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Grant Details

Grant Number: 5R01CA151393-05 Interpret this number
Primary Investigator: Sears, Cynthia
Organization: Johns Hopkins University
Project Title: Enterotoxigenic Bacteroides Fragilis: a Bacterial Promoter of Colon Oncogenesis
Fiscal Year: 2014
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Abstract

DESCRIPTION (provided by applicant): 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.

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Publications

Human colon mucosal biofilms from healthy or colon cancer hosts are carcinogenic.
Authors: Tomkovich S. , Dejea C.M. , Winglee K. , Drewes J.L. , Chung L. , Housseau F. , Pope J.L. , Gauthier J. , Sun X. , Mühlbauer M. , et al. .
Source: The Journal of clinical investigation, 2019-03-11; 130, p. 1699-1712.
EPub date: 2019-03-11.
PMID: 30855275
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Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria.
Authors: Dejea C.M. , Fathi P. , Craig J.M. , Boleij A. , Taddese R. , Geis A.L. , Wu X. , DeStefano Shields C.E. , Hechenbleikner E.M. , Huso D.L. , et al. .
Source: Science (New York, N.Y.), 2018-02-02; 359(6375), p. 592-597.
EPub date: 2018-02-01.
PMID: 29420293
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High-resolution bacterial 16S rRNA gene profile meta-analysis and biofilm status reveal common colorectal cancer consortia.
Authors: Drewes J.L. , White J.R. , Dejea C.M. , Fathi P. , Iyadorai T. , Vadivelu J. , Roslani A.C. , Wick E.C. , Mongodin E.F. , Loke M.F. , et al. .
Source: NPJ biofilms and microbiomes, 2017; 3, p. 34.
EPub date: 2017-11-29.
PMID: 29214046
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Sam68/KHDRBS1 is critical for colon tumorigenesis by regulating genotoxic stress-induced NF-?B activation.
Authors: Fu K. , Sun X. , Wier E.M. , Hodgson A. , Liu Y. , Sears C.L. , Wan F. .
Source: eLife, 2016-07-25; 5, .
EPub date: 2016-07-25.
PMID: 27458801
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Redundant Innate and Adaptive Sources of IL17 Production Drive Colon Tumorigenesis.
Authors: Housseau F. , Wu S. , Wick E.C. , Fan H. , Wu X. , Llosa N.J. , Smith K.N. , Tam A. , Ganguly S. , Wanyiri J.W. , et al. .
Source: Cancer research, 2016-04-15; 76(8), p. 2115-24.
EPub date: 2016-02-15.
PMID: 26880802
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Do biofilms confer a pro-carcinogenic state?
Authors: Dejea C.M. , Sears C.L. .
Source: Gut microbes, 2016; 7(1), p. 54-7.
PMID: 26939852
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The intestinal microbiome and health.
Authors: Tuddenham S. , Sears C.L. .
Source: Current opinion in infectious diseases, 2015 Oct; 28(5), p. 464-70.
PMID: 26237547
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Fecal detection of enterotoxigenic Bacteroides fragilis.
Authors: Chen L.A. , Van Meerbeke S. , Albesiano E. , Goodwin A. , Wu S. , Yu H. , Carroll K. , Sears C. .
Source: European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology, 2015 Sep; 34(9), p. 1871-7.
EPub date: 2015-07-15.
PMID: 26173688
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Metabolism links bacterial biofilms and colon carcinogenesis.
Authors: Johnson C.H. , Dejea C.M. , Edler D. , Hoang L.T. , Santidrian A.F. , Felding B.H. , Ivanisevic J. , Cho K. , Wick E.C. , Hechenbleikner E.M. , et al. .
Source: Cell metabolism, 2015-06-02; 21(6), p. 891-7.
EPub date: 2015-05-07.
PMID: 25959674
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The Bacteroides fragilis toxin gene is prevalent in the colon mucosa of colorectal cancer patients.
Authors: Boleij A. , Hechenbleikner E.M. , Goodwin A.C. , Badani R. , Stein E.M. , Lazarev M.G. , Ellis B. , Carroll K.C. , Albesiano E. , Wick E.C. , et al. .
Source: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2015-01-15; 60(2), p. 208-15.
EPub date: 2014-10-09.
PMID: 25305284
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The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints.
Authors: Llosa N.J. , Cruise M. , Tam A. , Wicks E.C. , Hechenbleikner E.M. , Taube J.M. , Blosser R.L. , Fan H. , Wang H. , Luber B.S. , et al. .
Source: Cancer discovery, 2015 Jan; 5(1), p. 43-51.
EPub date: 2014-10-30.
PMID: 25358689
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Microbiota organization is a distinct feature of proximal colorectal cancers.
Authors: Dejea C.M. , Wick E.C. , Hechenbleikner E.M. , White J.R. , Mark Welch J.L. , Rossetti B.J. , Peterson S.N. , Snesrud E.C. , Borisy G.G. , Lazarev M. , et al. .
Source: Proceedings of the National Academy of Sciences of the United States of America, 2014-12-23; 111(51), p. 18321-6.
EPub date: 2014-12-08.
PMID: 25489084
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Bacteroides fragilis subverts mucosal biology: from symbiont to colon carcinogenesis.
Authors: Sears C.L. , Geis A.L. , Housseau F. .
Source: The Journal of clinical investigation, 2014 Oct; 124(10), p. 4166-72.
EPub date: 2014-08-08.
PMID: 25105360
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A highly abundant bacteriophage discovered in the unknown sequences of human faecal metagenomes.
Authors: Dutilh B.E. , Cassman N. , McNair K. , Sanchez S.E. , Silva G.G. , Boling L. , Barr J.J. , Speth D.R. , Seguritan V. , Aziz R.K. , et al. .
Source: Nature communications, 2014-07-24; 5, p. 4498.
EPub date: 2014-07-24.
PMID: 25058116
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Microbiota and immune responses in colon cancer: more to learn.
Authors: McAllister F. , Housseau F. , Sears C.L. .
Source: Cancer journal (Sudbury, Mass.), 2014 May-Jun; 20(3), p. 232-6.
PMID: 24855013
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Microbes, microbiota, and colon cancer.
Authors: Sears C.L. , Garrett W.S. .
Source: Cell host & microbe, 2014-03-12; 15(3), p. 317-28.
PMID: 24629338
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Bacterial oncogenesis in the colon.
Authors: Dejea C. , Wick E. , Sears C.L. .
Source: Future microbiology, 2013 Apr; 8(4), p. 445-60.
PMID: 23534358
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Shift from pStat6 to pStat3 predominance is associated with inflammatory bowel disease-associated dysplasia.
Authors: Wick E.C. , LeBlanc R.E. , Ortega G. , Robinson C. , Platz E. , Pardoll D.M. , Iacobuzio-Donahue C. , Sears C.L. .
Source: Inflammatory bowel diseases, 2012 Jul; 18(7), p. 1267-74.
EPub date: 2011-10-21.
PMID: 22021169
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Perspective: alpha-bugs, their microbial partners, and the link to colon cancer.
Authors: Sears C.L. , Pardoll D.M. .
Source: The Journal of infectious diseases, 2011-02-01; 203(3), p. 306-11.
EPub date: 2010-12-08.
PMID: 21208921
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