Aspirin's effect on kinetic parameters of cells contributes to its role in reducing incidence of advanced colorectal adenomas, shown by a multiscale computational study.
Aspirin's effect on kinetic parameters of cells contributes to its role in reducing incidence of advanced colorectal adenomas, shown by a multiscale computational study.
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DOI：
10.7554/elife.71953
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发表时间：
2022-04-13
期刊：
影响因子：
7.7
通讯作者：
Komarova, Natalia L.
中科院分区：
文献类型：
--
作者：
Wang, Yifan;Boland, C. Richard;Goel, Ajay;Wodarz, Dominik;Komarova, Natalia L.
阿司匹林的摄入已被证明对结直肠癌有显著的保护作用，例如，高剂量的阿司匹林可以将结直肠腺瘤的发病率降低两倍。促进保护的机制尚未完全了解。虽然阿司匹林是一种抗炎药物，因此可以影响肿瘤微环境，但最近的体外和体内实验表明，阿司匹林也可以直接影响细胞动力学和适应性。它降低了肿瘤细胞分裂的速度，增加了细胞的死亡率。出现了这样的细胞适合性变化是否足以显著促进流行病学观察到的保护的问题。为了研究这一点，我们构建了一类晚期腺瘤体内进化的数学模型，用可用的估计对其进行了参数化，并计算了人群水平的发病率。将预测与年龄发病率数据进行拟合显示，只有包括结肠隐窝竞争的模型才能解释观察到的年龄-发病率曲线。然后，这个模型被用来预测如果阿司匹林治疗导致细胞动力学改变，修改的发病率模式。我们发现，在实验观察范围内的细胞适合性变化可以降低晚期腺瘤的发病率，其数量足以解释阿司匹林治疗患者队列中的年龄发病率数据。虽然阿司匹林保护作用的机制可能是复杂的和多因素的，但我们的研究表明，阿司匹林直接诱导的肿瘤细胞健康状况的改变可以显著促进流行病学观察到的发病率下降模式。
Aspirin intake has been shown to lead to significant protection against colorectal cancer, for example with an up to twofold reduction in colorectal adenoma incidence rates at higher doses. The mechanisms contributing to protection are not yet fully understood. While aspirin is an anti-inflammatory drug and can thus influence the tumor microenvironment, in vitro and in vivo experiments have recently shown that aspirin can also have a direct effect on cellular kinetics and fitness. It reduces the rate of tumor cell division and increases the rate of cell death. The question arises whether such changes in cellular fitness are sufficient to significantly contribute to the epidemiologically observed protection. To investigate this, we constructed a class of mathematical models of in vivo evolution of advanced adenomas, parameterized it with available estimates, and calculated population level incidence. Fitting the predictions to age incidence data revealed that only a model that included colonic crypt competition can account for the observed age-incidence curve. This model was then used to predict modified incidence patterns if cellular kinetics were altered as a result of aspirin treatment. We found that changes in cellular fitness that were within the experimentally observed ranges could reduce advanced adenoma incidence by a sufficient amount to account for age incidence data in aspirin-treated patient cohorts. While the mechanisms that contribute to the protective effect of aspirin are likely complex and multi-factorial, our study demonstrates that direct aspirin-induced changes of tumor cell fitness can significantly contribute to epidemiologically observed reduced incidence patterns.
影响因子：
4.3
作者：
Dewanji A;Jeon J;Meza R;Luebeck EG
通讯作者：
Luebeck EG