Locoregional Effects of Microbiota in a Preclinical Model of Colon Carcinogenesis.
Locoregional Effects of Microbiota in a Preclinical Model of Colon Carcinogenesis.
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DOI：
10.1158/0008-5472.can-16-3472
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发表时间：
2017-05-15
期刊：
影响因子：
11.2
通讯作者：
Jobin C
中科院分区：
文献类型：
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作者：
Tomkovich S;Yang Y;Winglee K;Gauthier J;Mühlbauer M;Sun X;Mohamadzadeh M;Liu X;Martin P;Wang GP;Oswald E;Fodor AA;Jobin C
炎症和微生物群是肠道肿瘤发生的关键组成部分。为了分析微生物群如何促进肿瘤分布，我们产生了无菌（GF）ApcMin/+和ApcMin/+; Il 10 −/−小鼠，并将它们暴露于无特定病原体（SPF）或结直肠癌相关细菌。我们发现，在SPF饲养的ApcMin/+; Il 10 −/−小鼠中，结肠肿瘤发生与炎症显著相关，但在ApcMin/+小鼠中则不然。相比之下，ApcMin/+; Il 10 −/−和ApcMin/+小鼠的小肠肿瘤发展与年龄显著相关。与GF小鼠相比，SPF微生物群常规化的GF ApcMin/+; Il 10 −/−小鼠具有显著更多的结肠肿瘤。无菌研究显示，虽然具有FadA和Fap 2粘附素的具核梭杆菌临床分离株未能诱导炎症和肿瘤发生，但pks+大肠杆菌以大肠杆菌素依赖性方式促进ApcMin/+; Il 10 −/−模型中的肿瘤发生，表明大肠杆菌素是致癌的驱动因素。我们的研究结果表明，肠道不同位置的癌症有不同的病因，结肠癌主要由炎症和微生物组驱动，而年龄是小肠癌的驱动力。
Inflammation and microbiota are critical components of intestinal tumorigenesis. To dissect how the microbiota contributes to tumor distribution, we generated germ-free (GF) ApcMin/+ and ApcMin/+;Il10−/− mice and exposed them to specific-pathogen-free (SPF) or colorectal cancer-associated bacteria. We found colon tumorigenesis significantly correlated with inflammation in SPF housed ApcMin/+;Il10−/−, but not ApcMin/+ mice. In contrast, small intestinal neoplasia development significantly correlated with age in both ApcMin/+;Il10−/− and ApcMin/+ mice. GF ApcMin/+;Il10−/− mice conventionalized by an SPF microbiota had significantly more colon tumors compared to GF mice. Gnotobiotic studies revealed that while Fusobacterium nucleatum clinical isolates with FadA and Fap2 adhesins failed to induce inflammation and tumorigenesis, pks+ Escherichia coli promoted tumorigenesis in the ApcMin/+;Il10−/− model in a colibactin-dependent manner, suggesting colibactin is a driver of carcinogenesis. Our results suggest a distinct etiology of cancers in different locations of the gut, where colon cancer is primarily driven by inflammation and the microbiome, while age is a driving force for small intestine cancer.