The overall goal of the proposed project grant (PPG) is to assemble an interdisciplinary group of talented investigators from different fields to study the biology of ovarian cancer. The general theme of the PPG deals with the growth aspects of ovarian tumor progression. The hypothesis to be addressed is that the onset and progression of ovarian tumors is dependent on aspects of growth regulation (i.e., genetic aberrations, stromal environment, angiogenesis, and local growth facto? production) that directly influence tumor categorization, grade and stage. The present application consists of 4 interdisciplinary individual research projects and three core facilities. Project 1. (Michael Skinner) investigates cell-cell interactions and ovarian cancer. The hypothesis tested is that ovarian surface epithelial cells. (OSE) are regulated by mesenchymal (stromal)-epithelial cell interactions mediated by the local production and action of growth stimulators and growth inhibitors. Observations indicate that ovarian tumor growth is dramatically influenced by the stromal environment. The biology of normal and tumorigenic OSE will be examined. Project 2 (Robert Jaffe) investigates angiogenesis in ovarian epithelial carcinoma. The hypothesis tested is that the action of vascular endothelial growth factor (VEGF) is necessary to promote the neovascularization and tumor growth of human ovarian epithelial carcinoma. The extent of angiogenesis and expression of VEGF will also be correlated with tumor progression (i.e., tumor stage and grade). Project 3 (Joe Gray) investigates the role of allelic imbalance in ovarian cancer progression. Using analysis of loss of heterozygosity (LOH), comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH), the chromosomal mapping of common allelic imbalance will be correlated with tumor progression (i.e., tumor stage and grade). Genes will be positionally cloned in regions of common imbalance and, in collaboration with the other projects, genes of interest (e.g., growth factors and receptors) will be mapped and correlated to chromosomal maps. Project 4 (Gordon Mills) investigates a recently purified ovarian cancer ascites factor (OCAF) from ascites fluid of ovarian cancer patients and its role in tumor growth and progression. The hypothesis tested is that OCAF produced by ovarian cancer cells plays a role in tumorigenesis by increasing proliferation of ovarian cancer cells, decreasing sensitivity to chemotherapy, and altering immune responsiveness. These research activities will be supported by the Administrative Core for the coordination and management of the PPG. Thr Molecular Cytometry Core will provide chromosomal mapping (i.e., LOH, CGH and FISH) and technical assistance with FISH of tissue sections. The Tissue/Pathology Core, directed by Bethan Powell, will collect, catalog, and prepare human ovarian cancer surgical specimens and cell-lines for the proposed research. The integrated activities of the four projects and investigators provides a comprehensive examination of the biology of ovarian cancer with emphasis on the growth aspects of tumor progression. Observations are anticipated to provide insight into the future design of more effective therapeutic agents for the prevention, early diagnosis and treatment of ovarian cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA064602-03
Application #
2654150
Study Section
Cancer Centers and Research Programs Review Committee (CCRP)
Program Officer
Freeman, Colette S
Project Start
1996-04-15
Project End
2000-01-31
Budget Start
1998-02-01
Budget End
1999-01-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Lu, Z; Yang, H; Sutton, M N et al. (2014) ARHI (DIRAS3) induces autophagy in ovarian cancer cells by downregulating the epidermal growth factor receptor, inhibiting PI3K and Ras/MAP signaling and activating the FOXo3a-mediated induction of Rab7. Cell Death Differ 21:1275-89
Cheng, Kwai Wa; Agarwal, Roshan; Mitra, Shreya et al. (2012) Rab25 increases cellular ATP and glycogen stores protecting cancer cells from bioenergetic stress. EMBO Mol Med 4:125-41
Badgwell, D B; Lu, Z; Le, K et al. (2012) The tumor-suppressor gene ARHI (DIRAS3) suppresses ovarian cancer cell migration through inhibition of the Stat3 and FAK/Rho signaling pathways. Oncogene 31:68-79
Zou, Chun-Fang; Jia, Luoqi; Jin, Hongyan et al. (2011) Re-expression of ARHI (DIRAS3) induces autophagy in breast cancer cells and enhances the inhibitory effect of paclitaxel. BMC Cancer 11:22
Cheong, Jae-Ho; Park, Eun Sung; Liang, Jiyong et al. (2011) Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models. Mol Cancer Ther 10:2350-62
Agarwal, Roshan; Carey, Mark; Hennessy, Bryan et al. (2010) PI3K pathway-directed therapeutic strategies in cancer. Curr Opin Investig Drugs 11:615-28
Ishida, Seiko; McCormick, Frank; Smith-McCune, Karen et al. (2010) Enhancing tumor-specific uptake of the anticancer drug cisplatin with a copper chelator. Cancer Cell 17:574-83
Short, John D; Dere, Ruhee; Houston, Kevin D et al. (2010) AMPK-mediated phosphorylation of murine p27 at T197 promotes binding of 14-3-3 proteins and increases p27 stability. Mol Carcinog 49:429-39
Liu, Shuying; Murph, Mandi; Panupinthu, Nattapon et al. (2009) ATX-LPA receptor axis in inflammation and cancer. Cell Cycle 8:3695-701
Huang, Shaoyi; Chang, In Soon; Lin, Wenbo et al. (2009) ARHI (DIRAS3), an imprinted tumour suppressor gene, binds to importins and blocks nuclear import of cargo proteins. Biosci Rep 30:159-68

Showing the most recent 10 out of 117 publications