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Katrina K Au, Nichole Peterson, Peter Truesdell, Gillian Reid-Schachter, Kasra Khalaj, Runhan Ren, Julie-Ann Francis, Charles H Graham, Andrew W Craig, Madhuri Koti
OBJECTIVE: We recently established that high STAT1 expression and associated T helper type I tumour immune microenvironment (TME) are prognostic and chemotherapy response predictive biomarkers in high-grade serous ovarian cancer (HGSC). STAT1 induced chemokine CXCL10 is key to the recruitment of lymphocytes in the TME and is significantly highly expressed in the tumours from patients with longer survival. In the current study we therefore aimed to elucidate the role CXCL10 in disease progression and tumour immune transcriptomic alterations using the ID8 syngeneic murine model of HGSC...
March 16, 2017: Gynecologic Oncology
Mee Rie Sheen, Steven Fiering
Many cancers including ovarian, pancreatic, colon, liver, and stomach cancers are largely confined to the peritoneal cavity. Peritoneal tumors are directly accessible by intraperitoneal injections. Previously we demonstrated that intraperitoneal injection of nanoparticles and subsequent ingestion by tumor-associated phagocytes can be used to either directly impact tumors or stimulate antitumor immune responses. Here we outline methods to specifically utilize iron oxide nanoparticles with the ID8-Defb29/Vegf-A murine ovarian cancer model and discuss the tendency of phagocytes to ingest nanoparticles and the potential of phagocytes to carry nanoparticles to tumors resulting in direct killing of tumor cells or stimulate antitumor immune responses in peritoneal cancers...
2017: Methods in Molecular Biology
Eric T Alexander, Allyson R Minton, Molly C Peters, Joanne van Ryn, Susan K Gilmour
Cancer is often associated with an increased risk of thrombotic complications which can be aggravated by treatment with chemotherapeutics such as cisplatin. Multiple lines of evidence suggest that thrombin activity promotes tumor growth and metastasis. We examined the effect of co-treatment with dabigatran etexilate, a direct thrombin inhibitor, and cisplatin using the murine ID8 ovarian cancer model. Mice receiving co-treatment with both dabigatran etexilate and low dose cisplatin had significantly smaller tumors, developed less ascites and had lower levels of circulating activated platelets and tissue factor (TF) positive microparticles than those treated with dabigatran etexilate or cisplatin alone...
December 20, 2016: Oncotarget
Thaïs Baert, Abhishek D Garg, Eva Vindevogel, Anaïs VAN Hoylandt, Godelieve Verbist, Patrizia Agostinis, Ignace Vergote, A N Coosemans
BACKGROUND/AIM: Dendritic cell (DC) immunotherapy induces tumor-reactive T-cells. We optimized the maturation of murine DC against ovarian cancer. MATERIALS AND METHODS: Immature DC were generated from bone-marrow progenitor cells and loaded with hypericin-photodynamic-treated (Hyp-PDT) tumor cells (primary maturation). Lipopolysacharide (LPS 1 μg/ml) was used as a secondary maturation stimulus. After 24 h, maturation was assessed using flow cytometry. For in vivo experiments, C57BL/6 mice were vaccinated subcutaneously with matured, loaded mature DC...
November 2016: Anticancer Research
Eva Vindevogel, Thaïs Baert, Anaïs VAN Hoylandt, Godelieve Verbist, Greetje Vande Velde, Abhishek D Garg, Patricia Agostinis, Ignace Vergote, A N Coosemans
BACKGROUND: Dendritic cell (DC) mono-immunotherapy has not been successful so far in ovarian cancer. The addition of a toll-like receptor (TLR) agonist has the potential to boost the innate immune system, in addition to the adoptive immune response initiated by DCs. MATERIALS AND METHODS: ID8-fLuc C57BL/6 mice were injected with DCs loaded with hypericin-based photodynamic therapy-treated tumor lysate. A TLR4 agonist [lipopolysaccharide (LPS)] was administered by different schedules)...
2016: Anticancer Research
Yan Huang, Lenard M Lichtenberger, Morgan Taylor, Justin N Bottsford-Miller, Monika Haemmerle, Michael J Wagner, Yasmin Lyons, Sunila Pradeep, Wei Hu, Rebecca A Previs, Jean M Hansen, Dexing Fang, Piotr L Dorniak, Justyna Filant, Elizabeth J Dial, Fangrong Shen, Hiroto Hatakeyama, Anil K Sood
To determine the efficacy of a novel and safer (for gastrointestinal tract) aspirin (aspirin-PC) in preclinical models of ovarian cancer, in vitro dose-response studies were performed to compare the growth-inhibitory effect of aspirin-PC versus aspirin on three human (A2780, SKOV3ip1, and HeyA8) and a mouse (ID8) ovarian cancer cell line over an 8-day culture period. In the in vivo studies, the aspirin test drugs were studied alone and in the presence of a VEGF-A inhibitor (bevacizumab or B20), due to an emerging role for platelets in tumor growth following antiangiogenic therapy, and we examined their underlying mechanisms...
December 2016: Molecular Cancer Therapeutics
Nicolle M Linnerth-Petrik, Lisa A Santry, Roger Moorehead, Manfred Jücker, Sarah K Wootton, Jim Petrik
Ovarian cancer remains a significant therapeutic problem and novel, effective therapies are needed. Akt is a serine-threonine kinase that is overexpressed in numerous cancers, including ovarian. Mammalian cells express three Akt isoforms which are encoded by distinct genes. Although there are several Akt inhibitors in clinical trials, most indiscriminately target all isoforms. Current in vitro data and animal knockout experiments suggest that the Akt isoforms may have divergent roles. In this paper, we determined the isoform-specific functions of Akt in ovarian cancer cell proliferation in vitro and in ovarian cancer progression in vivo...
November 15, 2016: Oncotarget
Josephine Walton, Julianna Blagih, Darren Ennis, Elaine Leung, Suzanne Dowson, Malcolm Farquharson, Laura A Tookman, Clare Orange, Dimitris Athineos, Susan Mason, David Stevenson, Karen Blyth, Douglas Strathdee, Frances R Balkwill, Karen Vousden, Michelle Lockley, Iain A McNeish
There is a need for transplantable murine models of ovarian high-grade serous carcinoma (HGSC) with regard to mutations in the human disease to assist investigations of the relationships between tumor genotype, chemotherapy response, and immune microenvironment. In addressing this need, we performed whole-exome sequencing of ID8, the most widely used transplantable model of ovarian cancer, covering 194,000 exomes at a mean depth of 400× with 90% exons sequenced >50×. We found no functional mutations in genes characteristic of HGSC (Trp53, Brca1, Brca2, Nf1, and Rb1), and p53 remained transcriptionally active...
October 15, 2016: Cancer Research
Xiulong Niu, Wenxing Liu, Yue Wang, Xiaomei Liu, Hongjian Zhang, Zhijun Li, Hongzhao Li, Yoichiro Iwakura, Weimin Deng
The major obstacle of the tumor chemotherapy, including ovarian cancer (OVCA), is drug resistance. However, the relevance of IL-17A with drug-resistance of OVCA has been poorly elaborated. In this study, we used 2 human OVCA cell lines to investigate the effects of IL-17A on cisplatin (CDDP or DDP)-based resistance in OVCA cells and the underlying mechanisms. Meanwhile, IL-17A-deficient mice and ID8 were used to verify the IL-17A's effects on OVCA chemo-resistance in vivo. Moreover, the relationship between IL-17A level and relevant indices were primarily assessed in ovarian specimens from 55 patients with OVCA...
July 18, 2016: Oncotarget
James B Greenaway, Carl Virtanen, Kata Osz, Tamas Revay, Daniel Hardy, Trevor Shepherd, Gabriel DiMattia, Jim Petrik
Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer and often is not detected until late stages when cancer cells transcoelomically metastasize to the abdomen and typically become resistant to therapy resulting in very low survival rates. We utilize an orthotopic, syngeneic mouse model to study late stage disease and have discovered that the tumor cells within the abdominal ascites are irreversibly re-programmed, with an increased tumorigenicity and resistance to apoptosis. The goal of this study was to characterize the reprogramming that occurred in the aggressive ascites-derived cells (28-2 cells) compared to the original cell line used for tumor induction (ID8 cells)...
July 26, 2016: Oncotarget
Suprita A Tawde, Lipika Chablani, Archana Akalkotkar, Martin J D'Souza
Ovarian cancer is the fifth most commonly occurring malignancy in women, with the highest mortality rate among all the gynecological tumors. Microparticulate vaccine can serve as an immunotherapeutic approach with a promising antigenic delivery system without a need for conventional adjuvants. In this study, a microparticulate vaccine using whole cell lysate of a murine ovarian cancer cell line, ID8 was prepared by spray drying. Further, the effect of interleukins (ILs) such as IL-2 and IL-12 was evaluated in a separate study group by administering them with vaccine particles to enhance the immune response...
August 10, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
Spencer D Martin, Scott D Brown, Darin A Wick, Julie S Nielsen, David R Kroeger, Kwame Twumasi-Boateng, Robert A Holt, Brad H Nelson
Due to advances in sequencing technology, somatically mutated cancer antigens, or neoantigens, are now readily identifiable and have become compelling targets for immunotherapy. In particular, neoantigen-targeted vaccines have shown promise in several pre-clinical and clinical studies. However, to date, neoantigen-targeted vaccine studies have involved tumors with exceptionally high mutation burdens. It remains unclear whether neoantigen-targeted vaccines will be broadly applicable to cancers with intermediate to low mutation burdens, such as ovarian cancer...
2016: PloS One
Adnan Munkarah, Ismail Mert, Jasdeep Chhina, Suhail Hamid, Laila Poisson, Sharon Hensley-Alford, Shailendra Giri, Ramandeep Rattan
OBJECTIVES: Adipocyte derived free fatty acids (FFA) promote epithelial ovarian cancer (EOC) by acting as a fuel source to support the energy requirement of the cancer cells. FFA may also exert biological effects through signaling pathways. Recently, a family of FFA activated G-protein coupled receptors (FFAR/GPCRs) was identified. Our objective was to investigate the role of FFAR/GPCRs in EOC and assess their potential as therapeutic targets. METHODS: The mRNA (RT-PCR) expression of FFAR/GPCR family members (FFAR1/GPR40; FFAR2/GPR43, FFAR3/GPR41, FFAR4/GPR120 and GPR84) was examined in: (1) a syngeneic mouse model of EOC fed high energy diet (60% fat) or regular diet (30% fat), (2) EOC cell lines exposed to free fatty acids and (3) specimens from 13 histologically normal ovaries and 28 high grade ovarian serous carcinomas...
April 2016: Gynecologic Oncology
Thaïs Baert, Tina Verschuere, Anaïs Van Hoylandt, Rik Gijsbers, Ignace Vergote, An Coosemans
Reliable mouse models are key in the discovery and development of novel anticancer treatments. Non-invasive monitoring techniques such as bioluminescence imaging (BLI) are useful tools to determine tumor engraftment and evaluate tumor growth. However, the development of ascites in ovarian cancer mouse models leads to possible difficulties. Ascites can interfere with the set-up of correct end points and can interfere with the evaluation of tumor volume using BLI. We provide optimized euthanasia criteria and in vivo data underlining the pitfalls of BLI...
2015: Journal for Immunotherapy of Cancer
Zhenwen Zhao, Qingchun Cai, Yan Xu
Despite huge advances in the research of epithelial ovarian cancer (EOC), it remains the most lethal gynecological malignancy. Peritoneal tumor cell dissemination with cell survival and drug-resistance to taxane and platinum-based chemotherapy are two of the major challenges of EOC treatment. We have generated highly aggressive EOC cell lines (ID8-P1 lines or P1) from ID8-P0 (without in vivo passage, or P0) through in vivo passage in mice. We conducted lipidomic analyses in cells from ID8-P0 versus three ID8-P1 cell lines using ultra-high-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry...
February 2016: Lipids
Cagri Sakalar, Suparna Mazumder, Justin M Johnson, Cengiz Z Altuntas, Ritika Jaini, Robert Aguilar, Sathyamangla V Naga Prasad, Denise C Connolly, Vincent K Tuohy
Anti-Müllerian hormone receptor, type II (AMHR2), is a differentiation protein expressed in 90% of primary epithelial ovarian carcinomas (EOCs), the most deadly gynecologic malignancy. We propose that AMHR2 may serve as a useful target for vaccination against EOC. To this end, we generated the recombinant 399-amino acid cytoplasmic domain of mouse AMHR2 (AMHR2-CD) and tested its efficacy as a vaccine target in inhibiting growth of the ID8 transplantable EOC cell line in C57BL/6 mice and in preventing growth of autochthonous EOCs that occur spontaneously in transgenic mice...
2015: Journal of Immunology Research
Andrew J Wilson, Jeanette Saskowski, Whitney Barham, Dineo Khabele, Fiona Yull
BACKGROUND: Ovarian cancer is the most lethal gynecologic malignancy, with limited treatment options for chemoresistant disease. An important link between inflammation and peritoneal spread of ovarian cancer is NF-κB signaling. Thymoquinone (TQ) exerts multiple anti-tumorigenic cellular effects, including NF-κB inhibition. We aimed to investigate the therapeutic potential of TQ in an established murine syngeneic model of ovarian cancer. METHODS: ID8-NGL mouse ovarian cancer cells stably expressing an NF-κB reporter transgene were injected intra-peritoneally into C57BL/6 mice, and mice were treated with TQ or vehicle for 10 or 30 days...
November 9, 2015: Molecular Cancer
Diana L Moughon, Huanhuan He, Shiruyeh Schokrpur, Ziyue Karen Jiang, Madeeha Yaqoob, John David, Crystal Lin, M Luisa Iruela-Arispe, Oliver Dorigo, Lily Wu
Malignant ascites is a common complication in the late stages of epithelial ovarian cancer (EOC) that greatly diminishes the quality of life of patients. Malignant ascites is a known consequence of vascular dysfunction, but current approved treatments are not effective in preventing fluid accumulation. In this study, we investigated an alternative strategy of targeting macrophage functions to reverse the vascular pathology of malignant ascites using fluid from human patients and an immunocompetent murine model (ID8) of EOC that mirrors human disease by developing progressive vascular disorganization and leakiness culminating in massive ascites...
November 15, 2015: Cancer Research
Martin Turcotte, Kathleen Spring, Sandra Pommey, Guillaume Chouinard, Isabelle Cousineau, Joshy George, Gregory M Chen, Deena M A Gendoo, Benjamin Haibe-Kains, Thomas Karn, Kurosh Rahimi, Cécile Le Page, Diane Provencher, Anne-Marie Mes-Masson, John Stagg
The cell surface nucleotidase CD73 is an immunosuppressive enzyme involved in tumor progression and metastasis. Although preclinical studies suggest that CD73 can be targeted for cancer treatment, the clinical impact of CD73 in ovarian cancer remains unclear. In this study, we investigated the prognostic value of CD73 in high-grade serous (HGS) ovarian cancer using gene and protein expression analyses. Our results demonstrate that high levels of CD73 are significantly associated with shorter disease-free survival and overall survival in patients with HGS ovarian cancer...
November 1, 2015: Cancer Research
Sue D Xiang, Qian Gao, Kirsty L Wilson, Arne Heyerick, Magdalena Plebanski
Ovarian cancer (OC) is the seventh most common cancer in women worldwide, and the leading cause of death from gynaecological malignancy. Immunotherapeutic strategies including cancer vaccines are considered less toxic and more specific than current treatments. Sperm surface protein (Sp17) is a protein aberrantly expressed in primary as well as in metastatic lesions in >83% of ovarian cancer patients. Vaccines based on the Sp17 protein are immunogenic and protective in animal models. To map the immunogenic regions and support the development of human Sp17 peptide based vaccines, we used 6 overlapping peptides of the human Sp17 sequence adjuvanted with CpG to immunise humanised HLA-A2...
November 4, 2015: Vaccine
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