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Cancer Res. 2017 May 15;77(10):2620-2632. doi: 10.1158/0008-5472.CAN-16-3472. Epub 2017 Apr 17.

Locoregional Effects of Microbiota in a Preclinical Model of Colon Carcinogenesis.

Author information

1
Department of Medicine, University of Florida, Gainesville, Florida.
2
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
3
Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, North Carolina.
4
Department of Infectious Diseases and Pathology, University of Florida, Gainesville, Florida.
5
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida.
6
IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France.
7
CHU Toulouse, Service de Bactériologie-Hygiène, Toulouse, France.
8
Department of Medicine, Division of Infectious Diseases and Global Medicine, University of Florida, Gainesville, Florida.
9
Department of Medicine, University of Florida, Gainesville, Florida. Christian.Jobin@medicine.ufl.edu.

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. ©2017 AACR.

PMID:
28416491
PMCID:
PMC5468752
DOI:
10.1158/0008-5472.CAN-16-3472
[Indexed for MEDLINE]
Free PMC Article

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