Masters Theses

Date of Award

12-2002

Degree Type

Thesis

Degree Name

Master of Science

Major

Nutrition

Major Professor

Jay Whelan

Abstract

Colorectal cancer is one of the leading causes of cancer-related death in the United States. Although a small percentage of human colorectal cancers result from inherited gene defects which confer a strong predisposition for tumor development, such as in familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), the majority of cases occur sporadically as a result of the accumulation of somatic mutations. Mutations in the adenomatous polyposis coli (APC) tumor-suppressor gene are responsible for FAP and are observed in a majority of sporadic colorectal cancers, making animal models with Ape gene defects ideal for studying this disease process. Several animal models have been developed with targeted APC mutations, and these models are useful in determining the effects of potential anti-tumorigenic treatments in APC-driven intestinal tumorigenesis. The Apc(min/+) mouse model is a murine model of human FAP in which intestinal tumors develop spontaneously throughout the intestinal tract that are sensitive to modulation of the arachidonic acid pathway via cyclooxygenase (COX) inhibition. COX catalyzes the committed step in the conversion of arachidonic acid to prostaglandins. There are two isoforms of this enzyme, known as COX-1 and COX-2. COX-1 is constitutively expressed in most tissues and is believed to be a housekeeping enzyme involved in maintaining homeostasis. COX-2 is inducible in inflammatory conditions and catalyzes the formation of prostaglandins involved in the 1 promotion of tumorigenesis. Prostaglandins can be pro-inflammatory and appear to be important in tumor progression. Intestinal tumors over-express COX-2, and it has been proposed that this up-regulation confers a growth advantage to tumors by promoting angiogenesis.

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