Locoregional effects of microbiota in a preclinical model of colon carcinogenesis

Sarah Tomkovich, Ye Yang, Kathryn Winglee, Josee Gauthier, Marcus Mühlbauer, Xiaolun Sun, Mansour Mohamadzadeh, Xiuli Liu, Patricia Martin, Gary P. Wang, Eric Oswald, Anthony A. Fodor, Christian Jobin

Research output: Contribution to journalArticlepeer-review

141 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2620-2632
Number of pages13
JournalCancer Research
Volume77
Issue number10
DOIs
StatePublished - May 15 2017
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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