Abstract SY34-03: Colon cancer: Alpha-bugs or community as disease drivers

The colonic microbiome perhaps aided by specific bacterial species is hypothesized to contribute to colorectal cancer (CRC) pathogenesis, possibly acting as an initiator and/or promoter of colon oncogenesis. Potential mechanisms include induction of specific mucosal pro-carcinogenic immune responses and the biologic action of specific microbial, particularly bacterial, virulence factors. Among specific bacterial species, Escherichia coli possessing the pks island with the DNA-damaging colibactin toxin, Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis (ETBF) that secrete the DNA-damaging B. fragilis toxin are carcinogenic species of particular interest. To address the hypothesis that microbial species or communities contribute to CRC pathogenesis, we are prospectively studying the microbial associations of human CRC together with parameters of mucosal immunity. Paired surgical CRC samples and normal colon mucosa are studied along with colon biopsies (right and left) of healthy controls undergoing screening colonoscopy. In both United States (Johns Hopkins) and Malaysian cohorts, our data demonstrate that sporadic colon tumors located proximal to the hepatic flexure are characterized by invasive polymicrobial biofilms that extend to normal colon tissue far distant from the tumor. In contrast, biofilm formation is infrequent in colon tumors distal to the hepatic flexure and in the mucosa of colonoscopy controls. Importantly, biofilm formation in colonoscopy controls occurs with similar frequency in the right and left colon demonstrating that the right colon is not inherently prone to biofilm formation. Biofilms induce colonic epithelial cell (CEC) and mucosal biologic changes. Namely, biofilm-containing normal tissues of CRC patients display significantly reduced crypt cell E-cadherin as well as increased CEC IL-6 and Stat3 activation that are not observed in biofilm-negative normal tissues from CRC hosts. Mucosal biofilms in colonoscopy controls are also associated with redistribution of E-cadherin and increased mucosal IL-6. Remarkably, biofilm formation on normal colon tissues from either CRC or healthy hosts is associated with increased crypt epithelial proliferation, a marker for CEC transformation. Collectively, these data indicate that biofilm formation promotes biologic changes known to increase colonic permeability, Wnt signaling, angiogenesis and CEC proliferation, all consistent with mucosal procarcinogenesis. To further identify the microbial links to human CRC, in these same cohorts, we have analyzed in more detail the association of Fusobacterium with CRC finding that a Fusobacterium bloom, largely consisting of F. nucleatum or closely related species, is associated with a subset of early stage CRC. F. nucleatum detection is rare in the normal colon mucosa of either CRC or healthy hosts. The Bacteroides fragilis toxin gene (bft) that identifies oncogenic ETBF is detected by PCR significantly more often on left (86%) and right (92%) tumor and/or paired normal tissues compared with left and right colon biopsies from individuals undergoing screening colonoscopy (53% and 55%, respectively; P Citation Format: Cynthia L. Sears. Colon cancer: Alpha-bugs or community as disease drivers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY34-03. doi:10.1158/1538-7445.AM2015-SY34-03