Figure 2. Enterotoxigenic Bacteroides fragilis promotes tumorigenesis by distinct mechanisms.

(A) B. fragilis toxins (BFTs) activate the Ras/mTOR and p38 mitogen-activated protein kinase (p38) intracellular signaling pathways. BFTs induce inhibitor of apoptosis protein-2 (IAP2) expression, resulting in increased tumor growth and inhibition of apoptosis. BFTs also increase intestinal cell proliferation and permeability by inducing c-myc expression after E-cadherin cleavage and β-catenin nuclear localization, in a process that was recently shown to involve G protein–coupled receptor 35 (GPR35). (B) Enterotoxigenic B. fragilis (ETBF) promotes epigenetic alterations with the potential to cause DNA damage by inducing DNA methyltransferase 1 (DNMT1) recruitment and inducing JmjC domain–containing histone demethylase 2B (JMJD2B) in CRC cells. ETBF-produced BFTs also induce DNA damage by increasing ROS generation. (C) ETBF and BFTs induce a proinflammatory environment that contributes to carcinogenesis. BFTs induce activation of the transcription factors STAT3 and NF-κB, increasing intestinal permeability and production of inflammatory cytokines. In a multistep process, ETBF induces phosphorylation (“P” in yellow circles) of STAT3 and IL-17–producing Th17 and γδ T cells. Both processes promote the recruitment of pro-tumorigenic myeloid cells that suppress cytotoxic antitumor immunity.