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

Peng Li,Jieru Lin,Scott Waldman,Adam Snook

doi:10.3390/toxins9090279

Abstract

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.

Highlights

Enterotoxigenic E. coli (ETEC) remain a major public health issue, causing almost 1 billion illnesses and half a million deaths worldwide each year, with deaths mostly occurring in developing countries in children less than 5 years old [1,2,3]
These include heat-labile enterotoxins (LT) which are structurally homologous to cholera toxin and induce cyclic adenosine monophosphate accumulation, and heat-stable enterotoxins (STa and STb) which induce cyclic GMP (cGMP) accumulation [1]
BL21(ST+) secreted immunoreactive heat-stable enterotoxin compared to BL21(ST−) (Figure 1A,B)

Summary

Introduction

Enterotoxigenic E. coli (ETEC) remain a major public health issue, causing almost 1 billion illnesses and half a million deaths worldwide each year, with deaths mostly occurring in developing countries in children less than 5 years old [1,2,3]. ETEC is a heterogeneous classification of bacteria, comprising molecular subtypes of E. coli identified by their toxins that produce secretion. These include heat-labile enterotoxins (LT) which are structurally homologous to cholera toxin and induce cyclic adenosine monophosphate (cAMP) accumulation, and heat-stable enterotoxins (STa and STb) which induce cGMP accumulation [1]. ST is structurally homologous to the paracrine hormones guanylin (GUCA2A) and uroguanylin (GUCA2B) which activate the intestinal guanylyl cyclase C (GUCY2C) receptor [4] Compared to these endogenous hormones, which contain only two disulfide bonds, ST is resistant to proteolysis, isomerically stable, pH-insensitive, and has a higher receptor affinity resulting in excess GUCY2C activation in the small intestine leading to diarrhea. Cyclic nucleotide accumulation activates cGMP-dependent protein kinase (PKG)

Methods

Results

Conclusion