How Do NSAIDs Prevent Colorectal Cancer

非甾体抗炎药如何预防结直肠癌

• 批准号: 8384151
• 负责人: Darryl K Shibata
• 金额: $ 22.32万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-13 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384151
• 关键词: A Mouse; Adverse effects; Algorithms; Aspirin; Cell Count; Cells; Chemoprevention; Chronic; Colorectal Cancer; Data; Dose; Individual; Intestines; Life Style; Malignant Neoplasms; Measurement; Measures; Minority; Mus; Mutation; Non-Steroidal Anti-Inflammatory Agents; Pharmaceutical Preparations; Risk; Schedule; Signal Transduction; Stem cells; Testing; Work; cancer chemoprevention; cancer risk; cytotoxic; improved; intestinal crypt; mouse model; mutant; prevent

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：长期使用低剂量阿司匹林可降低结直肠癌（CRC）风险。阿司匹林和其他非甾体抗炎药的化学预防如何从机制上降低结直肠癌风险尚不确定。我们建议非甾体抗炎药通过增强天然的“抗癌”隐窝生态位防御来降低结直肠癌风险。隐窝生态位本质上通过干细胞层次结构降低癌症风险，其中干细胞仅占所有细胞的少数。随机干细胞周转（中性漂移）进一步减少每个隐窝干细胞的“平均”数量，并且还可以通过分化消除突变干细胞。任何增加中性漂移的因素都应该通过减少“平均”干细胞数量来降低癌症风险。我们建议在可以测量干细胞中性漂移率的新小鼠模型中测试这一假设。易患癌症的突变（Apc）应减缓中性漂移率，而非甾体抗炎药通过调节隐窝生态位信号传导，应增加中性漂移率，降低“平均”干细胞数量和癌症风险。验证中性漂移率与癌症风险的相关性将把干细胞生态位确定为新的特定化学预防目标。中性漂移的小鼠模型将有助于快速测试新药或给药方案，从而有效减少“平均”干细胞数量，同时副作用更少。增强天然隐窝抗癌机制的化学预防比细胞毒性策略的副作用更可能更少。 公共健康相关性：我们建议非甾体抗炎药通过增强正常的隐窝抗癌机制来预防结直肠癌，该机制通过随机干细胞更新（中性漂移）本质上最大限度地减少平均干细胞数量。这一假设将在一种新的小鼠模型中进行测试，该模型允许进行中性漂移测量——易患癌症的突变应该会减缓中性漂移，而非甾体抗炎药应该会增加中性漂移，从而降低平均干细胞数量和癌症风险。