Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Cancer Prev Res (Phila). 2022 Aug 1;15(8):481-495. doi: 10.1158/1940-6207.CAPR-21-0531.
Obesity is associated with an increased risk of colon cancer. Our current study examines whether weight loss and/or treatment with the NSAID sulindac suppresses the protumor effects of obesity in a mouse model of colon cancer. Azoxymethane-treated male FVB/N mice were fed a low-fat diet (LFD) or high-fat diet (HFD) for 15 weeks, then HFD mice were randomized to remain on HFD (obese) or switch to LFD [formerly obese (FOb-LFD)]. Within the control (LFD), obese, and FOb-LFD groups, half the mice started sulindac treatment (140 ppm in the diet). All mice were euthanized 7 weeks later. FOb-LFD mice had intermediate body weight levels, lower than obese but higher than control (P < 0.05). Sulindac did not affect body weight. Obese mice had greater tumor multiplicity and burden than all other groups (P < 0.05). Transcriptomic profiling indicated that weight loss and sulindac each modulate the expression of tumor genes related to invasion and may promote a more antitumor immune landscape. Furthermore, the fecal microbes Coprobacillus, Prevotella, and Akkermansia muciniphila were positively correlated with tumor multiplicity and reduced by sulindac in obese mice. Coprobacillus abundance was also decreased in FOb-LFD mice. In sum, weight loss and sulindac treatment, alone and in combination, reversed the effects of chronic obesity on colon tumor multiplicity and burden. Our findings suggest that an investigation regarding the effects of NSAID treatment on colon cancer risk and/or progression in obese individuals is warranted, particularly for those unable to achieve moderate weight loss.
Obesity is a colon cancer risk and/or progression factor, but the underlying mechanisms are incompletely understood. Herein we demonstrate that obesity enhances murine colon carcinogenesis and expression of numerous tumoral procancer and immunosuppressive pathways. Moreover, we establish that weight loss via LFD and/or the NSAID sulindac mitigate procancer effects of obesity.
肥胖与结肠癌风险增加有关。我们目前的研究检查了减肥和/或使用非甾体抗炎药舒林酸是否抑制肥胖在结肠癌小鼠模型中的促肿瘤作用。用氧化偶氮甲烷处理的雄性 FVB/N 小鼠接受低脂饮食（LFD）或高脂饮食（HFD）喂养 15 周，然后 HFD 小鼠随机继续接受 HFD（肥胖）或切换至 LFD[先前肥胖（FOb-LFD）]。在对照（LFD）、肥胖和 FOb-LFD 组中，一半的小鼠开始舒林酸治疗（饮食中 140 ppm）。所有小鼠在 7 周后安乐死。FOb-LFD 小鼠的体重水平居中，低于肥胖组但高于对照组（P<0.05）。舒林酸对体重没有影响。肥胖组的肿瘤多发性和负担均高于其他所有组（P<0.05）。转录组谱分析表明，减肥和舒林酸各自调节与侵袭相关的肿瘤基因的表达，并可能促进更抗肿瘤免疫景观。此外，粪便微生物 Coprobacillus、Prevotella 和 Akkermansia muciniphila 与肿瘤多发性呈正相关，并在肥胖小鼠中被舒林酸减少。Coprobacillus 的丰度在 FOb-LFD 小鼠中也降低了。总之，减肥和舒林酸治疗，单独或联合使用，逆转了慢性肥胖对结肠肿瘤多发性和负担的影响。我们的研究结果表明，有必要对 NSAID 治疗对肥胖个体的结肠癌风险和/或进展的影响进行调查，特别是对于那些无法实现适度减肥的人。
肥胖是结肠癌的风险和/或进展因素，但潜在机制尚不完全清楚。在此，我们证明肥胖增强了小鼠结肠癌的发生和许多肿瘤促癌和免疫抑制途径的表达。此外，我们确定通过 LFD 和/或 NSAID 舒林酸减肥减轻肥胖的促癌作用。
