Colorectal cancer affects a significant number of individuals in most industrialized countries around the world. It alone is responsible for an annual death toll in the United States of approximately 56,000 people. Many patients present with advanced disease with which the outcome is poor and mortality high even with the most advanced treatment options available. Based on a better understanding of the biology of the large intestine and the specific signaling pathways affected during colorectal carcinogenesis, investigators are evaluating better ways to detect and prevent this disease. Along these lines, we have found that a particular enzyme, cyclooxygenase-2 (COX-2), is upregulated in colorectal cancer tissue and in pre-malignant adenomas. Our previous funding cycle was devoted to understanding the mechanisms which led to increased expression of the COX-2 gene and the role this gene played in gut biology and carcinogenesis. Now we propose to evaluate the downstream signaling pathways affected by increased COX-2 activity. Cyclooxygenase is a key enzyme in the production of prostaglandins which are bioactive lipids that activate several downstream signaling pathways. Others have shown that overexpression of COX-2 in the skin or breast leads to a dramatic increase in risk for skin or breast carcinoma. We have shown in preliminary data that PGEz can lead to pro-neoplastic effects in a number of situations. We propose the following specific alms to investigate this problem further: 1) To determine the mechanism(s) by which COX-2 derived PGE2 regulates the motility and invasiveness of colorectal carcinoma cells. 2) To delineate the role of the nuclear PGI2 receptor, PPAR_i, in the development of coloreetal cancer. 3) To determine the relative contribution of COX-2 expressed in malignant epithelial cells versus the surrounding stroma (host) in promoting colorectal cancer. This work will help to delineate additional important targets for treatment and/or prevention of colorectal cancer. It is becoming clear that just targeting one single molecule will not be as effective as needed to have a significant impact on this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK047297-19
Application #
8311771
Study Section
Special Emphasis Panel (NSS)
Program Officer
Carrington, Jill L
Project Start
1994-08-20
Project End
2012-11-30
Budget Start
2012-08-01
Budget End
2012-11-30
Support Year
19
Fiscal Year
2012
Total Cost
$146,339
Indirect Cost
$51,314
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Kim, Sun-Hee; Margalit, Ofer; Katoh, Hiroshi et al. (2014) CG100649, a novel COX-2 inhibitor, inhibits colorectal adenoma and carcinoma growth in mouse models. Invest New Drugs 32:1105-12
Dubois, Raymond N (2014) Role of inflammation and inflammatory mediators in colorectal cancer. Trans Am Clin Climatol Assoc 125:358-72; discussion 372-3
Wang, Dingzhi; Fu, Lingchen; Ning, Wei et al. (2014) Peroxisome proliferator-activated receptor ? promotes colonic inflammation and tumor growth. Proc Natl Acad Sci U S A 111:7084-9
Wang, Dingzhi; DuBois, Raymond N (2013) The role of anti-inflammatory drugs in colorectal cancer. Annu Rev Med 64:131-44
Charo, Chantale; Holla, Vijaykumar; Arumugam, Thiruvengadam et al. (2013) Prostaglandin E2 regulates pancreatic stellate cell activity via the EP4 receptor. Pancreas 42:467-74
Katoh, Hiroshi; Wang, Dingzhi; Daikoku, Takiko et al. (2013) CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis. Cancer Cell 24:631-44
Wang, Dingzhi; DuBois, Raymond N (2013) Urinary PGE-M: a promising cancer biomarker. Cancer Prev Res (Phila) 6:507-10
Kim, Sun-Hee; Wang, Dingzhi; Park, Yun-Yong et al. (2013) HIG2 promotes colorectal cancer progression via hypoxia-dependent and independent pathways. Cancer Lett 341:159-65
Wang, Dingzhi; Margalit, Ofer; DuBois, Raymond N (2013) Metronomic topotecan for colorectal cancer: a promising new option. Gut 62:190-1
Wang, Dingzhi; Dubois, Raymond N (2012) Epoxyeicosatrienoic acids: a double-edged sword in cardiovascular diseases and cancer. J Clin Invest 122:19-22

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