An Orthotopic Model of Serous Ovarian Cancer in Immunocompetent Mice for <em>in vivo</em> Tumor Imaging and Monitoring of Tumor Immune Responses

Precision radiogenomics: fusion biopsies to target tumour habitats in vivo

British Journal of Cancer ◽

10.1038/s41416-021-01381-2 ◽

2021 ◽

Author(s):

Mireia Crispin-Ortuzar ◽

Evis Sala

Keyword(s):

Ovarian Cancer ◽

Ct Scans ◽

High Grade ◽

Serous Ovarian Cancer ◽

High Degree ◽

Degree Of Heterogeneity

SummaryHigh-grade serous ovarian cancer lesions display a high degree of heterogeneity on CT scans. We have recently shown that regions with distinct imaging profiles can be accurately biopsied in vivo using a technique based on the fusion of CT and ultrasound scans.

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In vivo modeling of metastatic human high-grade serous ovarian cancer in mice

PLoS Genetics ◽

10.1371/journal.pgen.1008808 ◽

2020 ◽

Vol 16 (6) ◽

pp. e1008808 ◽

Cited By ~ 1

Author(s):

Olga Kim ◽

Eun Young Park ◽

David L. Klinkebiel ◽

Svetlana D. Pack ◽

Yong-Hyun Shin ◽

...

Keyword(s):

Ovarian Cancer ◽

High Grade ◽

Serous Ovarian Cancer

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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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Long non-coding RNA HAL suppresses the migration and invasion of serous ovarian cancer by inhibiting EMT signaling pathway

Bioscience Reports ◽

10.1042/bsr20194496 ◽

2020 ◽

Vol 40 (3) ◽

Cited By ~ 1

Author(s):

Ke Wu ◽

Lei Li ◽

Lin Li ◽

Dong Wang

Keyword(s):

Ovarian Cancer ◽

Signaling Pathway ◽

Migration And Invasion ◽

Serous Ovarian Cancer ◽

Mice Model ◽

Protein Levels ◽

Non Coding Rna ◽

Skov3 Cells ◽

Long Non Coding Rna

Abstract Objective: To investigate the specific function of long non-coding RNA HAL in serous ovarian cancer (SOC) and to further clarify the regulation of HAL on EMT pathway. Materials and methods: The expression of HAL and TWIST1 was detected by qRT-PCR. CCK8 assay, wound healing assay, transwell assay and flow cytometry were used to detect the HAL function on proliferation, migration, invasion and apoptosis in SOC cells. Western blot was used to calculate protein level of Vimentin, N-cadherin and E-cadherin. The effect of HAL on tumorigenesis of SOC was confirmed by xenograft nude mice model. Results: HAL was significantly decreased in SOC tissues and cells. Overexpression of HAL inhibited the proliferation, migration and invasion of SKOV3 cells, but promoted apoptosis. Furthermore, overexpression of HAL decreased the mRNA and protein levels of TWIST1 via a binding between HAL and TWIST1. Forced expression of TWIST1 reversed the inhibitory role of HAL on SOC cells’ migration and invasion. The in vivo tumor growth assay showed that HAL suppressed SOC tumorigenesis with inhibiting EMT pathway. Conclusions: Our research emphasized HAL acting as a tumor-inhibiting gene by regulating EMT signaling pathway, thus providing some novel experimental basis for clinical treatment of SOC.

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SPR965, a Dual PI3K/mTOR Inhibitor, as a Targeted Therapy in Ovarian Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.624498 ◽

2021 ◽

Vol 10 ◽

Author(s):

Arthur-Quan Tran ◽

Stephanie A. Sullivan ◽

Leo Li-Ying Chan ◽

Yajie Yin ◽

Wenchuan Sun ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Transition Process ◽

Ovarian Cancer Cells ◽

Serous Ovarian Cancer ◽

Mesenchymal Transition

SPR965 is an inhibitor of PI3K and mTOR C1/C2 and has demonstrated anti-tumorigenic activity in a variety of solid tumors. We sought to determine the effects of SPR965 on cell proliferation and tumor growth in human serous ovarian cancer cell lines and a transgenic mouse model of high grade serous ovarian cancer (KpB model) and identify the underlying mechanisms by which SPR965 inhibits cell and tumor growth. SPR965 showed marked anti-proliferative activity by causing cell cycle arrest and inducing cellular stress in ovarian cancer cells. Treatment with SPR965 significantly inhibited tumor growth in KpB mice, accompanied by downregulation of Ki67 and VEGF and upregulation of Bip expression in ovarian tumors. SPR965 also inhibited adhesion and invasion through induction of the epithelial–mesenchymal transition process. As expected, downregulation of phosphorylation of AKT and S6 was observed in SPR965-treated ovarian cancer cells and tumors. Our results suggest that SPR965 has significant anti-tumorigenic effects in serous ovarian cancer in vitro and in vivo. Thus, SPR965 should be evaluated as a promising targeted agent in future clinical trials of ovarian cancer.

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Development of a Bioluminescent BRCA1-Deficient Xenograft Model of Disseminated, High-Grade Serous Ovarian Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20102498 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2498

Author(s):

Yen Ting Shen ◽

Lucy Wang ◽

James C. Evans ◽

Christine Allen ◽

Micheline Piquette-Miller

Keyword(s):

Ovarian Cancer ◽

Tumor Growth ◽

Current Model ◽

Intraperitoneal Administration ◽

Xenograft Model ◽

High Grade ◽

Serous Ovarian Cancer ◽

Ovarian Cancer Cell Lines ◽

Resected Tumor

Successful translation of preclinical data relies on valid and comprehensive animal models. While high-grade serous ovarian cancer (HGSOC) is the most prevalent subtype, the most commonly used ovarian cancer cell lines are not representative of HGSOC. In addition, 50% of ovarian cancer patients present with dysfunctional BRCA1/2, however currently there is a shortage of BRCA-deficient models. By utilizing the OVCAR8 cell line, which contains a hypermethylated BRCA1 promoter, the aim of the current study was to establish and characterize an animal model for BRCA-deficient HGSOC. Transfection of the luciferase gene to OVCAR8 cells enabled bioluminescent imaging for real-time, non-invasive monitoring of tumor growth. The resulting model was characterized by peritoneal metastasis and ascites formation at late stages of disease. Immunohistochemical staining revealed high-grade serous histology in all resected tumor nodules. Immunoblotting and qPCR analysis demonstrated BRCA1 deficiency was maintained in vivo. Moderate to strong correlations were observed between bioluminescent signal and tumor weight. Lastly, intraperitoneal administration of carboplatin significantly reduced tumor growth as measured by bioluminescence. The current model demonstrated BRCA1 deficiency and a high resemblance of the clinical features of HGSOC. This model may be well-suited for evaluation of therapeutic efficacy in BRCA-deficient 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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