Trends in Molecular Medicine
ReviewMismatch Repair and Colon Cancer: Mechanisms and Therapies Explored
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Colorectal Cancer: An Urgent Need for Targeted Therapies
Colorectal cancer (CRC) is the third most common cancer worldwide, resulting in over 690 000 deaths annually [1]. The overwhelming morbidity and mortality caused by CRC impacts on the global economy through loss of productivity and the burden on the healthcare system. In the USA alone, CRC is projected to exceed $17 billion in medical care by the year 2020 [2]. Consequently, researchers have expended considerable resources to develop treatments and preventative strategies to reduce the
Mismatch Repair Defects and CRC
The development of CRC is a multistep process whereby normal colon epithelial cells (CECs) develop into colorectal adenoma (polyps) and, over time, can give rise to colorectal adenocarcinoma. Genetic lesions have been identified as central contributors to CRC development, and inactivation of the DNA MMR pathway contributes to genetic mutations (Figure 2). Deficiency in MMR caused by germline mutations manifests as Lynch syndrome in humans, which occurs in 1 in 35 total CRC cases, making it the
Mechanism of Mammalian MMR
MMR is a multistep process involving key proteins at each stage to maintain genomic stability (Figure 3). Initiation of MMR begins when a heterodimer of the MutS homolog (MSH), either MSH2–MSH6 (MutSα) or MSH2–MSH3 (MutSβ), binds to mismatched DNA. MutSα recognizes base–base mismatches and 1–2 base pair (bp) IDLs, whereas MutSβ recognizes IDLs longer than 2 bp [41]. Following mismatch or IDL recognition, a heterodimer of MutL homolog (MLH) consisting of MLH1 and the post-meiotic segregation 2
Non-canonical Roles of MMR in CRC
Although MMR is able to recognize and repair mismatched DNA base pairs and IDLs, there are additional biological roles for MMR which are independent of DNA replication. Discussed below are a few non-canonical roles of MMR which could contribute to the progression of CRC.
Inflammation and CRC
Genetic and epigenetic alterations are observed in CRC, and these changes could be promoted by inflammation in the intestinal tract. Inflammation in the colon can be triggered by the gut microbiota and their metabolites or byproducts [65]. Immune cells and CECs produce regulatory signals so as to maintain homeostatic levels of inflammation. The intestinal microbiota is recognized by pattern recognition receptors, such as Toll-like receptors (TLRs) expressed on CECs and immune cells, which are
The Gut Microbiota and CRC
The availability of high resolution next-generation sequencing (NGS) technologies has begun to elucidate the etiologic complexity of the relationship between the microbiome and CRC. It is currently well accepted that the intestinal microbiota forms a symbiotic relationship between its host and has broad functions in metabolism and immunity 83, 84. NGS analyses on human CRC tissues have allowed researchers to determine the bacterial composition of the microbiome associated with subtypes of CRC.
Butyrate Production by Gut Microbiota and its Contribution to MMR-deficient CRC
Diet is one of the risk factors for CRC, and even short-term changes in diet can alter the microbial communities in the gut [92]. The metabolic products of the gut microbiota influence the development of CRC [65]. Short-chain fatty acids, including acetate, propionate, and butyrate, are produced within the intestinal lumen by bacterial fermentation. Normal CECs utilize bacterially produced butyrate as a primary energy source [93]. However, butyrate has contrasting proliferative effects between
Anti-PD-1 Immunotherapy Against MMR-Deficient CRC
Tumor cells can evade the immune system by expressing inhibitory ligands and receptors. For example, the surface receptor programmed death ligand 1 (PD-L-1) is expressed by many tumor cells and binds to its ligand programmed death 1 (PD-1) on T cells, blocking T cell-mediated immunity. As such, there has been increased interest in developing immunotherapies that block these inhibitory interactions to enable T cell effector function against tumors. With respect to MMR-deficient CRCs, the
NSAIDs in CRC Chemoprevention
The chemopreventive effects of nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin (acetylsalicylic acid; ASA) on colorectal cancer have been supported by experimental data in mice and humans 98, 99. Mice with conditionally deleted Msh2 in the intestinal epithelium (Villin–Cre Msh2lox/lox) that were administered ASA in their food exhibited a 20% increase in median survival time when compared to untreated controls [99]. In an AOM-induced CRC model using Msh2−/− mice, the NSAID sulindac
Molecular Biomarkers for CRC Detection
Tumor biomarkers have been studied in relation to genetics, immunity, and the microbiota. Investigations into the interactions between different etiologic factors of CRC have been incorporated into an interdisciplinary field termed ‘molecular pathological epidemiology’ (MPE). Determining molecular associations and biomarkers within specific subsets of CRC can then be associated with host and environmental factors to improve personalized risk assessment 102, 103, 104.
There are currently few
Concluding Remarks
MMR-deficient CRC is clinically distinct from other subtypes of CRC. The relationship between MMR status, inflammation, and the intestinal microbiota will need to be further examined and validated (see Outstanding Questions). Inflammation and oxidative damage mediated by microbes are only a few of the many mechanisms which could promote tumorigenesis, and there are likely many additional bacterial species which influence or are associated with MMR-deficient CRC. Presently, there are few human
Acknowledgments
We would like to thank Ursula Flojanczyk (Figure 1, Figure 3), Lauren Huff (Figure 2), Matan Berson (Figure 4), and Cheng Jou (Ruth) Chang (Figure 5) for their contributions to the illustrations. We also thank Thergiory Irrazabal and Mingsong Kang for critically reading the manuscript. This work is funded by the Canadian Cancer Society (grant 703185).
Glossary
- ApcMin/+
- a mouse line containing a point mutation in one allele of the Apc gene. These mice spontaneously develop intestinal adenomas and are commonly used as a model for sporadic CRC.
- Azoxymethane (AOM)
- a common mutagen used to induce CRC in animals. AOM is metabolized into methylazoxymethanol by cytochrome P450 2E1, generating DNA mutations.
- Cdx2Cre Apclox/lox
- a mouse model where Apc is deleted specifically in the intestinal epithelium. The Apc gene is ‘floxed’, and the gene is excised by Cre
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