scholarly journals Hypoxia Regulated Inhibin Promotes Tumor Growth and Vascular Permeability By ACVRL1 and CD105 Dependent VE-Cadherin Internalization

2021 ◽  
Author(s):  
Karthikeyan Mythreye ◽  
Ben Horst ◽  
Shrikant Pradhan ◽  
Roohi Chaudhary ◽  
Eduardo Listik ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Ovarian Cancer Cell ◽  
Vascular Normalization ◽  
Cancer Management ◽  
Vessel Normalization ◽  
Ovarian Cancer Cell Lines ◽  
Tumor Growth And Metastasis ◽  
Early Tumor

Abstract Hypoxia, a driver of tumor growth and metastasis, regulates angiogenic pathways that are targets for vessel normalization and ovarian cancer management. However, toxicities and resistance to anti-angiogenics limits their use making identification of new targets vital. Inhibin, a heteromeric TGFb ligand, is a contextual regulator of tumor progression acting as an early tumor suppressor, yet also an established biomarker for ovarian cancers. Here, we demonstrate a previously unknown role for inhibins and find that hypoxia increases inhibin levels in ovarian cancer cell lines, xenograft tumors, and patients. Inhibin is regulated specifically through HIF-1, shifting the balance from activins to inhibins. Hypoxia regulated inhibin promotes tumor growth, endothelial cell invasion and permeability. Targeting inhibin in vivo through knockdown and anti-inhibin strategies robustly reduces permeability in vivo and alters the balance of pro and anti-angiogenic mechanisms resulting in vascular normalization. Mechanistically, inhibin regulates permeability by increasing VE-cadherin internalization via ACVRL1 and CD105, a receptor complex that we find stabilized directly by inhibin. Our findings are the first to demonstrate direct roles for inhibins in vascular normalization via TGF-b receptors providing new insights into the therapeutic significance of inhibins as a strategy to normalize the tumor vasculature in ovarian cancer.

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 In vivo tumor growth of high-grade serous ovarian cancer cell lines

2015 ◽  
Vol 138 (2) ◽  
pp. 372-377 ◽  
Author(s):  
Anirban K. Mitra ◽  
David A. Davis ◽  
Sunil Tomar ◽  
Lynn Roy ◽  
Hilal Gurler ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Cancer Cell Lines ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Ovarian Cancer Cell Lines

scholarly journals Characterization of SOX2, OCT4 and NANOG in Ovarian Cancer Tumor-Initiating Cells

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 262
Author(s):  
Mikella Robinson ◽  
Samuel F. Gilbert ◽  
Jennifer A. Waters ◽  
Omar Lujano-Olazaba ◽  
Jacqueline Lara ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Chemotherapy Resistance ◽  
Tumor Initiating Cells ◽  
In Vivo Experiments ◽  
Nanog Expression ◽  
Ovarian Cancer Cell Lines ◽  
Cancer Tumor ◽  
Early Tumor ◽  
Cycle Regulation

The identification of tumor-initiating cells (TICs) has traditionally relied on surface markers including CD133, CD44, CD117, and the aldehyde dehydrogenase (ALDH) enzyme, which have diverse expression across samples. A more reliable indication of TICs may include the expression of embryonic transcription factors that support long-term self-renewal, multipotency, and quiescence. We hypothesize that SOX2, OCT4, and NANOG will be enriched in ovarian TICs and may indicate TICs with high relapse potential. We evaluated a panel of eight ovarian cancer cell lines grown in standard 2-D culture or in spheroid-enriching 3-D culture, and correlated expression with growth characteristics, TIC marker expression, and chemotherapy resistance. RNA-sequencing showed that cell cycle regulation pathways involving SOX2 were elevated in 3-D conditions. HGSOC lines had longer doubling-times, greater chemoresistance, and significantly increased expression of SOX2, OCT4, and NANOG in 3-D conditions. CD117+ or ALDH+/CD133+ cells had increased SOX2, OCT4, and NANOG expression. Limiting dilution in in vivo experiments implicated SOX2, but not OCT4 or NANOG, with early tumor-initiation. An analysis of patient data suggested a stronger role for SOX2, relative to OCT4 or NANOG, for tumor relapse potential. Overall, our findings suggest that SOX2 may be a more consistent indicator of ovarian TICs that contribute to tumor repopulation following chemotherapy. Future studies evaluating SOX2 in TIC biology will increase our understanding of the mechanisms that drive ovarian cancer relapse.

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

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.

Antitumor activity of irofulven against human ovarian cancer cell lines, human tumor colony-forming units, and xenografts

2004 ◽  
Vol 14 (5) ◽  
pp. 824-831 ◽  
Author(s):  
E. S. Van Laar ◽  
E. Izbicka ◽  
S. Weitman ◽  
L. Medina-Gundrum ◽  
J. R. Macdonald ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Antitumor Activity ◽  
Tumor Growth ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Tumor ◽  
Ovarian Cancer Cell ◽  
Human Tumor ◽  
Ovarian Cancer Cell Lines

The objective of this study was to investigate the cytotoxic activity of irofulven (HMAF, MGI 114), a unique chemotherapeutic agent currently under clinical investigation, in various preclinical models of ovarian cancer. Antiproliferative effects of irofulven in ovarian cancer cell lines and ovarian tumor specimens were characterized in vitro using sulforhodamine B and human tumor colony-forming assays, respectively. Irofulven demonstrated marked activity against a panel of ovarian tumor cell lines, including IGROV1, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, and SK-OV-3, all of which exhibit various drug resistance mechanisms. In human tumor cloning assays, irofulven inhibited colony formation in surgically derived ovarian tumors at concentrations as low as 0.001 μg /ml and indicated superior activity in comparison with paclitaxel when tested against the same tumor specimens. The antitumor activity of irofulven compared to that of paclitaxel was also examined using the SK-OV-3 xenograft model. In mice bearing subcutaneously implanted SK-OV-3 tumors, treatment with paclitaxel failed to inhibit tumor growth; whereas mice treated with maximum tolerated doses of irofulven had a 25% partial shrinkage rate, and the remaining animals had a mean tumor growth inhibition of 82%. The potent activity of irofulven against ovarian tumors in vitro and in vivo supports the evaluation of its clinical activity in ovarian cancer.

scholarly journals Resveratrol, Acetyl-Resveratrol, and Polydatin Exhibit Antigrowth Activity against 3D Cell Aggregates of the SKOV-3 and OVCAR-8 Ovarian Cancer Cell Lines

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Simon J. Hogg ◽  
Kenny Chitcholtan ◽  
Wafaa Hassan ◽  
Peter H. Sykes ◽  
Ashley Garrill
Keyword(s):  
Ovarian Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Cancer Cell Lines ◽  
Cell Aggregates ◽  
Signalling Molecules ◽  
Ovarian Cancer Cell Lines ◽  
Her 2

Resveratrol has aroused significant scientific interest as it has been claimed that it exhibits a spectrum of health benefits. These include effects as an anti-inflammatory and an antitumour compound. The purpose of this study was to investigate and compare any potential antigrowth effects of resveratrol and two of its derivatives, acetyl-resveratrol and polydatin, on 3D cell aggregates of the EGFR/Her-2 positive and negative ovarian cancer cell lines SKOV-3 and OVCAR-8, respectively. Results showed that resveratrol and acetyl-resveratrol reduced cell growth in the SKOV-3 and OVCAR-8 in a dose-dependant manner. The growth reduction was mediated by the induction of apoptosis via the cleavage of poly(ADP-ribose) polymerase (PARP-1). At lower concentrations, 5 and 10 µM, resveratrol, acetyl-resveratrol, and polydatin were less effective than higher concentrations, 50 and 100 µM. In SKOV-3 line, at higher concentrations, resveratrol and polydatin significantly reduced the phosphorylation of Her-2 and EGFR and the expression of Erk. Acetyl-resveratrol, on the other hand, did not change the activation of Her-2 and EGFR. Resveratrol, acetyl-resveratrol, and polydatin suppressed the secretion of VEGF in a dose-dependant fashion. In the OVCAR-8 cell line, resveratrol and acetyl-resveratrol at 5 and 10 µM increased the activation of Erk. Above these concentrations they decreased activation. Polydatin did not produce this effect. This study demonstrates that resveratrol and its derivatives may inhibit growth of 3D cell aggregates of ovarian cancer cell lines via different signalling molecules. Resveratrol and its derivatives, therefore, warrant furtherin vivoevaluation to assess their potential clinical utility.

The Novel IκB Kinase β Inhibitor, IMD-0560, Has Potent Therapeutic Efficacy in Ovarian Cancer Xenograft Model Mice

2016 ◽  
Vol 26 (4) ◽  
pp. 610-618 ◽  
Author(s):  
Ikuko Sawada ◽  
Kae Hashimoto ◽  
Kenjiro Sawada ◽  
Yasuto Kinose ◽  
Koji Nakamura ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Therapeutic Potential ◽  
Ovarian Cancer Cell Lines ◽  
Iκb Kinase ◽  
Xenograft Mice

ObjectiveAberrant activation of nuclear factor-kappa β (NF-κB) signaling has been correlated with poor outcome among patients with ovarian cancer. Although the therapeutic potential of NF-κB pathway disruption in cancers has been extensively studied, most classical NF-κB inhibitors are poorly selective, exhibit off-target effects, and have failed to be applied in clinical use. IMD-0560,N-[2,5-bis (trifluoromethyl) phenyl]-5-bromo-2-hydroxybenzamide, is a novel low-molecular-weight compound that selectively inhibits the IκB kinase complex and works as an inhibitor of NF-κB signaling. The aim of this study was to assess the therapeutic potential of IMD-0560 against ovarian cancer in vitro and in vivo.MethodsNF-κB activity (phosphorylation) was determined in 9 ovarian cancer cell lines and the inhibitory effect of IMD-0560 on NF-κB activation was analyzed by Western blotting. Cell viability, cell cycle, vascular endothelial growth factor (VEGF) expression, and angiogenesis were assessed in vitro to evaluate the effect of IMD-0560 on ovarian cancer cells. In vivo efficacy of IMD-0560 was also investigated using an ovarian cancer xenograft mouse model.ResultsThe NF-κB signaling pathway was constitutively activated in 8 of 9 ovarian cancer cell lines. IMD-0560 inhibited NF-κB activation and suppressed ovarian cancer cell proliferation by inducing G1 phase arrest. IMD-0560 decreased VEGF secretion from cancer cells and inhibited the tube formation of human umbilical vein endothelial cells. IMD-0560 significantly inhibited peritoneal metastasis and prolonged the survival in an ovarian cancer xenograft mice model. Immunohistochemical staining of excised tumors revealed that IMD-0560 suppressed VEGF expression, tumor angiogenesis, and cancer cell proliferation.ConclusionsIMD-0560 showed promising therapeutic efficacy against ovarian cancer xenograft mice by inducing cell cycle arrest and suppressing VEGF production from cancer cells. IMD-0560 may be a potential future option in regimens for the treatment of ovarian cancer.

scholarly journals Abrogation of group III phospholipase A2 inhibits tumor growth and metastasis in ovarian cancer and promotes chemo-sensitization

2021 ◽  
Author(s):  
Upasana Ray ◽  
Debarshi Roy ◽  
Ling Jin ◽  
Prabhu Thirusangu ◽  
Julie Staub ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Cell Viability ◽  
Phospholipase A2 ◽  
Mtt Assay ◽  
Ciliated Cells ◽  
Group Iii ◽  
Tumor Growth And Metastasis

Abstract Background Aberrant lipogenicity and deregulated autophagy are common in most advanced human cancer and therapeutic strategies to exploit these pathways are currently under consideration. Group III Phospholipase A2 (sPLA2-III/PLA2G3), an atypical secretory PLA2, is recognized as a regulator of lipid metabolism associated with oncogenesis. Though recent studies reveal that high PLA2G3 expression significantly correlates with poor prognosis in several cancers, however, role of PLA2G3 in ovarian cancer (OC) pathogenesis is still undetermined. Methods CRISPR-Cas9 and shRNA mediated knockout and knockdown of PLA2G3 in OC cells were used to evaluate lipid droplet (LD) biogenesis by confocal and Transmission electron microscopy analysis, and the cell viability and sensitization of the cells to platinum-mediated cytotoxicity by MTT assay. Regulation of primary ciliation by PLA2G3 downregulation both genetically and by metabolic inhibitor PFK-158 induced autophagy was assessed by immunofluorescence-based confocal analysis and immunoblot. Transient transfection with GFP-RFP-LC3B and confocal analysis was used to assess the autophagic flux in OC cells. PLA2G3 knockout OVCAR5 xenograft in combination with carboplatin on tumor growth and metastasis was assessed in vivo. Efficacy of PFK158 alone and with platinum drugs was determined in patient-derived primary ascites cultures expressing PLA2G3 by MTT assay and immunoblot analysis. Results Downregulation of PLA2G3 in OVCAR8 and 5 cells inhibited LD biogenesis, decreased growth and sensitized cells to platinum drug mediated cytotoxicity in vitro and in in vivo OVCAR5 xenograft. PLA2G3 knockdown in HeyA8MDR-resistant cells showed sensitivity to carboplatin treatment. We found that both PFK158 inhibitor-mediated and genetic downregulation of PLA2G3 resulted in increased number of percent ciliated cells and inhibited oncogenesis. Mechanistically, we found that PFK158-induced autophagy targeted PLA2G3 to restore primary cilia in OC cells. Of clinical relevance, PFK158 also induces percent ciliated cells in human-derived primary ascites cells and reduces cell viability with sensitization to chemotherapy. Conclusions Taken together, our study for the first time emphasizes the role of PLA2G3 in regulating the OC metastasis. This study further suggests the therapeutic potential of targeting phospholipases and/or restoration of PC for future OC treatment and the critical role of PLA2G3 in regulating ciliary function by coordinating interface between lipogenesis and metastasis.

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