Abstract

Mutation of the APC gene is widely recognized as an important early event in colorectal carinogenesis. The availability of humans and mice carrying germline mutations in APC provides a unique opportunity to study both colorectal cancer pathogenesis and tumor prevention. Nonsteroidal antiinflammatory drugs (NSAIDs) can prevent and reverse neoplastic changes in intestinal mucosa affected by APC gene mutation. Some of these neoplastic changes, such as altered levels of enterocyte proliferation and apoptosis, are present even in histologically-normal mucosa from individuals with APC mutation. By studying the mucosa of individuals with APC mutation before and during administration of NSAIDs, we can obtain information concerning the pathogenesis of colorectal cancer, as well as develop useful predictive biomarkers to evaluate cancer chemoprevention strategies. In this proposal, we describe a study of the effect of APC gene mutation upon intestinal epithelial cell turnover time and arachidonic acid metabolism in mice with Apc mutation. Using these measurements of epithelial homeostasis, we will study the effect of several NSAIDs and other related agents upon intestinal carcinogenesis related to Apc mutation. Finally, we will apply this information to a study of NSAID-induced tumor regression in humans with Familial Adenomatous Polyposis, a condition characterized by germline mutation of the APC gene.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
7R29CA074162-04
Application #
6173165
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Srivastava, Sudhir
Project Start
1997-04-01
Project End
2002-03-31
Budget Start
2000-09-30
Budget End
2001-03-31
Support Year
4
Fiscal Year
2000
Total Cost
$116,672
Indirect Cost

  Institution

Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Carothers, Adelaide M; Javid, Sara H; Moran, Amy E et al. (2006) Deficient E-cadherin adhesion in C57BL/6J-Min/+ mice is associated with increased tyrosine kinase activity and RhoA-dependent actomyosin contractility. Exp Cell Res 312:387-400
Moran, Amy E; Carothers, Adelaide M; Weyant, Michael J et al. (2005) Carnosol inhibits beta-catenin tyrosine phosphorylation and prevents adenoma formation in the C57BL/6J/Min/+ (Min/+) mouse. Cancer Res 65:1097-104
Carothers, A M; Hughes, S A; Ortega, D et al. (2002) 2-Methoxyestradiol induces p53-associated apoptosis of colorectal cancer cells. Cancer Lett 187:77-86
Weyant, M J; Carothers, A M; Dannenberg, A J et al. (2001) (+)-Catechin inhibits intestinal tumor formation and suppresses focal adhesion kinase activation in the min/+ mouse. Cancer Res 61:118-25
Carothers, A M; Melstrom Jr, K A; Mueller, J D et al. (2001) Progressive changes in adherens junction structure during intestinal adenoma formation in Apc mutant mice. J Biol Chem 276:39094-102
Mahmoud, N N; Carothers, A M; Grunberger, D et al. (2000) Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis. Carcinogenesis 21:921-7
Weyant, M J; Carothers, A M; Bertagnolli, M E et al. (2000) Colon cancer chemopreventive drugs modulate integrin-mediated signaling pathways. Clin Cancer Res 6:949-56
Churchill, M; Chadburn, A; Bilinski, R T et al. (2000) Inhibition of intestinal tumors by curcumin is associated with changes in the intestinal immune cell profile. J Surg Res 89:169-75
Mahmoud, N N; Bilinski, R T; Churchill, M R et al. (1999) Genotype-phenotype correlation in murine Apc mutation: differences in enterocyte migration and response to sulindac. Cancer Res 59:353-9
Mahmoud, N N; Dannenberg, A J; Bilinski, R T et al. (1999) Administration of an unconjugated bile acid increases duodenal tumors in a murine model of familial adenomatous polyposis. Carcinogenesis 20:299-303

Showing the most recent 10 out of 13 publications