Effects of inflammaging on intestinal epithelial cells and aspirin chemoprevention.

炎症对肠上皮细胞的影响和阿司匹林化学预防。

• 批准号: 10597250
• 负责人: Andrew T Chan
• 金额: $ 62.54万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-05 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597250
• 关键词: APC gene; Address; Adult; Age; Aging; Aspirin; Benefits and Risks; Biological; Biological Assay; Biological Markers; Biopsy; Cancer Model; Cell Count; Cell Culture Techniques; Cell physiology; Cells; Chemoprevention; Chemopreventive Agent; Chemoprotective Agent; Chronic Disease; Clinical; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Data; Depreciation; Development; Dinoprostone; Dose; Double-Blind Method; Elderly; Endowment; Enrollment; Epithelial Cells; Epithelium; Etiology; Experimental Models; Gene Expression Profile; Genetic; Guidelines; Human; Incidence; Individual; Inflammaging; Inflammation; Inflammatory; Intervention; Intestinal Cancer; Intestines; LGR5 gene; Life; Measures; Mediating; Methods; Modeling; Mucous Membrane; Mus; Mutation; Non-Steroidal Anti-Inflammatory Agents; Oncogenic; Organoids; Pathway interactions; Patients; Placebo Control; Population; Pre-Clinical Model; Process; Prostaglandin Inhibition; Prostaglandins; Randomized, Controlled Trials; Recommendation; Reporter; Reporting; Resistance; Resolution; Risk Reduction; Role; Secondary to; Shapes; Signal Transduction; Small Intestines; Testing; United States Preventative Services Task Force; age effect; age related; aged; anti-cancer; biomarker development; cancer biomarkers; colorectal cancer prevention; colorectal cancer risk; disorder prevention; epithelial stem cell; fetal; human old age (65+); in vitro Model; in vivo; intestinal epithelium; mortality; mouse model; novel; pharmacologic; pre-clinical; premalignant; receptor; regenerative; single-cell RNA sequencing; stem cell function; stem cells; tumor; tumor initiation; tumor progression; tumorigenesis; tumorigenic; urinary; young adult

PROJECT ABSTRACT Previous randomized controlled trials (RCT)s demonstrate that low-dose aspirin (LDA, 81-100mg/day) reduces the risk of colorectal cancer (CRC). The U.S. Preventive Services Task Force (USPSTF) recommends LDA to prevent CRC in adults aged 50-59. However, a recent RCT among 19,114 older (65+) individuals reported that initiating LDA late in life had no benefit on CRC incidence and was potentially detrimental for mortality. Because CRC incidence rises with age, understanding the relationship and functional impact of aging on the chemopreventive effects of LDA is a high priority. Our working model is that the effect of LDA on the colon differs in older individuals due to age-related changes in intestinal stem cell (ISC) number and function secondary to a process of higher basal inflammatory tone, a.k.a. “inflammaging”. Normally, CRC appears to be primarily driven by oncogenic mutations in Lgr5+ ISCs and aspirin-like NSAIDs appear to preferentially eliminate premalignant Lgr5+ ISCs. However, our preliminary data demonstrates that old mice (20-22 months [mos]), as compared to young mice (2-3 mos), have fewer, less regenerative small intestinal Lgr5+ ISCs, which are also less tumorigenic in an Apc tumor suppressor model. Nonetheless, like humans, aged mice spontaneously develop a greater number of tumors, indicating that non-Lgr5+ cells are also the origin of intestinal cancers in aged mice and that these cells are less sensitive to LDA. LDA modulates prostaglandin (PG) levels, including PGE2. We also find that PGE2 impacts ISC function through its receptor Ptger4 and this signaling can drive ISCs into a fetal-like state (Hopx+) that is mediated by Hippo/Yap signaling. Thus, in the setting of inflammaging, elevated PGE2 may irreversibly compromise the colon (cISC) pool leading to compensatory functions within select cISCs that promote tumorigenesis. Through our double-blind, placebo-controlled RCT, we demonstrated that modulation of PG tone and inhibition of PG synthesis is central to aspirin’s mode of action. Our central hypothesis is that aging and age-related processes promote a decrease in the cISC pool (Lgr5+ cISCs) that is normally sensitive to aspirin chemoprevention. We propose that initiation of LDA earlier in life protects against this age-related, inflammation-associated, and/or PGE2-mediated damage to the cISC pool. In contrast, with advancing age there may be a “point-of-no-return” in which initiation of LDA is no longer protective against age- related changes in the cISC pool. In this proposal, we will expand our existing RCT to examine the impact of LDA on colonic epithelium at single cell resolution, patient-derived organoids, and urinary PGs in older adults. We will use novel in vivo preclinical models to dissect the role of inflammaging on PG signaling and LDA on cISCs. We will then examine the causality of these pathways on colon tumor incidence and progression. These studies may offer a biological explanation for the unexpected finding of a differential effect of LDA in older adults, which may influence clinical guidelines or the development of biomarkers to optimize LDA’s risk-benefit profile.

项目摘要 先前的随机对照试验（RCT）S表明低剂量阿司匹林（LDA，81-100mg/天）会减少 结直肠癌（CRC）的风险。美国预防服务工作队（USPSTF）建议LDA 预防50-59岁成年人的CRC。但是，最近有19,114名（65岁以上）的RCT报告说 在生命后期开始LDA对CRC事件没有好处，并且可能对死亡率有害。因为 CRC事件随着年龄的增长而增加，了解衰老对衰老的关系和功能影响 LDA的化学预防作用是高度优先级。我们的工作模型是LDA对结肠的影响 由于年龄相关的肠道干细胞（ISC）数量和次要功能的变化而导致的老年人的差异 对于较高碱性炎症语调的过程，也就是“炎症”。通常，CRC似乎是主要的 由LGR5+ ISC中的致癌突变和阿司匹林样NSAID驱动似乎优先消除 前lgr5+ iscs。但是，我们的初步数据表明旧小鼠（20-22个月[MOS]） 与年轻小鼠（2-3 MO）相比，再生小肠LGR5+ ISC的再生较少，这也是 在APC肿瘤抑制器模型中，肿瘤症较少。尽管如此，像人类一样，老年老鼠赞助 开发更多的肿瘤，表明非LGR5+细胞也是肠癌的起源 老年小鼠，这些细胞对LDA不太敏感。 LDA调节前列腺素（PG）水平，包括 PGE2。我们还发现PGE2通过其接收器PTGER4影响ISC函数，此信号可以驱动ISCS 通过河马/YAP信号传导介导的胎儿状状态（HOPX+）。在炎症的情况下， 升高的PGE2可能会不可逆转地损害结肠（CISC）池，导致内部的补偿功能 选择促进肿瘤发生的CISC。通过我们的双盲，安慰剂控制的RCT，我们证明了 PG张力的调节和PG合成的抑制是阿司匹林作用方式至关重要的。我们的中心 假设是，衰老和与年龄有关的过程促进了CISC池（LGR5+ CISC）的减少，即 通常对阿司匹林化学预防敏感。我们建议LDA早期的LDA倡议预防 这种与年龄相关的，与炎症相关的和/或PGE2介导的CISC池的损害。相反，与 提高年龄可能会有一个“无返回点”，其中LDA的倡议不再受到保护 - CISC池的相关变化。在此提案中，我们将扩大现有的RCT，以研究 在单细胞分辨率，患者衍生的类器官和老年人的尿PG上的结肠上皮上的LDA。 我们将使用新颖的体内临床前模型来剖析炎症在PG信号传导上的作用 CISC。然后，我们将检查这些途径在结肠肿瘤的发病率和进展方面的因果关系。这些 研究可能为意外发现LDA在老年人中的差异作用的意外发现提供生物学解释， 这可能会影响临床指南或生物标志物的开发，以优化LDA的风险效果。

项目成果

Aspirin and the Risk of Colorectal Cancer According to Genetic Susceptibility among Older Individuals.

• DOI: 10.1158/1940-6207.capr-22-0011
• 发表时间: 2022-07-05
• 期刊: Cancer prevention research (Philadelphia, Pa.)