How Do NSAIDs Prevent Colorectal Cancer

描述(由申请人提供)：长期使用小剂量阿司匹林可降低结直肠癌(CRC)的风险。目前尚不确定阿司匹林和其他非类固醇抗炎药的化学预防如何机械地降低CRC风险。我们建议非类固醇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的风险。干细胞在所有细胞中占少数，这种干细胞层次结构固有地降低了患癌症的风险。随机干细胞周转(中性漂移)进一步减少了每个隐窝的“平均”干细胞数量，也可以通过分化消除突变的干细胞。任何增加中性漂移的东西都应该通过减少“平均”干细胞数量来降低癌症风险。我们建议在一种新的小鼠模型中测试这一假设，该模型可以测量干细胞中性漂移率。易患癌症的突变(APC)应该减缓中性漂移率，而非类固醇抗炎药通过调节隐窝利基信号，应该增加中性漂移率，降低“平均”干细胞数量和癌症风险。证实中性漂移率与癌症风险相关，将把干细胞作为新的特定化学预防目标。中性漂移的小鼠模型将促进新药或给药计划的快速测试，这些新药或给药计划可以有效地减少“平均”干细胞数量，副作用更少。增强天然隐窝抗癌机制的化学预防比细胞毒策略更有可能产生更少的副作用。 公共卫生相关性：我们建议非类固醇抗炎药通过增强正常的隐窝抗癌机制来预防结直肠癌，这种机制通过随机的干细胞周转(中性漂移)固有地将平均干细胞数量降至最低。这一假设将在一种允许中性漂移测量的新小鼠模型中得到验证-易患癌症的突变应该减缓中性漂移，而非类固醇抗炎药应该增加中性漂移，减少平均干细胞数量和癌症风险。

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.