We have identified a human colon anaerobic bacterium, enterotoxigenic Bacteroides fragilis (ETBF), as a candidate etiologic agent for colon cancer and our murine models of ETBF colonization delineate a potential procarcinogenic immune pathway that ETBF induce. Just as the understanding of peptic ulcer disease and ensuing stomach cancer was transformed by the discovery of H. pylori, we hypothesize that ETBF, by secreting the potent B. fragilis toxin (BFT), precipitate procarcinogenic mucosal immune responses, thereby promoting formation of colon cancer. Our model does not propose to alter existing mutational paradigms of colon cancer but rather proposes that ETBF colonization is an integral mechanism accounting for the accumulation of genetic mutations necessary for colon carcinogenesis. This proposal will study the relationship between colon colonization by ETBF in humans, specific colon immune responses and, ultimately, colon cancer. Defining a microbial etiology for colon cancer has key implications as colon cancer is a major public health problem being the second leading cause of cancer death in the United States in women and men. A significant correlation between any two of the studied variables - ETBF colonization, colon immune responses and colon cancer -- will substantively alter current paradigms for the pathogenesis, prevention and therapy of colon cancer.

Public Health Relevance

Colon cancer is the second leading cause of cancer death for women and men. Current approaches to prevention of colon cancer are cumbersome and underutilized due to their expense and inconvenience. This project proposes that colon cancer is triggered by a common stool bacterium called enterotoxigenic Bacteroides fragilis (ETBF) and will test whether detection of ETBF and/or the colon immune response to ETBF provide new, easier approaches to the prevention of the morbidity and mortality due to colon cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA151393-03
Application #
8303450
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Starks, Vaurice
Project Start
2010-09-02
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$570,309
Indirect Cost
$222,560
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Llosa, Nicolas J; Cruise, Michael; Tam, Ada et al. (2015) The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 5:43-51
Sears, Cynthia L; Geis, Abby L; Housseau, Franck (2014) Bacteroides fragilis subverts mucosal biology: from symbiont to colon carcinogenesis. J Clin Invest 124:4166-72
McAllister, Florencia; Housseau, Franck; Sears, Cynthia L (2014) Microbiota and immune responses in colon cancer: more to learn. Cancer J 20:232-6
Sears, Cynthia L; Garrett, Wendy S (2014) Microbes, microbiota, and colon cancer. Cell Host Microbe 15:317-28
Dutilh, Bas E; Cassman, Noriko; McNair, Katelyn et al. (2014) A highly abundant bacteriophage discovered in the unknown sequences of human faecal metagenomes. Nat Commun 5:4498
Dejea, Christine; Wick, Elizabeth; Sears, Cynthia L (2013) Bacterial oncogenesis in the colon. Future Microbiol 8:445-60
Sears, Cynthia L; Pardoll, Drew M (2011) Perspective: alpha-bugs, their microbial partners, and the link to colon cancer. J Infect Dis 203:306-11