The Multifaceted Role of the Intestinal Microbiota in Colon Cancer Thergiory Irrazábal, Antoaneta Belcheva, Stephen E. Girardin, Alberto Martin, Dana J. Philpott  Molecular Cell  Volume 54, Issue 2, Pages 309-320 (April 2014) DOI: 10.1016/j.molcel.2014.03.039 Copyright © 2014 Elsevier Inc. Terms and Conditions

Figure 1 Mutations in Genes and Signaling Pathways that Affect Colorectal Cancer Initiation and Progression CRC development is a multistep process that begins when normal epithelium forms aberrant crypts and further advances into stages of early and late adenomatous polyps, invasive carcinoma, and metastasis. CRC is associated with numerous genetic changes, including gain-of-function and loss-of-function mutations and epigenetic alterations. Some of the most frequently affected genes and pathways are shown. The arrows show the oncogenes that are turned on, while the red blocked arrows denote the tumor suppressor genes that are turned off at different stages of CRC development. MMR, mismatch repair pathway; APC, adenomatous polyposis coli; CIN, chromosomal instability; 15-PGDH, 15-prostaglandin dehydrogenase; TGF-β, transforming growth factor β. Molecular Cell 2014 54, 309-320DOI: (10.1016/j.molcel.2014.03.039) Copyright © 2014 Elsevier Inc. Terms and Conditions

Figure 2 Role of Dysbiosis and Immune Dysfunctions in Colon Carcinogenesis (A) Dysbiosis, as a result of inflammasome deficiencies, could promote tumorigenesis. Inflammasome-derived IL-18 is necessary for tissue repair, protection against tumors, and the maintenance of the microbial ecology equilibrium. In turn, this phenotype associated with the lack of IL-18 could be exacerbated by a dysbiotic microbiota that could lead to chronic inflammation, increased IL-6 signaling, and tumorigenesis. In intestinal epithelial cells, IL-6 activates STAT3 signaling, protecting normal and premalignant cells from apoptosis. (B) Dysbiosis and immune dysfunctions may allow increased bacterial translocation due to altered barrier function. Microorganism-associated molecular patterns (MAMPs) are detected by Toll-like receptors (TLRs) present in epithelial cells, macrophages, and myofibroblasts, leading to the activation of different pathways that promote cancer development. Epiregulin (EREG) and amphiregulin (AREG) are epidermal growth factor receptor (EGFR) ligands and therefore induce proliferation through MAPK/ERK pathway activation. Th17 cytokines mark the early stages of CRC by induction of STAT3. Molecular Cell 2014 54, 309-320DOI: (10.1016/j.molcel.2014.03.039) Copyright © 2014 Elsevier Inc. Terms and Conditions

Figure 3 Inflammation-Induced Mechanisms of Cancer Development in the Colon (1) During dysbiosis, specific mutagens could reach colon epithelial cells. (1a) Mutagens from food or released by luminal microbiota enter into the cell, where they can directly cause DNA damage or induce the expression of enzymes like spermine oxidase (SMO) that lead to increased reactive oxygen species (ROS). (1b) ROS and reactive nitrogen intermediates (RNI) species released by either microbes in the lumen or immune cells within the lamina propria can also lead to genotoxicity. (2) Inflammation leads to the activation of different pathways that could lead to gene dysregulation and tumorigenesis. (2a) Certain cytokines activate transcription factors that drive the expression of genes that control survival, proliferation, and angiogenesis. (2b) Cytokines, including IL-6 and IL-1β, have been associated with the induction of DNA methyltransferases (DNMT), which silence tumor suppressor genes. (2c) Other cytokine inflammatory pathways induce miRNA expression, which downregulates the expression of tumor suppressor genes. Molecular Cell 2014 54, 309-320DOI: (10.1016/j.molcel.2014.03.039) Copyright © 2014 Elsevier Inc. Terms and Conditions