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

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.

APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis

“…18,19,34 Conversely, luminal replacement of GUCY2C agonists reduces the number and size of tumors driven by Apc mutations in mice. 26,32,33,35 These observations support the hypothesis that guanylin loss and silencing of the GUCY2C axis is one molecular mechanism contributing to the progression of tumorigenesis initiated by mutant APC-β-catenin-TCF signaling.…”

“…In that context, GUCY2C agonists reduce epithelial transformation in genetic, carcinogen, and inflammatory mouse models of intestinal tumorigenesis. 26,[32][33][34][35] These observations suggest a pathophysiological model in which transformation reduces guanylin expression, driving tumorigenesis by suppressing GUCY2C-cGMP signaling. Here, we reveal that guanylin hormone expression is eliminated, and GUCY2C-cGMP signaling is silenced, as an immediate downstream consequence of mutant APC-β-catenin-TCF nuclear transcriptional re-programming.…”

Silencing the intestinal GUCY2C tumor suppressor axis requires APC loss of heterozygosity

“…29,30 Similarly, chronic colonization of mice with bacteria constitutively secreting GUCY2C ligand opposed azoxymethane-induced colorectal tumorigenesis primarily by reducing tumor number, with a minor effect on tumor size. 28 These observations suggest that, beyond progression after APC LOH, hormone repression silencing the GUCY2C signaling axis might contribute to creating the epithelial genetic vulnerability underlying tumor initiation through APC LOH. In that context, the established link between dysregulated nuclear APC-β-catenin signaling and transcriptional repression of hormone expression 34 suggested a model in which APC heterozygosity suppressed hormone expression silencing GUCY2C leading to genetic vulnerability.…”

“…25,26 In turn, cGMP signaling regulates homeostatic processes in intestine that are canonically disrupted in cancer, 27 including maintenance of DNA integrity and genomic stability. 19,28 In that context, silencing the GUCY2C axis amplifies intestinal epithelial cell vulnerability for APC LOH in mouse models of FAP. 19 Indeed, loss of GUCY2C signaling drives intestinal transformation, specifically at the step of tumor initiation, induced by genetic mutations or carcinogens.…”

The Guanylate Cyclase C—cGMP Signaling Axis Opposes Intestinal Epithelial Injury and Neoplasia

“…Our group recently confirmed a role for chronic ST-exposure in tumor prevention. Mice colonized for 18 weeks with ST-producing E. coli , mimicking chronic ST exposure in endemic regions of the world, developed a 50% lower tumor burden in response to the carcinogen, azoxymethane, than mice colonized with ST-negative E. coli ( 143 ). This finding reinforces the role of the GUCY2C-cGMP signaling axis, as well as the role of microbiome composition, in tumor susceptibility.…”