS) and overall survival (OS). High FSHR protein expression was associated with increased PFS (p = 0.050) and OS (p = 0.025). HGSOC patients with both high FSHR and high LHCGR protein levels had the best survival outcome, whilst both low FSHR and low LHCGR expression was associated with poorest survival (p = 0.019). Knockdown of FSHR significantly increased the invasion of serous ovarian cancer cells (OVCAR3 and COV362) in vitro. LHCGR knockdown also promoted invasion of COV362 cells. This study highlights that lower FSHR and LHCGR expression is associated with a more aggressive epithelial ovarian cancer phenotype and promotes pro-metastatic behaviour.

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Molecular Mechanism of Gleditsiae Spina for the Treatment of High-grade Serous Ovarian Cancer Based on Network Pharmacology and Experimental Verification

10.21203/rs.3.rs-744923/v1 ◽

2021 ◽

Author(s):

Boran Zhang ◽

Wenchao Dan ◽

Xing Chen ◽

Cunfang Dai ◽

Guangda Li ◽

...

Keyword(s):

Ovarian Cancer ◽

Protein Interaction ◽

Interaction Analysis ◽

Dynamics Simulation ◽

Network Pharmacology ◽

High Grade ◽

Serous Ovarian Cancer ◽

Active Ingredients ◽

Protein Protein Interaction

Abstract Background In this study, we aimed to analyze the pharmacological mechanism of Gleditsiae Spina in the treatment of high-grade serous ovarian cancer (HGSC) based on network pharmacology and in vitro experiments. Methods The main active ingredients of Gleditsiae Spina were identified by high performance liquid chromatography and mass spectrometry, and ADME screening was performed. The component targets of Gleditsiae Spina were screened using the pharmMapper platform, and differentially expressed genes in normal and HGSC tissues were identified through GEO database. Thereafter, Cytoscape 3.7.2 software was used to construct the network of "active ingredient-targets," and the BioGenet database was used for protein-protein interaction analysis. Furthermore, the protein-protein interaction network was established, and the potential protein function module was mined. Biological processes and pathways were analyzed through gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Results The core active ingredients of Gleditsiae Spina for regulating HGSC included luteolin, genistein, D-(+)-tryptophan, ursolic acid, and berberine. The ideal targets were HPSE, PI3KCA, AKT1, and CTNNB1. The prediction results were verified by molecular docking, molecular dynamics simulation, and western blot analysis. Conclusions This study revealed the mechanism of Gleditsiae Spina for the treatment of HGSC based on multi-components, multi-targets, and multi-channels. It also provides a theoretical basis for the prevention of ovarian cancer and its treatment using traditional Chinese medicine in the future.

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C/EBPβ promotes poly(ADP-ribose) polymerase inhibitor resistance by enhancing homologous recombination repair in high-grade serous ovarian cancer

Oncogene ◽

10.1038/s41388-021-01788-4 ◽

2021 ◽

Author(s):

Jiahong Tan ◽

Xu Zheng ◽

Mengchen Li ◽

Fei Ye ◽

Chunyan Song ◽

...

Keyword(s):

Ovarian Cancer ◽

Homologous Recombination ◽

Parp Inhibitors ◽

High Grade ◽

Serous Ovarian Cancer ◽

Enhancer Binding Protein ◽

Recombination Repair ◽

Inhibitor Resistance

AbstractPARP inhibitors (PARPi) are efficacious in treating high-grade serous ovarian cancer (HG-SOC) with homologous recombination (HR) deficiency. However, they exhibit suboptimal efficiency in HR-proficient cancers. Here, we found that the expression of CCAAT/enhancer-binding protein β (C/EBPβ), a transcription factor, was inversely correlated with PARPi sensitivity in vitro and in vivo, both in HR-proficient condition. High C/EBPβ expression enhanced PARPi tolerance; PARPi treatment in turn induced C/EBPβ expression. C/EBPβ directly targeted and upregulated multiple HR genes (BRCA1, BRIP1, BRIT1, and RAD51), thereby inducing restoration of HR capacity and mediating acquired PARPi resistance. C/EBPβ is a key regulator of the HR pathway and an indicator of PARPi responsiveness. Targeting C/EBPβ could induce HR deficiency and rescue PARPi sensitivity accordingly. Our findings indicate that HR-proficient patients may benefit from PARPi via targeting C/EBPβ, and C/EBPβ expression levels enable predicting and tracking PARPi responsiveness during treatment.

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