Ovarian cancer represents an impending candidate for intense research and a target for chemoprevention, because it is the most lethal gynecological malignancy and associated with a high mortality rate. The underlying causes of ovarian cancers remain elusive and treatment options for patients with advanced disease are still inadequate. While several studies suggest that the use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a decreased risk of developing ovarian cancer, other studies failed to detect any significant association. The cyclooxygenase (COX) enzymes, COX-1 and COX-2, catalyze prostaglandin (PG) biosynthesis. Research primarily on colorectal cancer has established that NSAIDs are effective in cancer prevention, and treatment of established tumors. These drugs are believed to inhibit cancer growth primarily by inhibiting COX-2. COX-2 is also upregulated in a range of extra-colonic cancers and selective COX-2 inhibitors show potent anti-neoplastic effects. These findings have led to the initiation of several clinical trials testing the efficacy of COX-2 selective inhibitors in the prevention of cancer or as part of a combination therapy for established tumors. The expression pattern of COX isoforms in ovarian cancer remains conflicting. Using multiple approaches, our preliminary results provide evidence that both human and mouse epithelial ovarian tumors show heightened expression of COX-1, not COX-2. To define whether the COX-derived PGs play any role in ovarian cancer and to determine whether a scientific rationale exists for the use of COX inhibitors in the prevention and/or treatment of the disease, in-depth studies are warranted. We hypothesize that COX-1 derived PGs play a major role in the genesis and progression of ovarian epithelial cancer by upregulating proangiogenic events. We will test our hypothesis by using human ovarian cancer samples with or without cytoreductive treatment, human ovarian cancer cell lines and mouse models of ovarian cancers.
Our specific aims are to: (1) Characterize models of ovarian cancer with respect to PG biosynthesis as well as the potential mechanisms of actions of the dominant PGs formed in executing proneoplastic effects and (2) Analyze the effects of COX inhibitors on the initiation and progression of ovarian tumors in mouse models. Our proposed genetic and molecular approaches in vivo and in vitro using human and mice as model systems will provide valuable information for better understanding of prevention and treatment of ovarian cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA077839-08
Application #
7229596
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
8
Fiscal Year
2006
Total Cost
$150,188
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Hsu, Alice H; Lum, Michelle A; Shim, Kang-Sup et al. (2018) Crosstalk between PKC? and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium. Cell Rep 24:655-669
Liang, Xiaohuan; Daikoku, Takiko; Terakawa, Jumpei et al. (2018) The uterine epithelial loss of Pten is inefficient to induce endometrial cancer with intact stromal Pten. PLoS Genet 14:e1007630
Wang, Dingzhi; DuBois, Raymond N (2018) Role of prostanoids in gastrointestinal cancer. J Clin Invest 128:2732-2742
Yuan, Jia; Deng, Wenbo; Cha, Jeeyeon et al. (2018) Tridimensional visualization reveals direct communication between the embryo and glands critical for implantation. Nat Commun 9:603
Cha, Jeeyeon; Dey, Sudhansu K (2017) Hunting for Fox(A2): Dual roles in female fertility. Proc Natl Acad Sci U S A 114:1226-1228
Wang, Dingzhi; Sun, Haiyan; Wei, Jie et al. (2017) CXCL1 Is Critical for Premetastatic Niche Formation and Metastasis in Colorectal Cancer. Cancer Res 77:3655-3665
Mendelson, Karen; Pandey, Suveg; Hisano, Yu et al. (2017) The ceramide synthase 2b gene mediates genomic sensing and regulation of sphingosine levels during zebrafish embryogenesis. Elife 6:
Yanagida, Keisuke; Hla, Timothy (2017) Vascular and Immunobiology of the Circulatory Sphingosine 1-Phosphate Gradient. Annu Rev Physiol 79:67-91
Sones, Jenny L; Cha, Jeeyeon; Woods, Ashley K et al. (2016) Decidual Cox2 inhibition improves fetal and maternal outcomes in a preeclampsia-like mouse model. JCI Insight 1:
Yuan, Jia; Cha, Jeeyeon; Deng, Wenbo et al. (2016) Planar cell polarity signaling in the uterus directs appropriate positioning of the crypt for embryo implantation. Proc Natl Acad Sci U S A 113:E8079-E8088

Showing the most recent 10 out of 336 publications