Expression data from murine colon tumors induced by azoxymethane. Tumors from control, obese, formerly obese, or sulindac-treated mice.. Expression data from murine colon tumors induced by azoxymethane. Tumors from control, obese, formerly obese, or sulindac-treated mice.

Obesity is associated with an increased risk of colon cancer. Our current study examines whether weight loss and/or treatment with the non-steroidal anti-inflammatory drug (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 were also randomized to start sulindac treatment (140 ppm in the diet). All mice were euthanized seven weeks later. FOb-LFD mice had intermediate levels of body weight, lower than obese but higher than control mice (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 both weight loss and sulindac modulate the expression of tumor genes related to invasion and may promote a more anti-tumor immune landscape. Furthermore, the fecal microbes Prevotella and Akkermansia muciniphila, both known to be elevated in colorectal cancer patients, were positively correlated with tumor multiplicity and reduced by sulindac in obese mice. In sum, either moderate weight loss or sulindac treatment completely reversed the effects of chronic obesity on colon tumorigenesis. 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. Overall design: 22 samples were analyzed

肥胖与结直肠癌风险升高密切相关。本研究旨在探讨体重减轻，以及/或使用非甾体抗炎药（non-steroidal anti-inflammatory drug, NSAID）舒林酸（sulindac），是否可在结直肠癌小鼠模型中抑制肥胖的促瘤效应。我们将经偶氮甲烷（Azoxymethane）处理的雄性FVB/N品系小鼠分为两组，分别喂食低脂肪饮食（low-fat diet, LFD）与高脂肪饮食（high-fat diet, HFD），干预时长为15周；随后将高脂饮食组小鼠随机分为两组，一组维持高脂肪饮食（即肥胖组），另一组切换为低脂肪饮食（即既往肥胖-低脂肪饮食组，FOb-LFD）。在对照组（LFD组）、肥胖组与FOb-LFD组中，各有一半小鼠被随机分配接受舒林酸干预（饲料中添加140 ppm舒林酸）。所有小鼠于7周后实施安乐死。FOb-LFD组小鼠的体重处于中间水平，低于肥胖组但高于对照组（P<0.05）。舒林酸对小鼠体重无显著影响。肥胖组小鼠的肿瘤多发率与肿瘤负荷均高于其余所有组别（P<0.05）。转录组测序分析显示，体重减轻与舒林酸干预均可调控与肿瘤侵袭相关基因的表达，并可塑造更具抗肿瘤活性的免疫微环境。此外，已知在结直肠癌患者中丰度升高的粪便微生物普雷沃氏菌属（Prevotella）与黏液嗜黏蛋白阿克曼氏菌（Akkermansia muciniphila），均与肿瘤多发率呈正相关，且可在肥胖小鼠中被舒林酸下调。综上，适度体重减轻或舒林酸干预均可完全逆转慢性肥胖对结肠肿瘤发生的影响。本研究结果提示，有必要开展针对NSAID干预对肥胖人群结直肠癌风险及/或疾病进展影响的研究，尤其针对无法实现适度体重减轻的人群。整体实验设计：共分析22份样本。