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Open AccessFeature PaperArticle

ST-Producing E. coli Oppose Carcinogen-Induced Colorectal Tumorigenesis in Mice

Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA
University of Illinois Chicago School of Medicine, Chicago, IL 60612, USA
Author to whom correspondence should be addressed.
Academic Editor: Yukako Fujinaga
Toxins 2017, 9(9), 279;
Received: 15 August 2017 / Revised: 31 August 2017 / Accepted: 6 September 2017 / Published: 12 September 2017
(This article belongs to the Special Issue Heat-Stable Enterotoxins)
There 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
Keywords: enterotoxigenic E. coli; heat-stable enterotoxins; azoxymethane; colorectal cancer; GUCY2C-cGMP axis; chemoprevention enterotoxigenic E. coli; heat-stable enterotoxins; azoxymethane; colorectal cancer; GUCY2C-cGMP axis; chemoprevention
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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.

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