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.

Keywords: AOM, azoxymethane; CM, conditioned medium; CRC, colorectal cancer; DSS, dextran sodium sulfate; Escherichia coli, microbiota; MOI, multiplicity of infection; SA-β-gal, senescence-associated β-galactosidase; SASP, senescence-associated secretory phenotype; SENP1; SUMO; colibactin; colorectal cancer; miR, microRNA; pks+ E. coli, colibactin-producing E. coli; pks- E. coli, isogenic mutant of pks+ E. coli deficient for colibactin production; toxin, microRNA.

Figure 1.

Tumor growth in response to infection with pks+ E. coli. (A) HCT116 cells (2 × 10⁶) were subcutaneously injected into nude mice and immediately infected for 3 hours with pks+ E. coli or pks- E. coli. The infection was performed at low (20) and high (100) multiplicity of infections (MOIs). Tumor size was monitored during the indicated period (n = 5/group; *P < 0 .05). (B) Cell signaling associated with pks+ E. coli-induced cellular senescence and tumor growth. (C) Model outlining the impact of pks+ bacteria on CRC according to the ratio of pks+ bacteria:tumor cells.