Chronic inflammation and, specifically, infection-associated inflammatory processes, enhance carcinogenesis in the affected organs. Chronic innate immune responses are known to contribute to these processes whereas the contributions of adaptive immunity to carcinogenesis are less clear. We have identified a human colon anaerobic bacterium, enterotoxigenic Bacteroides fragilis (ETBF), that induces a rapid and dramatic increase in colon tumors in multiple intestinal neoplasia mice (MinApc). This model replicates features of human colorectal cancer and our data demonstrate that colon tumorigenesis in this system is dependent, in part, on a novel Stat3/Th17 pathway, thereby defining a distinct role for adaptive immunity in colon cancer pathogenesis. Herein we seek to further define the mechanisms by which Stat3 activation in distinct cellular compartments and the resultant components of the Th17 response crosstalk with the colonic epithelium, inducing genetic and/or epigenetic epithelial cell changes that result in colon tumorigenesis. Our studies will begin to identify links between specific inflammatory mediators and the genetic changes critical to colon carcinogenesis. This work has direct relevance to the design of studies to investigate the pathogenesis of human colorectal cancer and may have implications for novel approaches to colorectal cancer therapy. Colorectal cancer is a major public health problem being the second leading cause of cancer death in the United States in women and men.

Public Health Relevance

Colon cancer is the second leading cause of cancer death for women and men. The microbial and immunologic mechanisms contributing to colon cancer are unknown. This project will study the immune and genetic mechanisms by which a newly recognized common human stool bacterium called enterotoxigenic Bacteroides fragilis (ETBF) triggers colon tumors in mice, providing new insights into how colon cancer developes and potentially new approaches to colon cancer therapy.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA151325-05
Application #
8657874
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Daschner, Phillip J
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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
Wick, Elizabeth C; Rabizadeh, Shervin; Albesiano, Emilia et al. (2014) Stat3 activation in murine colitis induced by enterotoxigenic Bacteroides fragilis. Inflamm Bowel Dis 20:821-34
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
Dejea, Christine; Wick, Elizabeth; Sears, Cynthia L (2013) Bacterial oncogenesis in the colon. Future Microbiol 8:445-60
Sears, Cynthia L (2012) In celebration of Sydney M. Finegold, M.D.: bacteroides fragilis in the colon: the good & the bad. Anaerobe 18:192-6
Goodwin, Andrew C; Destefano Shields, Christina E; Wu, Shaoguang et al. (2011) Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis. Proc Natl Acad Sci U S A 108:15354-9
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
O'Hagan, Heather M; Wang, Wei; Sen, Subhojit et al. (2011) Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands. Cancer Cell 20:606-19