期刊论文详细信息
BMC Cancer
Integrated genomics of ovarian xenograft tumor progression and chemotherapy response
Research Article
Anna Ritz1  Benjamin J Raphael1  Andrew Fischer2  Sara Hillenmeyer2  Alexander S Brodsky2  Daniel H Miller2  Laurent Brard3  Rakesh K Singh4  Ashley Stuckey4  Kyu K Kim4 
[1] Department of Computer Science & Center for Computational Molecular Biology, Brown University, 02912, Providence, RI, USA;Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, 02903, Providence, RI, USA;Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Southern Illinois University School of Medicine, 62794-9640, Springfield, IL, USA;Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants7 Hospital, Alpert Medical School of Brown University, 02905, Providence, RI, USA;
关键词: Rosiglitazone;    Epithelial Ovarian Cancer;    Ovarian Cancer Cell;    Xenograft Tumor;    Ingenuity Pathway Analysis;   
DOI  :  10.1186/1471-2407-11-308
 received in 2010-09-10, accepted in 2011-07-22,  发布年份 2011
来源: Springer
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【 摘 要 】

BackgroundOvarian cancer is the most deadly gynecological cancer with a very poor prognosis. Xenograft mouse models have proven to be one very useful tool in testing candidate therapeutic agents and gene function in vivo. In this study we identify genes and gene networks important for the efficacy of a pre-clinical anti-tumor therapeutic, MT19c.MethodsIn order to understand how ovarian xenograft tumors may be growing and responding to anti-tumor therapeutics, we used genome-wide mRNA expression and DNA copy number measurements to identify key genes and pathways that may be critical for SKOV-3 xenograft tumor progression. We compared SKOV-3 xenografts treated with the ergocalciferol derived, MT19c, to untreated tumors collected at multiple time points. Cell viability assays were used to test the function of the PPARγ agonist, Rosiglitazone, on SKOV-3 cell growth.ResultsThese data indicate that a number of known survival and growth pathways including Notch signaling and general apoptosis factors are differentially expressed in treated vs. untreated xenografts. As tumors grow, cell cycle and DNA replication genes show increased expression, consistent with faster growth. The steroid nuclear receptor, PPARγ, was significantly up-regulated in MT19c treated xenografts. Surprisingly, stimulation of PPARγ with Rosiglitazone reduced the efficacy of MT19c and cisplatin suggesting that PPARγ is regulating a survival pathway in SKOV-3 cells. To identify which genes may be important for tumor growth and treatment response, we observed that MT19c down-regulates some high copy number genes and stimulates expression of some low copy number genes suggesting that these genes are particularly important for SKOV-3 xenograft growth and survival.ConclusionsWe have characterized the time dependent responses of ovarian xenograft tumors to the vitamin D analog, MT19c. Our results suggest that PPARγ promotes survival for some ovarian tumor cells. We propose that a combination of regulated expression and copy number can identify genes that are likely important for chemotherapy response. Our findings suggest a new approach to identify candidate genes that are critical for anti-tumor therapy.

【 授权许可】

Unknown   
© Stuckey et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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