Chronic low dose aspirin use decreases colorectal cancer (CRC) risks. It is uncertain how chemoprevention by aspirin and other NSAIDs mechanistically reduce CRC risks. We propose that NSAIDs reduce CRC risks by augmenting natural "anticancer" crypt niche defenses. Crypt niches inherently reduce cancer risks with a stem cell hierarchy where stem cells are a minority of all cells. Random stem cell turnover (neutral drift) further reduces "average" numbers of stem cells per crypt and can also eliminate mutant stem cells via differentiation. Anything that increases neutral drift should decrease cancer risks by decreasing "average" stem cell numbers. We propose to test this hypothesis in a new mouse model that can measure stem cell neutral drift rates. Mutations (Apc) that predispose to cancer should slow neutral drift rates whereas NSAIDs, by modulating crypt niche signaling, should increase neutral drift rates, decreasing "average" stem cell numbers and cancer risks. Verifying that neutral drift rates correlate with cancer risks will identify the stemcell niche as a new specific chemoprevention target. A mouse model of neutral drift will facilitate the rapid testing of new drugs or dosing schedules that can effectively reduce "average" stem cell numbers with fewer side effects. Chemoprevention that augments natural crypt anticancer mechanisms is more likely to have fewer side effects than cytotoxic strategies.

Public Health Relevance

We propose that NSAIDs prevent colorectal cancer by enhancing normal crypt anticancer mechanisms that inherently minimize average stem cell numbers though random stem cell turnover (neutral drift). This hypothesis will be tested in a new mouse model that allows neutral drift measurements---mutations that predispose to cancer should slow neutral drift, whereas NSAIDs should increase neutral drift, decreasing average stem cell numbers and cancer risks.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA170814-02
Application #
8545125
Study Section
Special Emphasis Panel (ZCA1-SRLB-D (M1))
Program Officer
Umar, Asad
Project Start
2012-09-13
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$161,830
Indirect Cost
$27,986
Name
University of Southern California
Department
Pathology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089