Clinical evidence, epidemiological results and experimental animal studies overwhelmingly suggest that COX-2 over-expression plays a modulatory and even causal role in development of many epithelial cancers. Recent studies demonstrate that stromal fibroblasts and blood vessel endothelial cells modulate epithelial tumor formation. There also exist substantial correlative data suggesting that COX-2 expression in stromal fibroblasts and blood vessel endothelial cells - and not in the initiated epithelial tumor precursor cells - may mediate pre-neoplastic emergence and subsequent progression of epithelial cancers. However, existing COX-2 pharmacologic experiments and global Cox2 knockout mice do not permit either physiological or genetic analyses to determine the specific cell populations - fibroblasts, epithelial or blood vessel endothelial cells - in which COX-2 over expression plays a critical role(s) in tumor development. We have developed (i) COX2 COE transgenic mice, in which we can conditionally over-express COX-2 in targeted cells and tissues and (ii) Cox2flox mice, in which we can conditionally delete the Cox2 gene in targeted cells and tissues. By crossing COX2 COE mice and Cox2flox mice to transgenic mice in which a tamoxifen-regulated CreERT recombinase is expressed in either epithelial cells, stromal fibroblasts or blood vessel endothelial cells, we will be able to determine (1) whether COX-2 over production in epithelial cells, fibroblasts and/or blood vessel endothelial cells modulates cancer development and (2) whether COX-2 expression is required in epithelial cells, fibroblasts or blood vessel endothelial cells for cancer development. Skin cancer is among the best-studied epithelial tumor induction models. We chose skin cancer to study the role(s) of COX-2 in epithelial cells, stromal fibroblasts and blood vessel endothelial cells during development of epithelial cancer because of the extensive literature on this model, the ease with which tumors can be monitored non-invasively, and the ease with which CreERT can be activated locally. The """"""""broad, long-term objectives and specific aims"""""""" of this application are to determine (1) whether COX-2 plays a modulatory and/or a required role(s) in development of epithelial cancer and (2) in which cell(s) - initiated epithelial tumor precursor cell and/or stromal fibroblast and/or blood vessel endothelial cell - COX-2 modulates either pre-malignant epithelial tumor development or progression of benign tumors to carcinomas. The relevance of this research to public health. COX-2 inhibitors are still investigated as therapeutic and preventive agents for epithelial cancers, despite cardiovascular side effects. """"""""Down-stream"""""""" COX-2 pathway effectors (prostanoid synthases and receptors) have become targets for similar research. If we can pinpoint the cell type(s) in which COX-2 expression and the prostanoid effectors regulate cancer development, we may be able to target those steps with lower concentrations and less prolonged application of pharmacologic agents. We anticipate we will be able to define the critical cells and times for COX-2 cancer enhancement.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA123055-04
Application #
7845543
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2007-08-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
4
Fiscal Year
2010
Total Cost
$292,600
Indirect Cost
Name
University of California Los Angeles
Department
Pharmacology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Ishikawa, Tomo-o; Herschman, Harvey R (2011) Conditional bicistronic Cre reporter line expressing both firefly luciferase and ?-galactosidase. Mol Imaging Biol 13:284-92
Ishikawa, Tomo-O; Oshima, Masanobu; Herschman, Harvey R (2011) Cox-2 deletion in myeloid and endothelial cells, but not in epithelial cells, exacerbates murine colitis. Carcinogenesis 32:417-26
Ishikawa, Tomo-o; Jain, Naveen K; Herschman, Harvey R (2010) Cox-2 gene expression in chemically induced skin papillomas cannot predict subsequent tumor fate. Mol Oncol 4:347-56
Ishikawa, Tomo-O; Herschman, Harvey R (2010) Tumor formation in a mouse model of colitis-associated colon cancer does not require COX-1 or COX-2 expression. Carcinogenesis 31:729-36
Ishikawa, Tomo-O; Kumar, Indracanti Prem; Machado, Hidevaldo B et al. (2010) Positron emission tomography imaging of DMBA/TPA mouse skin multi-step tumorigenesis. Mol Oncol 4:119-25
Papanicolaou, Kyriakos N; Streicher, John M; Ishikawa, Tomo-O et al. (2010) Preserved heart function and maintained response to cardiac stresses in a genetic model of cardiomyocyte-targeted deficiency of cyclooxygenase-2. J Mol Cell Cardiol 49:196-209
Ishikawa, Tomo-O; Jain, Naveen; Herschman, Harvey R (2009) Feedback regulation of cyclooxygenase-2 transcription ex vivo and in vivo. Biochem Biophys Res Commun 378:534-8

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