How Do NSAIDs Prevent Colorectal Cancer

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。目前尚不清楚阿司匹林和其他NSAID的化学预防如何降低CRC风险。我们建议，非甾体抗炎药通过增强天然的“抗癌”隐窝小生境防御来降低CRC风险。地穴壁龛本质上降低了干细胞层次的癌症风险，其中干细胞是所有细胞中的少数。随机干细胞更新（中性漂移）进一步降低了每个隐窝干细胞的“平均”数量，也可以通过分化消除突变干细胞。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NSAID通过调节隐窝小生境信号传导，应该增加中性漂移率，降低“平均”干细胞数量和癌症风险。证明中性漂移率与癌症风险相关将确定干细胞生态位作为新的特异性化学预防靶点。中性漂移的小鼠模型将有助于快速测试新药或给药方案，这些药物或给药方案可以有效地减少“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性策略更可能具有更少的副作用。

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.