A Familial Adenomatous Polyposis' (FAR) patient has inherited a heterozygous mutation in the tumor suppressor gene APC (adenomatous polyposis coli) and will most likely develop colon cancer in his/her lifetime often because of loss of heterozygosity that inactivates the remaining APC allele. APC function is also lost in over 85% of sporadic colon cancer cases, confirming its causal role in colon cancer. One of several animal models, an Ape heterozygous codon 850 nonsense mutation in the C57BL/6J mice, is Min (multiple intestinal neoplasia) and is characterized by the appearance of benign tumors (polyps) in the small intestine. The strain propagated at the Fox Chase Cancer Center uniquely shows a high incidence of tumors in the colon and in the small intestines, thus representing a model similar to FAR. Our laboratory has completed the first detailed proteomic comparison of apparently-non-neoplastic human FAR colon crypts against crypts from non-mutation carriers, encompassing over 4000 protein species in which over half of the protein species were identified by mass spectrometry. We discovered that the protein profile of the FAR colon crypt is already significantly changed by the heterozygous APC mutation. This finding suggests that when a cell of the normal colon sustains the first APC mutation, it creates a previously unsuspected new cellular environment in which proteomic information may lead to the identification of biomarkers and potential targets for therapy. At least 80% of these human crypt proteins have orthologs in mouse.
The Specific Aims are:
Aim 1 : To produce high resolution proteomic maps of colon crypts from the FCCC Min mice and C57BL/6J control mice and to test whether they correspond to the human counterparts in FAR patients and non-FAP controls; and whether the proteomic differences between APC and control are similar in humans and mice.
Aim 2 : Age is a major factor in colon cancer. Min mice and C57BL/6J control mice of four age groups will be compared to elucidate the effects of age on the onset of the proteomic changes in the apparently-non-neoplastic colon crypts of the Min mice. We expect that the cross-species validations offered by these experiments will confirm whether Min mice are a valid resource for further biomarker discovery and enable chemoprevention experiments that capitalize on the biomarker changes discovered in the normal colon crypts of FAR patients. Although our laboratory has discovered several new potential biomarkers in the colon that signal early changes towards colon cancer, we need an animal model for testing whether some of these markers can be targeted with cancer prevention drugs. The Min mouse model genetically mimics humans for colon cancer. The proposed work will demonstrate whether it is a perfect model for the human disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA125849-01
Application #
7215018
Study Section
Special Emphasis Panel (ZCA1-SRRB-F (O1))
Program Officer
Steele, Vernon E
Project Start
2006-09-25
Project End
2008-08-31
Budget Start
2006-09-25
Budget End
2007-08-31
Support Year
1
Fiscal Year
2006
Total Cost
$85,500
Indirect Cost
Name
Institute for Cancer Research
Department
Type
DUNS #
064367329
City
Philadelphia
State
PA
Country
United States
Zip Code
19111