Biofilms of Colorectal Cancer
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Date
2015-02-02
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Johns Hopkins University
Abstract
The human colon hosts a diverse and metabolically complex community of microorganisms. While the colonic microbiome has long been suggested to contribute to the development of colorectal cancer (CRC), a definitive link has not been made. In this thesis, studies that define the bacterial associations of CRC in the genetically normal host (sporadic CRC) and the host predisposed to early colon carcinogenesis [familial adenomatous polyposis (FAP)] are presented. We demonstrate for the first time that bacterial biofilms are a common feature of many sporadic colorectal cancers, one of the leading malignancies in the United States and abroad. Colon biofilms, dense communities of bacteria encased in a mucus matrix that contact the colon epithelial cells, are a nearly universal feature of sporadic right colon tumors with broad extension over the right colon in the tumor host. Most remarkably, biofilm presence correlates with bacterial tissue invasion and a change in tissue biology including changes in oncogenic signaling pathways [E-cadherin, IL-6 and signal transducer and activator of transcription 3 (Stat3)], enhanced polyamine metabolites and increased cellular proliferation, changes capable of promoting oncogenic transformation. Deep sequencing revealed that biofilm communities on paired normal mucosa cluster with tumor microbiomes but lack distinct taxa differences. In striking contrast, biofilms were detected throughout the colons of individuals with the hereditary CRC condition (FAP) and lacked the diverse composition of biofilms associated with sporadic CRC. Namely, biofilms of FAP patients are comprised largely of pathogenic subtypes of Escherichia coli (pks+) and Bacteroides fragilis (bft+). This work introduces a new concept whereby the microbial community structural organization contributes to disease progression.
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Keywords
Microbiome, Biofilm, Colorectal Cancer