The Four Horsemen in Colon Cancer

Figure 1

Oncogenic activity of Fusobacterium nucleatum and Escherichia coli. (a) Gal-GalNAc overexpression in colon cells promotes the recruitment of Fusobacterium nucleatum via the Fap2 protein. After interacting with TLR4, the bacterium activates the protein PAK 1 and in turn, β catenin; the latter can also be activated through the effect of FadA on E-Cadherin. Activation of these signaling pathways promotes cellular proliferation and decreases proteins of the TOX family, which are associated with decreased apoptosis, failures in DNA repair and increased metastases. Likewise, bacterial interaction with TLR4 and its signaling via MYD88, modulates specific microRNAs that activate the autophagy associated with chemotherapy resistance. Also, Fusobacterium nucleatum increases the inflammatory process characterized by the presence of cytokines such as TNF-α, IL-6 and IL-8, that are regulated by the transcription factor NF-κB, whose increased activation has also been documented in colon cancer. Fusobacterium nucleatum has also been shown to be associated with the development of mutations in the genes BRAF and KRAS, microsatellite instability (MSI) and the methylation phenotype in CpG islands (CIMP). (b). The Adherent Invasive Escherichia coli strain (AIEC) colonizes the intestinal epithelium and uses CEACAM6 to invade the cells of the colonic epithelium; once internalized, it produces colibactin, a cyclomodulin encoded by the pks island, that damages DNA by alkylation and promotes the development of mutations. Colibactin also fosters cellular senescence by favoring SUMOylation of p53. Infection with the Enteropathogenic Escherichia coli (EPEC) strain, promotes the autophosphorylation of EGFR, a protein associated with an increase in proliferation, survival and metastases; it also decreases the expression of the DNA repair proteins, MLH1 and MSH2, and favors the rupture of tight junctions, a process involved in the development of metastases. All these EPEC-dependent mechanisms have been associated with the EspF protein.

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