ST-Producing E. coli Oppose Carcinogen-Induced Colorectal Tumorigenesis in Mice
AbstractThere is a geographic inequality in the incidence of colorectal cancer, lowest in developing countries, and greatest in developed countries. This disparity suggests an environmental contribution to cancer resistance in endemic populations. Enterotoxigenic bacteria associated with diarrheal disease are prevalent in developing countries, including enterotoxigenic E. coli (ETEC) producing heat-stable enterotoxins (STs). STs are peptides that are structurally homologous to paracrine hormones that regulate the intestinal guanylyl cyclase C (GUCY2C) receptor. Beyond secretion, GUCY2C is a tumor suppressor universally silenced by loss of expression of its paracrine hormone during carcinogenesis. Thus, the geographic imbalance in colorectal cancer, in part, may reflect chronic exposure to ST-producing organisms that restore GUCY2C signaling silenced by hormone loss during transformation. Here, mice colonized for 18 weeks with control E. coli or those engineered to secrete ST exhibited normal growth, with comparable weight gain and normal stool water content, without evidence of secretory diarrhea. Enterotoxin-producing, but not control, E. coli, generated ST that activated colonic GUCY2C signaling, cyclic guanosine monophosphate (cGMP) production, and cGMP-dependent protein phosphorylation in colonized mice. Moreover, mice colonized with ST-producing E. coli exhibited a 50% reduction in carcinogen-induced colorectal tumor burden. Thus, chronic colonization with ETEC producing ST could contribute to endemic cancer resistance in developing countries, reinforcing a novel paradigm of colorectal cancer chemoprevention with oral GUCY2C-targeted agents. View Full-Text
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Li, P.; Lin, J.E.; Snook, A.E.; Waldman, S.A. ST-Producing E. coli Oppose Carcinogen-Induced Colorectal Tumorigenesis in Mice. Toxins 2017, 9, 279.
Li P, Lin JE, Snook AE, Waldman SA. ST-Producing E. coli Oppose Carcinogen-Induced Colorectal Tumorigenesis in Mice. Toxins. 2017; 9(9):279.Chicago/Turabian Style
Li, Peng; Lin, Jieru E.; Snook, Adam E.; Waldman, Scott A. 2017. "ST-Producing E. coli Oppose Carcinogen-Induced Colorectal Tumorigenesis in Mice." Toxins 9, no. 9: 279.
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