Genotoxins: The Mechanistic Links between Escherichia coli and Colorectal Cancer

Simple Summary Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, and its incidence is steadily rising in developing areas. Bacterial pathogens from the gut microbiota have been recognized as important risk factors for CRC. This review updates the current knowledge of Escherichia coli-produced genotoxins related to CRC. Emerging evidence indicates bacterial infections contribute to the formation of cancers. Bacterial genotoxins are effectors that cause DNA damage by introducing single- and double-strand DNA breaks in the host cells. The first bacterial genotoxin cytolethal distending toxin (CDT) was a protein identified in 1987 in a pathogenic strain in Escherichia coli (E. coli) isolated from a young patient. The peptide-polyketide genotoxin colibactin is produced by the phylogenetic group B-2 of E. coli. Recently, a protein produced by attaching/effacing (A/E) pathogens, including enteropathogenic and enterohemorrhagic E. coli (EPEC and EHEC) and their murine equivalent Citrobacter rodentium (CR), has been reported as a novel protein genotoxin, being injected via the type III secretion system (T3SS) into host cells and harboring direct DNA digestion activity with a catalytic histidine-aspartic acid dyad. These E. coli-produced genotoxins impair host DNA, which results in senescence or apoptosis of the target cells if the damage is beyond repair. Conversely, host cells can survive and proliferate if the genotoxin-induced DNA damage is not severe enough to kill them. The surviving cells may accumulate genomic instability and acquire malignant traits. This review presents the cellular responses of infection with the genotoxins-producing E. coli and discusses the current knowledge of the tumorigenic potential of these toxins.

Automated summary

Colorectal cancer (CRC) is a major cause of cancer-related death worldwide, with an increasing incidence in developing areas. Bacterial pathogens from the gut microbiota, particularly Escherichia coli (E. coli), are recognized as significant risk factors for CRC. This review provides an update on the knowledge of E. coli-produced genotoxins associated with CRC. It discusses the various genotoxins produced by E. coli, their mechanisms of action, and their potential to induce tumorigenesis through DNA damage and cellular responses.