Chemistry meets biology in colitis-associated carcinogenesis

Abstract

The intestine comprises an exceptional venue for a dynamic and complex interplay of numerous chemical and biological processes. Here, multiple chemical and biological systems, including the intestinal tissue itself, its associated immune system, the gut microbiota, xenobiotics, and metabolites meet and interact to form a sophisticated and tightly regulated state of tissue homoeostasis. Disturbance of this homeostasis can cause inflammatory bowel disease (IBD)-a chronic disease of multifactorial etiology that is strongly associated with increased risk for cancer development. This review addresses recent developments in research into chemical and biological mechanisms underlying the etiology of inflammation-induced colon cancer. Beginning with a general overview of reactive chemical species generated during colonic inflammation, the mechanistic interplay between chemical and biological mediators of inflammation, the role of genetic toxicology, and microbial pathogenesis in disease development are discussed. When possible, we systematically compare evidence from studies utilizing human IBD patients with experimental investigations in mice. The comparison reveals that many strong pathological and mechanistic correlates exist between mouse models of colitis-associated cancer, and the clinically relevant situation in humans. We also summarize several emerging issues in the field, such as the carcinogenic potential of novel inflammation-related DNA adducts and genotoxic microbial factors, the systemic dimension of inflammation-induced genotoxicity, and the complex role of genome maintenance mechanisms during these processes. Taken together, current evidence points to the induction of genetic and epigenetic alterations by chemical and biological inflammatory stimuli ultimately leading to cancer formation.

Figure 1. Colon histopathology in H. hepaticus infected Rag2^−/− mice

Photomicrographs of H&E-stained sections of ileocecocolic junction. Representative sections from control (1 and 4) and H. hepaticus-infected (2–3 and 5–6) mice at 10 and 20 weeks post infection (wks pi). Images 2 and 5 show marked mucosal hyperplasia in infected mice at both time-points. Images 3 and 6 represent higher magnification photomicrographs to demonstrate the associated dysplasia and carcinoma development. Reprinted from [27]; with permission of the PNAS.

Figure 2. Chemical and biological mechanisms of inflammation [Illustration by Jeff Dixon]

For details see text. iNOS, inducible nitric oxide synthase; MPO, myeloperoxidase; NOX, NADPH oxidase; XO, xanthine oxidase.

Figure 3. Computational modeling of colonic NO concentration

A. Schematic representation of colonic crypt anatomy. The inner lining of the colonic mucosa consists of three distinct layers: the muscularis mucosa, the lamina propria, and the epithelium. B. NO concentration as a function of height above crypt base taking into account NO synthesis by macrophages and epithelial cells. The NO synthesis rate per unit volume in epithelial cells was assumed here to be 5.6 µM/s, the same as the baseline rate for macrophages. This is a conservative value; it is conceivable that rates in vivo are much higher. Axial concentration variations are shown for radial positions r = 0, 18, 32 µm, which corresponds to the center of the luminal fluid, middle of the epithelium, and middle of the lamina propria region, respectively. C. Time-dependent NO concentration and cumulative NO dose experienced by an epithelial cell as it migrates from the crypt base to the mucosal surface. The total time for migration was assumed to be 96 h. The ‘monolayer model’ assumes that the main source of NO is a confluent monolayer of macrophages localized in the region below the crypt base (see A.), whereas the ‘monolayer + distributed model’ assumes that macrophages are also distributed throughout the lamina propria. Reprinted from [72] (with permission of Elsevier).

Figure 4. Examples of NO delivery systems for cell culture studies and cytotoxic profiles of different cell lines

A. Sin-1 is used as a chemical donor of NO and ONOO⁻. B. Delivery via NO and O₂-permeable polydimethylsiloxande (Silastic) tubing enables controlled exposure of an adherent target cell line to NO/O₂. Shown is a schematic of a typical delivery apparatus. C. Co-cultivation of a target cell line with activated macrophages. D. Cell viability in TK6 and NH32 cells at 48 h and HCT116 cells at 24 h after exposure to NO and O₂ or argon. Reprinted from [139] and [241] (with permissions of Elsevier and ACS).

Figure 5. Overview of DNA damage products that are related to colitis-associated carcinogenesis

For details see text.

Figure 6. Overview of mechanisms that may contribute to tumor initiation and promotion during colitis-associated carcinogenesis

Modified from [27]; with permission of PNAS.