Center for Gastrointestinal Research, Center from Translational Genomics and Oncology, Baylor Scott and White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA.
Department of Mathematics, University of California, Irvine, CA, USA.
Carcinogenesis. 2020 Jul 10;41(6):751-760. doi: 10.1093/carcin/bgz195.
Accumulating evidence suggests that aspirin has anti-tumorigenic properties in colorectal cancer (CRC). Herein, we undertook a comprehensive and systematic series of in vivo animal experiments followed by 3D-mathematical modeling to determine the kinetics of aspirin's anti-cancer effects on CRC growth. In this study, CRC xenografts were generated using four CRC cell lines with and without PIK3CA mutations and microsatellite instability, and the animals were administered with various aspirin doses (0, 15, 50, and 100 mg/kg) for 2 weeks. Cell proliferation, apoptosis and protein expression were evaluated, followed by 3D-mathematical modeling analysis to estimate cellular division and death rates and their impact on aspirin-mediated changes on tumor growth. We observed that aspirin resulted in a dose-dependent decrease in the cell division rate, and a concomitant increase in the cell death rates in xenografts from all cell lines. Aspirin significantly inhibited cell proliferation as measured by Ki67 staining (P < 0.05-0.01). The negative effect of aspirin on the rate of tumor cell proliferation was more significant in xenograft tumors derived from PIK3CA mutant versus wild-type cells. A computational model of 3D-tumor growth suggests that the growth inhibitory effect of aspirin on the tumor growth kinetics is due to a reduction of tumor colony formation, and that this effect is sufficiently strong to be an important contributor to the reduction of CRC incidence in aspirin-treated patients. In conclusion, we provide a detailed kinetics of aspirin-mediated inhibition of tumor cell proliferation, which support the epidemiological data for the observed protective effect of aspirin in CRC patients.
越来越多的证据表明，阿司匹林在结直肠癌（CRC）中具有抗肿瘤特性。在此，我们进行了一系列全面而系统的体内动物实验，并结合 3D 数学建模，以确定阿司匹林对 CRC 生长的抗癌作用的动力学。在这项研究中，我们使用具有和不具有 PIK3CA 突变和微卫星不稳定的四种 CRC 细胞系生成 CRC 异种移植物，并给动物施用不同剂量的阿司匹林（0、15、50 和 100mg/kg）2 周。评估细胞增殖、凋亡和蛋白表达，然后进行 3D 数学建模分析，以估计细胞分裂和死亡率及其对阿司匹林介导的肿瘤生长变化的影响。我们观察到，阿司匹林导致所有细胞系的异种移植物中的细胞分裂率呈剂量依赖性下降，同时细胞死亡率增加。阿司匹林通过 Ki67 染色显著抑制细胞增殖（P<0.05-0.01）。与野生型细胞相比，源自 PIK3CA 突变型细胞的异种移植物中，阿司匹林对肿瘤细胞增殖率的负作用更为显著。3D 肿瘤生长的计算模型表明，阿司匹林对肿瘤生长动力学的抑制作用是由于肿瘤集落形成减少所致，并且这种作用足够强，是阿司匹林治疗患者 CRC 发病率降低的重要因素。总之，我们提供了阿司匹林介导的肿瘤细胞增殖抑制的详细动力学，这支持了阿司匹林在 CRC 患者中观察到的保护作用的流行病学数据。
