SITE SPECIFICITY OF GASTROINTESTINAL TUMORIGENESIS

Project: Research project

Project Details

Description

DESCRIPTION: (Applicant's Abstract) Mice that inherit a mutant allele of the
Apc gene develop tumors principally in the small intestine (SI), unlike
patients with familial polyposis (FAP) who develop large bowel cancer. However,
the applicant has shown that several mouse models are not refractory to large
bowel tumor formation. This application focuses on mechanisms regulating the
ability of sulindac, an NSAID to stimulate the formation of large bowel tumors
in the Apc1638, ApcMin, and ApcMlh1 mouse models, even though it has an
inhibitory effect on tumor formation of the SI. This is similar to reports that
patients given sulindac develop rectal tumors. The applicant proposes to
utilize the Apc1638, ApcMin, and ApcMlh1 models to determine mechanisms by
which probability of tumor formation is modulated at different sites in the
intestine by sulindac and celecoxib, a specific Cox-2 inhibitor. A significant
aspect of the experimental design is that alterations on a cellular,
biochemical and molecular level will be assayed in regions of the intestinal
tract undergoing both increases and decreases in tumor formation in the same
mouse. Detailed immunohistopathology of tumor formation will include analysis
of proliferation and apoptosis in the mucosa and tumors. In addition, Cox-1,
Cox-2, arachidonic acid metabolism, and beta-catenin-Tcf signaling will be
monitored to determine the role of these pathways in site-specific modulation
of tumorigenesis. Lastly, using microarray analyses, the profiles of gene
expression that characterize genetic and dietary modulation of risk will be
defined.
StatusFinished
Effective start/end date3/1/012/28/02

Funding

  • National Cancer Institute: $228,556.00

ASJC

  • Gastroenterology
  • Molecular Medicine
  • Cancer Research
  • Histology
  • Pharmacology

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