Locoregional Effects of Microbiota in a Preclinical Model of Colon Carcinogenesis

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 10; pp. 2620 - 2632
• Main Authors: Tomkovich, Sarah, Yang, Ye, Winglee, Kathryn, Gauthier, Josee, Mühlbauer, Marcus, Sun, Xiaolun, Mohamadzadeh, Mansour, Liu, Xiuli, Martin, Patricia, Wang, Gary P., Oswald, Eric, Fodor, Anthony A., Jobin, Christian
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 15.05.2017; American Association for Cancer Research
• Subjects: Adenomatous Polyposis Coli Protein - deficiency; Adhesins; Age; Animals; Bacteria - classification; Bacteria - genetics; Cancer; Carcinogenesis; Cell Transformation, Neoplastic; Clinical isolates; Colon; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - etiology; Colorectal Neoplasms - pathology; Disease Models, Animal; Etiology; Fusobacterium nucleatum; Gastrointestinal Microbiome; Germfree; Gnotobiotic; Human health and pathology; Hépatology and Gastroenterology; Inflammation; Inflammation - complications; Inflammation - pathology; Interleukin 1; Interleukin 10; Interleukin-10 - deficiency; Large intestine; Life Sciences; Mice; Mice, Knockout; Mice, Transgenic; Microbiomes; Microbiota; Small intestine; Specific pathogen free; Tumorigenesis; cancer du colon; colon cancer; microbiote digestif; inflammation du colon
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-3472

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 that colon tumorigenesis significantly correlated with inflammation in SPF-housed ApcMin/+;Il10−/−, but not in 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 with 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. Cancer Res; 77(10); 2620–32. ©2017 AACR.