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.

Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages

“…Myeloid cells play a critical role in sustaining cancer progression (1). Moreover, inflammatory myeloid cells help to create and fuel the mutagenic pressure underlying the genetic instability of neoplastic cells by both direct mechanisms, such as the production of free-radical compounds (2), and indirect processes, such as the disruption of host defense barriers (3).…”

Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer

“…By generating reactive chemical entities (e.g., reactive oxygen, nitrogen, and halogen species) intended to neutralize invading pathogens, inflammatory responses may also inflict chemical collateral damage on nucleic acids and proteins in surrounding healthy tissues (7)(8)(9)(10). When the immune response aberrantly persists over months and years, the chemical damage may exceed the repair capabilities of the exposed cells, leading to cell death or to genetic and epigenetic modifications that, in principle, can set the stage for malignant transformation (7)(8)(9)(10).…”

Formation and repair of oxidatively generated damage in cellular DNA

“…In a subsequent study, the halogenated pyrimidine base 5-ClCyt was higher in the DNA of diabetic patients than in healthy volunteers, suggesting that this product may be used as a relevant biomarker of inflammation [266]. This idea is supported by the [265] observation of a significant increase in the steady-state level of highly mutagenic 5-ClCyt [267] in the colon and liver of Rag2−/− mice that were subjected to chronic inflammation as the result of infection with Helicobacter hepaticus [256]. Similarly high values of this biomarker of inflammation, half of which were close or more than 10 5-ClCyt lesions per 10 8 normal bases, were assessed by HPLC-ESI-MS/MS in the human colon of patients suffering from inflammatory bowel disease [268].…”

“…It should be noted that the measurement of Sp was performed by HPLC-MS operating in the SIM mode, a method with shortcomings and well-documented lack of compound selectivity as already discussed ( vide supra ). The above extremely high value of Sp has to be compared with the relatively low level of secondary oxidation products of 8-oxoGua that were measured in the DNA of liver and colon tissues of Rag2 −/− mice infected with Helicobacter hepaticus using the relevant and accurate HPLC-ESI-MS/MS method [256,257]. The frequency of Sp and Gh was found to be within the range of 1 to 7 lesions per 10 8 nucleosides, which is close to the limit of detection.…”