Colorectal cancer: the facts in the case of the microbiota
Slater L. Clay, … , Diogo Fonseca-Pereira, Wendy S. Garrett
Slater L. Clay, … , Diogo Fonseca-Pereira, Wendy S. Garrett
Published February 15, 2022
Citation Information: J Clin Invest. 2022;132(4):e155101. https://doi.org/10.1172/JCI155101.
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Colorectal cancer: the facts in the case of the microbiota

Abstract

The importance of the microbiota in the development of colorectal cancer (CRC) is increasingly evident, but identifying specific microbial features that influence CRC initiation and progression remains a central task for investigators. Studies determining the microbial mechanisms that directly contribute to CRC development or progression are revealing bacterial factors such as toxins that contribute to colorectal carcinogenesis. However, even when investigators have identified bacteria that express toxins, questions remain about the host determinants of a toxin’s cancer-potentiating effects. For other cancer-correlating bacteria that lack toxins, the challenge is to define cancer-relevant virulence factors. Herein, we evaluate three CRC-correlating bacteria, colibactin-producing Escherichia coli, enterotoxigenic Bacteroides fragilis, and Fusobacterium nucleatum, for their virulence features relevant to CRC. We also consider the beneficial bioactivity of gut microbes by highlighting a microbial metabolite that may enhance CRC antitumor immunity. In doing so, we aim to elucidate unique and shared mechanisms underlying the microbiota’s contributions to CRC and to accelerate investigation from target validation to CRC therapeutic discovery.

Authors

Slater L. Clay, Diogo Fonseca-Pereira, Wendy S. Garrett

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Figure 2

Enterotoxigenic Bacteroides fragilis promotes tumorigenesis by distinct mechanisms.

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Enterotoxigenic Bacteroides fragilis promotes tumorigenesis by distinct ...
(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.