Ovarian cancer-derived exosomes promote tumour metastasis in vivo: an effect modulated by the invasiveness capacity of their originating cells

2019 ◽  
Vol 133 (13) ◽  
pp. 1401-1419 ◽  
Author(s):  
Mona Alharbi ◽  
Andrew Lai ◽  
Dominic Guanzon ◽  
Carlos Palma ◽  
Felipe Zuñiga ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Line ◽  
Imaging System ◽  
Tumour Microenvironment ◽  
Bioactive Molecules ◽  
Tumour Metastasis ◽  
Elevated Expression ◽  
Cell Migration And Proliferation ◽  
Ovca Cell

Abstract Exosomes are small nanovesicles that carry bioactive molecules which can be delivered to neighbouring cells to modify their biological functions. Studies have showed that exosomes from ovarian cancer (OVCA) cells can alter the cell migration and proliferation of cells within the tumour microenvironment, an effect modulated by the invasiveness capacity of their originating cells. Using an OVCA cell line xenograph mouse model, we showed that exosomes derived from a high invasiveness capacity cell line (exo-SKOV-3) promoted metastasis in vivo compared with exosomes from a low invasiveness capacity cell line (exo-OVCAR-3). Analysis from anin vivo imaging system (IVIS) revealed that exo-SKOV-3 formed metastatic niches, whereas exo-OVCAR-3 formed colonies of clustered cells close to the site of injection. Interestingly, kinetic parameters showed that the half-maximal stimulatory time (ST50) of tumour growth with exo-OVCAR-3 (4.0 ± 0.31 weeks) was significantly lower compared with the ST50 in mice injected with exo-SKOV-3 (4.5 ± 0.32 weeks). However, the number of metastic nodes in mice injected with exo-SKOV-3 was higher compared with exo-OVCAR-3. Using a quantitative mass spectrometry approach (SWATH MS/MS) followed by bioinformatics analysis using the Ingenuity Pathway Analysis (IPA), we identified a total of 771 proteins. Furthermore, 40 of these proteins were differentially expressed in tumour tissues from mice injected with exo-SKOV-3 compared with exo-OVCAR-3, and associated with Wnt canonical pathway (β-catenin). Finally, we identified a set of proteins which had elevated expression in the circulating exosomes in association with tumour metastasis. These observations suggest that exosomal signalling plays an important role in OVCA metastasis.

scholarly journals Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 969
Author(s):  
John S. Lazo ◽  
Elizabeth R. Sharlow ◽  
Robert Cornelison ◽  
Duncan J. Hart ◽  
Danielle C. Llaneza ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Migration ◽  
Tyrosine Phosphatase ◽  
In Vitro Cytotoxicity ◽  
Mrna Levels ◽  
High Grade ◽  
Drug Resistant ◽  
Ovca Cell

High grade serous ovarian cancer (OvCa) frequently becomes drug resistant and often recurs. Consequently, new drug targets and therapies are needed. Bioinformatics-based studies uncovered a relationship between high Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3 also known as PTP4A3) expression and poor patient survival in both early and late stage OvCa. PTP4A3 mRNA levels were 5–20 fold higher in drug resistant or high grade serous OvCa cell lines compared to nonmalignant cells. JMS-053 is a potent allosteric small molecule PTP4A3 inhibitor and to explore further the role of PTP4A3 in OvCa, we synthesized and interrogated a series of JMS-053-based analogs in OvCa cell line-based phenotypic assays. While the JMS-053 analogs inhibit in vitro PTP4A3 enzyme activity, none were superior to JMS-053 in reducing high grade serous OvCa cell survival. Because PTP4A3 controls cell migration, we interrogated the effect of JMS-053 on this cancer-relevant process. Both JMS-053 and CRISPR/Cas9 PTP4A3 depletion blocked cell migration. The inhibition caused by JMS-053 required the presence of PTP4A3. JMS-053 caused additive or synergistic in vitro cytotoxicity when combined with paclitaxel and reduced in vivo OvCa dissemination. These results indicate the importance of PTP4A3 in OvCa and support further investigations of the lead inhibitor, JMS-053.

scholarly journals Overexpressing the CCL2 chemokine in an epithelial ovarian cancer cell line results in latency of in vivo tumourigenicity

Oncogenesis ◽  
2012 ◽  
Vol 1 (9) ◽  
pp. e27-e27 ◽  
Author(s):  
P Wojnarowicz ◽  
K Gambaro ◽  
M de Ladurantaye ◽  
M C J Quinn ◽  
D Provencher ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Cell Line ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Ovarian Cancer Cell Line ◽  
Cancer Cell Line ◽  
Epithelial Ovarian Cancer Cell

Therapeutic efficacy of an oncolytic adenovirus monitored by in vivo imaging of an ovarian cancer model

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10061-10061
Author(s):  
Y. Tsuruta ◽  
L. Pereboeva ◽  
D. T. Rein ◽  
M. Breidenbach ◽  
D. T. Curiel
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Murine Model ◽  
Ovarian Cancer Cell ◽  
Imaging System ◽  
Wild Type ◽  
Non Invasive ◽  
Ovarian Cancer Cell Lines

10061 Background: Although a number of advances in ovarian cancer treatment have occurred in the last decade, most patients will experience a recurrence after standard therapies. Recently, virotherapy has been proposed as a new therapeutic approach for ovarian cancer. Conditionally replicative adenovirus (CRAd) contains tumor-specific promoters that restrict virus replication to cancer cells and has shown particular promise as oncolytic viral agents. However, the lack of a tumor-volume monitoring system hinders the evaluation of CRAd impact on cancer treatment. Therefore, methods for analyzing CRAd efficacy and tumor response are required. Mesothelin, a cell surface glycoprotein, is overexpressed in ovarian cancer but not in normal ovarian tissues. The purpose of this study was to explore the therapeutic utility of a mesothelin promoter-based CRAd in a murine model of ovarian cancer, using a non-invasive biological imaging system. Methods: We constructed a mesothelin promoter based CRAd which also contains a modified fiber (Ad5/3 fiber) previously shown to improve infectivity of many ovarian cancer cells (Ad5/3MSLN). Viral replication and oncolysis were assessed in a panel of ovarian cancer cell lines. To test the oncolytic efficacy of Ad5/3MSLN in murine model, firefly luciferase-expressing SK-OV-3-luc cells were injected intraperitoneally (i.p.), followed by an i.p. injection of viruses. Then, bioluminescence imaging of tumor luciferase activity was carried out. Results: Ad5/3MSLN achieved up to 10,000-fold higher cell killing effect and up to 120-fold higher levels of viral replication in all ovarian cancer cell lines tested, compared to wild type Ad5. In vivo tumor imaging confirmed that Ad5/3MSLN significantly inhibited tumor growth, while the untreated mice had rapid tumor growth (p<0.05). Survival with Ad5/3MSLN was significantly enhanced when compared with no virus, or wild type Ad5-treated group (p<0.05). Conclusions: The robust replication, oncolysis, and in vivo therapeutic efficacy of Ad5/3MSLN demonstrated that this CRAd is a promising candidate for treating ovarian cancer. Importantly, we have established an in vivo non-invasive imaging system, which has allowed repeated and longitudinal measurements of tumor growth after CRAd treatment. No significant financial relationships to disclose.

scholarly journals Forkhead Box Protein C2 (FOXC2) Promotes the Resistance of Human Ovarian Cancer Cells to Cisplatin In Vitro and In Vivo

2016 ◽  
Vol 39 (1) ◽  
pp. 242-252 ◽  
Author(s):  
Chanjuan Li ◽  
Hongjuan Ding ◽  
Jing Tian ◽  
Lili Wu ◽  
Yun Wang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Mapk Signaling ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
Cancer Tissues ◽  
Mapk Signaling Pathways

Background/Aims: FOXC2 has been reported to play a role in tumor progression, but the correlations of FOXC2 with the cisplatin (CDDP) resistance of ovarian cancer cells are still unclear. The purpose of the present study is to investigate the roles of FOXC2 in the CDDP resistance of ovarian cancer cells and its possible mechanisms. Methods: Quantitative real-time PCR (qRT-PCR) was performed to detect the expression of FOXC2 mRNA in CDDP-resistant or sensitive ovarian cancer tissues and cell lines (SKOV3/CDDP and SKOV3). Gain- and loss-of-function assays were performed to analyze the effects of FOXC2 knockdown or overexpression on the in vitro and in vivo sensitivity of ovarian cancer cells to CDDP and its possible molecular mechanisms. Results: The relative expression level of FOXC2 mRNA in CDDP-resistant ovarian cancer tissues was higher than that in CDDP-sensitive tissues. Also, the expression of FOXC2 mRNA and protein in CDDP-resistant ovarian cancer cell line (SKOV3/CDDP) cell line was higher than that in its parental cell line (SOKV3). Small hairpin RNA (shRNA)-mediated FOXC2 knockdown significantly increased the in vitro and in vive sensitivity of SKOV3/CDDP cells to CDDP by enhancing apoptosis, while upregulation of FOXC2 significantly decreased the in vitro and in vivo sensitivity of SKOV3 cells to CDDP by reducing apoptosis. Furthermore, FOXC2 activates the Akt and MAPK signaling pathways, and then induced the decreased expression of Bcl-2 protein and the increased expression of Bax and cleaved caspase-3 proteins. Conclusions: FOXC2 mediates the CDDP resistance of ovarian cancer cells by activation of the Akt and MAPK signaling pathways, and may be a potential novel therapeutic target for overcoming CDDP resistance in human ovarian cancer.

B7-H4 Expression Promotes Tumorigenesis in Ovarian Cancer

2009 ◽  
Vol 19 (9) ◽  
pp. 1481-1486 ◽  
Author(s):  
Lei Cheng ◽  
Jie Jiang ◽  
Ran Gao ◽  
Shuangyan Wei ◽  
Fangfang Nan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Green Fluorescent Protein ◽  
Cell Line ◽  
Cellular Proliferation ◽  
Fluorescent Protein ◽  
Ovarian Cancer Cell ◽  
Ovarian Cancer Cell Line ◽  
Cancer Cell Line ◽  
Green Fluorescent

Introduction:It has been previously shown that B7-H4, one of the B7 family members that serve as negative regulators of T cell function, has altered expression levels in a variety of cancers, overexpression of B7-H4 promotes cellular transformation. However, there is still lack of adequate evidence to establish a direct connection between B7-H4 expression and malignant transformation.Methods:Herein, we constructed pE-green fluorescent protein-N1/B7-H4 mammalian expression vector and transfected into B7-H4-negative human ovarian cancer cell line SKOV3. Cellular proliferation, apoptosis, adhesion, motility, and invasion were examined in vitro. Cells injected subcutaneously into severe combined immunodeficient mouse were analyzed for the possible functions of B7-H4 in ovarian tumorigenesis in vivo.Results:Fluorescence microscopy studies confirmed that the B7-H4-green fluorescent protein localizes in the cytoplasm of SKOV3/B7-H4 cells, whereas green fluorescent protein is uniformly distributed throughout the cell. B7-H4 promoted cellular proliferation rate and increased cell adhesion, migration, and invasion. In addition, SKOV3 cells expressing B7-H4 gained growth advantage in the xenograft model in vivo.Conclusions:These studies demonstrate that B7-H4 directly promotes malignant transformation of ovarian cancer cell line, and provides a potential therapeutic strategy for targeting B7-H4 to inhibit progression of human ovarian cancers.

scholarly journals An in-tumor genetic screen reveals that the BET bromodomain protein, BRD4, is a potential therapeutic target in ovarian carcinoma

2014 ◽  
Vol 112 (1) ◽  
pp. 232-237 ◽  
Author(s):  
Maria Giuseppina Baratta ◽  
Anna C. Schinzel ◽  
Yaara Zwang ◽  
Pratiti Bandopadhayay ◽  
Christian Bowman-Colin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
Cell Line ◽  
Cancer Cell ◽  
Therapeutic Target ◽  
Ovarian Cancer Cell ◽  
Ovarian Cancer Cell Line ◽  
Cancer Cell Line ◽  
Brd4 Inhibition

High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive form of epithelial ovarian cancer, for which few targeted therapies exist. To search for new therapeutic target proteins, we performed an in vivo shRNA screen using an established human HGSOC cell line growing either subcutaneously or intraperitoneally in immunocompromised mice. We identified genes previously implicated in ovarian cancer such as AURKA1, ERBB3, CDK2, and mTOR, as well as several novel candidates including BRD4, VRK1, and GALK2. We confirmed, using both genetic and pharmacologic approaches, that the activity of BRD4, an epigenetic transcription modulator, is necessary for proliferation/survival of both an established human ovarian cancer cell line (OVCAR8) and a subset of primary serous ovarian cancer cell strains (DFs). Among the DFs tested, the strains sensitive to BRD4 inhibition revealed elevated expression of either MYCN or c-MYC, with MYCN expression correlating closely with JQ1 sensitivity. Accordingly, primary human xenografts derived from high-MYCN or c-MYC strains exhibited sensitivity to BRD4 inhibition. These data suggest that BRD4 inhibition represents a new therapeutic approach for MYC-overexpressing HGSOCs.

scholarly journals Equol-induces apoptosis in chemoresistant ovarian cancer cells via external pathway

2015 ◽  
Vol 11 (1) ◽  
pp. 75
Author(s):  
Xue-Mei Gong ◽  
Cheng-Jiu Hu ◽  
Quan-Jing Zhao ◽  
Dong-Mei Shi
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Ovarian Cancer Cell Line ◽  
Cancer Cell Line ◽  
Bioactive Molecules ◽  
Ovarian Cancer Cells ◽  
Wide Range

<p>Polyphenolic compounds present in fruits, vegetables and grains are bioactive molecules which elicit a wide range of responses both in vivo and in vitro. The aim of this study was to investigate whether the soybean isoflavone Equol could induce apoptosis in ovarian cancer cells. In this study, we evaluated molecular events associated with apoptosis induced by Equol and paclitaxel (PTX) in an ovarian cancer cell line SKOV-3. To assess whether growth inhibition was due to apoptosis, flow cytometry, colorimetry experiments, immunoblot analyses through measuring DNA fragmentation, the level of TRAIL,the cleavage of poly(ADP-ribose) polymerase (PARP) and the activation of caspase-3, -8 and -9 were also performed. Additional markers of apoptosis were also measured like phosphatidylserine externalization and morphological changes. In addition, glycoprotein P (P-gp) activity in SKOV-3 ovarian cancer cell line was also estimated. The experimental results showed that apoptosis was induced by extrinsic pathway triggered by certain TNF family members. Overall results suggested that Equol induces apoptosis in SKOV-3 cells via a TRAIL and caspase 8-dependent pathway whereas paclitaxel leads to smaller apoptotic events when compared to that of Equol.</p>

scholarly journals Mucins and Truncated O-Glycans Unveil Phenotypic Discrepancies between Serous Ovarian Cancer Cell Lines and Primary Tumours

2018 ◽  
Vol 19 (7) ◽  
pp. 2045 ◽  
Author(s):  
Ricardo Coelho ◽  
Lara Marcos-Silva ◽  
Nuno Mendes ◽  
Daniela Pereira ◽  
Catarina Brito ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Lines ◽  
Expression Profiles ◽  
Ovarian Carcinomas ◽  
Cellular Models ◽  
Ovarian Cancer Cell Lines ◽  
Ovca Cell

Optimal research results rely on the selection of cellular models capable of recapitulating the characteristics of primary tumours from which they originate. The expression of mucins (MUC16 and MUC1) and truncated O-glycans (Tn, STn and T) represents a characteristic footprint of serous ovarian carcinomas (SOCs). Therefore, selecting ovarian cancer (OVCA) cell lines that reflect this phenotype is crucial to explore the putative biological role of these biomarkers in the SOC setting. Here, we investigated a panel of OVCA cell lines commonly used as SOC models, and tested whether, when cultured in 2D and 3D conditions, these recapitulate the mucin and O-glycan expression profiles of SOCs. We further explored the role of truncating the O-glycosylation capacity in OVCAR3 cells through knockout of the COSMC chaperone, using in vitro and in vivo assays. We found that the majority of OVCA cell lines of serous origin do not share the mucin and truncated O-glycan footprint of SOCs, although 3D cultures showed a higher resemblance. We also found that genetic truncation of the O-glycosylation capacity of OVCAR3 cells did not enhance oncogenic features either in vitro or in vivo. This study underscores the importance of well-characterized cellular models to study specific features of ovarian cancer.

scholarly journals Use of Transabdominal Ultrasound for the Detection of Intra-Peritoneal Tumor Engraftment and Growth in Mouse Xenografts of Epithelial Ovarian Cancer

2020 ◽  
Author(s):  
Laura M. Chambers ◽  
Emily Esakov ◽  
Chad Braley ◽  
Mariam AlHilli ◽  
Chad Michener ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Epithelial Ovarian Cancer ◽  
Tumor Volume ◽  
Imaging System ◽  
Tumor Detection ◽  
Study Endpoint ◽  
Post Injection ◽  
Transabdominal Ultrasound

AbstractObjectiveTo evaluate intraperitoneal (IP) tumor engraftment, metastasis and growth in a pre-clinical murine epithelial ovarian cancer (EOC) model using both transabdominal ultrasound (TAUS) and bioluminescence in vivo imaging system (IVIS).MethodsTen female C57Bl/6J mice at six weeks of age were included in this study. Five mice underwent IP injection of 5×106 ID8-luc cells (+ D-luciferin) and the remaining five mice underwent IP injection of ID8-VEGF cells. Monitoring of tumor growth and ascites was performed weekly starting at seven days post-injection until study endpoint. ID8-luc mice were monitored using both TAUS and IVIS, and ID8-VEGF mice underwent TAUS monitoring only. Individual tumor implant dimension and total tumor volume were calculated. Average luminescent intensity was calculated and reported per mouse abdomen. Tumor detection was confirmed by gross evaluation and histopathology. All data are presented as mean +/- standard deviation.ResultsOverall, tumors were successfully detected in all ten mice using TAUS and IVIS, and tumor detection correlated with terminal endpoint histology/ H&E staining. For TAUS, the smallest confirmed tumor measurements were at seven days post-injection with mean long axis of 2.23mm and mean tumor volume of 4.17mm3. However, IVIS imaging was able to detect tumor growth at 14 days post-injection.ConclusionsTAUS is highly discriminatory for monitoring EOC in pre-clinical murine model, allowing for detection of tumor dimension as small as 2 mm and as early as seven days post-injection compared to IVUS. In addition, TAUS provides relevant information for ascites development and detection of multiple small metastatic tumor implants. TAUS provides an accurate and reliable method to detect and monitor IP EOC growth in mouse xenografts.

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