The bacterial genotoxin colibactin promotes colon tumor growth by modifying the tumor microenvironment

Abstract

The gut microbiota is suspected to promote colorectal cancer (CRC). Escherichia coli are more frequently found in CCR biopsies than in healthy mucosa; furthermore, the majority of mucosa-associated E. coli isolated from CCR harbors the pks genomic island (pks+ E. coli) that is responsible for the synthesis of colibactin, a genotoxic compound. We have recently reported that transient contact of a few malignant cells with colibactin-producing E. coli increases tumor growth in a xenograft mouse model. Growth is sustained by cellular senescence that is accompanied by the production of growth factors. We demonstrated that cellular senescence is a consequence of the pks+ E. coli-induced alteration of p53 SUMOylation, an essential post-translational modification in eukaryotic cells. The underlying mechanisms for this process involve the induction of miR-20a-5p expression, which targets SENP1, a key protein in the regulation of the SUMOylation process. These results are consistent with the expression of SENP1, miR-20a-5p and growth factors that are observed in a CRC mouse model and in human CCR biopsies colonized by pks+ E. coli. Overall, the data reveal a new paradigm for carcinogenesis in which pks+ E. coli infection induces cellular senescence characterized by the production of growth factors that promote the proliferation of uninfected cells and, subsequently, tumor growth.

The Role of Escherichia coli in the Development and Progression of Cancer

“…Recent findings support this idea, because an increased tumor progression in murine xenograft model was observed after infection with pks + E. coli strains compared with those infected by pks -strains (45,46). Although the mechanism by which pks + E. coli strains induced tumor progression is not completely clear, it was reported that infection with pks + E. coli strains produced DNA damage, cell cycle arrest, melanocytosis, aneuploidy and tetraploidy, thus all these effects could be associated with DNA mutations, and accordingly induce cancer (38,47).…”

Iron Homeostasis Regulates the Genotoxicity of Escherichia coli That Produces Colibactin

“…We confirmed that this regulation occurred in three different strains; however, the quantitative differences observed could be explained by the genetic diversity between strains. Colibactin was demonstrated to be a virulence factor, for example, in neonatal systemic infections (19), but it is also associated with the development of colorectal cancer (31)(32)(33). The fact that colibactin is regulated by the two major regulators of iron homeostasis could link iron availability in the gut and blood and E. coli-mediated carcinogenesis and systemic infections, respectively.…”

Domain-Targeted Metabolomics Delineates the Heterocycle Assembly Steps of Colibactin Biosynthesis

“…8 The clb locus has been shown to initiate tumor formation in colitis mouse models and is epidemiologically correlated to colorectal cancer patients. 9 Paradoxically, a gene in the locus ( clbA ) has also been shown to be required for the efficacy of probiotic E. coli Nissle 1917 used to treat ulcerative colitis. 10 Despite the importance of this pathway, natural colibactins capable of recapitulating cellular activities have not been isolated.…”