Tumorigenic bacteria in colorectal cancer: mechanisms and treatments

Carcinogenic mechanism of specific intestinal bacteria. (A) Intestinal F. nucleatum may be at least partially of oral origin. F. nucleatum rarely settles in the intestine, but accumulates in large amounts in the intestine by binding to Gal-GalNAc, which significantly increases when CRC occurs. (B) (1) By binding to E-cadherin, F. nucleatum activates Wnt/β-catenin signaling and leads to overexpression of c-Myc and CCND1. This binding process is regulated by ANXA1. (2) F. nucleatum binds to TLR4 and activates the NF-κB pathway, thereby enhancing the expression of miR-21, and inhibiting the RAS signal terminator, RASA1. F. nucleatum induces expression of multiple pro-inflammatory cytokines by activating the NF-κB pathway. (3) F. nucleatum binds to the inhibitory receptors, TIGIT and CEACAM1, of T cells and NK cells and protects F. nucleatum and tumor cells from being killed by immune cells. (4) F. nucleatum promotes the proliferation and migration of macrophages/monocytes and increases the ratio of MDSCs. (5) F. nucleatum inhibits macrophage apoptosis by activating PI3K and ERK pathways. (C) B. fragilis mediates Stat3, E-cadherin/B-catenin, NF-κB, and p38 MAPK/AP-1 signaling pathways to induce translation of c-Myc, IL-8, and MCP-1. B. fragilis inhibits apoptosis by activating the p38 MAPK/COX2/ PGE2 /cIAP2 pathway triggered by SMO/ROS production. (D) Salmonella secretes 2 toxic factors, AvrA and TT. AvrA stabilizes β-catenin and IκBα by inhibiting ubiquitination, which in turn up-regulates their downstream target genes, c-Myc and CCND1. TT induces DNA single-strand and double-strand breaks (DSBs). (E) E. faecalis upregulates expression of COX2 and 4 HNE in macrophages, which could invade and integrate with DNA in adjacent cells. (F) The pks + E. coli induces CRC via producing a genotoxin called colibactin, which causes severe DNA damage. (G) After processing on the NRPS-PKS assembly line, precolibactin composed of colibactin and prodrug motif is transported into the periplasm by ClbM and deacylated by ClbP in the periplasm to become mature colibactin. It is then transported into the host cell via an unknown mechanism. In addition, bacterial cells degrade colibactin through the self-protection protein, ClbS, to protect their own DNA from damage. (H) Several structurally characterized colibactins bind to host DNA by cyclopropane. (I) Intracellularly accumulated SQSTM1 caused by pks+E. coli bind to and inhibit the histone H2A ubiquitin enzyme, RNF168, thus inhibiting the recruitment of RAD51 to DSBs sites. (J) By interacting with TLR2 and TLR4, P. anaerobius upregulates reactive oxygen species and SREBF2, thereby promoting cholesterol synthesis and cell proliferation.