Colonic adenomatous polyps are common tumors occurring in approximately 50% of Western populations with about 10% risk of malignant progression. Key factors in the pathogenesis of colonic neoplasia are germline mutations in the adenomatous polyposis coli (ARC) gene and chronic inflammation as exemplified by patients with familial adenomatous polyposis or ulcerative colitis, respectively, who are highly susceptible to developing colon cancer. Bacteroides fragilis are common colonic commensals (up to 70% of adults colonized) and the leading anaerobe in human disease. One molecular subset of B. fragilis, enterotoxigenic B. fragilis (ETBF), is a human inflammatory diarrheal disease pathogen. However, asymptomatic colonization with ETBF is common (between 4% to 30% of individuals) and recent data link ETBF to active inflammatory bowel disease and colorectal cancer. The only known virulence factor of ETBF is a 20 kDa zinc-dependent metalloprotease toxin termed B. fragilis toxin (BFT). By cell-surface proteolysis, matrix metalloproteases regulate eukaryotic cell signal transduction and function including cell proliferation, tumor progression and metastasis. Our data reveal that BFT treatment of human intestinal epithelial cells (IEC) stimulates cleavage of the intercellular adhesion protein, E-cadherin, and triggers the activation of multiple signal transduction pathways including beta-catenin, gamma-secretase, tyrosine kinases, Nuclear Factor-kB (NF-kB) and mitogen-activated protein kinases (MARK) resulting in c-Myc induction, IEC proliferation with enhanced cellular migration and IEC secretion of the proinflammatory cytokine, interleukin-8 (IL-8). The proliferative and inflammatory potential of ETBF are further supported by our preliminary data showing ETBF colonization yields colonic hyperplasia and inflammation in conventional mice; rapid, lethal colitis in germ-free mice; and increased colon adenomas in multiple intestinal neoplasia (Min) mice. Our data show that BFT secretion is critical to murine ETBF colonic disease. Thus, we hypothesize that chronic colonization with ETBF, at least in part through BFT, acts as a co-factor in the pathogenesis of colonic neoplasia and inflammation via cleavage of E-cadherin and nuclear activation of protoooncogenes and proinflammatory genes. To test this hypothesis, we will: 1) identify the BFT receptor. We postulate this receptor mediates, in part, colon inflammation and hyperplasia stimulated by ETBF in vivo.; and 2) determine if ETBF colonization promotes colonic tumor formation in mouse models prone to colon neoplasia. Colon cancer is the third most common cancer worldwide and the second leading cause of cancer deaths in the United States in men and women. Our studies may indicate that a common stool bacterium is oncogenic and contributes to colon cancer risk. If so, these data will lead to new public health approaches to the prevention of colon cancer. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045496-15
Application #
7261291
Study Section
Special Emphasis Panel (ZRG1-HIBP-H (01))
Program Officer
Hamilton, Frank A
Project Start
1993-08-20
Project End
2011-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
15
Fiscal Year
2007
Total Cost
$326,450
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Qiang, Xiaoling; Liotta, Anthony S; Shiloach, Joseph et al. (2017) New melanocortin-like peptide of E. coli can suppress inflammation via the mammalian melanocortin-1 receptor (MC1R): possible endocrine-like function for microbes of the gut. NPJ Biofilms Microbiomes 3:31
Chen, L A; Van Meerbeke, S; Albesiano, E et al. (2015) Fecal detection of enterotoxigenic Bacteroides fragilis. Eur J Clin Microbiol Infect Dis 34:1871-7
McAllister, Florencia; Housseau, Franck; Sears, Cynthia L (2014) Microbiota and immune responses in colon cancer: more to learn. Cancer J 20:232-6
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
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
Wick, Elizabeth C; LeBlanc, Robert E; Ortega, Guillermo et al. (2012) Shift from pStat6 to pStat3 predominance is associated with inflammatory bowel disease-associated dysplasia. Inflamm Bowel Dis 18:1267-74
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
Housseau, Franck; Sears, Cynthia L (2010) Enterotoxigenic Bacteroides fragilis (ETBF)-mediated colitis in Min (Apc+/-) mice: a human commensal-based murine model of colon carcinogenesis. Cell Cycle 9:3-5

Showing the most recent 10 out of 42 publications