colitis-associated colorectal cancer (CAC) - Coggle Diagram
colitis-associated colorectal cancer (CAC)
(disease) a major complication for patients with inflammatory bowel disease (IBD)
These patients have higher risk of developing colorectal cancer
Colon and rectum cancer
Damaged oxidative DNA
reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI) produced by activated immune cells causes genetic damage
It can damage DNA via strand breakage or through the oxidation of guanine, the nucleotide with the highest oxidation potential
Continuous inflammation of bowel triggers 8-oxoguanine DNA lesions
During inflammation, large amounts of superoxide (O2•−), and the highly diffusible and membrane-permeant nitric oxide radical (•NO) is generated by the NADPH oxidase enzyme and the inducible nitric oxide synthase (iNOS), respectively
Superoxide and nitric oxide radicals do not directly damage the DNA. They react with different molecules and form products that damage the DNA.
antioxidants or iNOS inhibitors reduce 8-oxoguanine and polyps in CAC
BER (base-excision repair)
Cellular systems that repair oxidative lesions in DNA
Are carried out by 8-oxoguanine DNA glycosylase (OGG1) and MutY DNA glycosylase (MUTYH), and mismatch repair (MMR)
: enzyme used when during replication, an adenine can be inserted opposite 8-oxoG, generating an A:8-oxoG pair (A:G) --> This pair is not possible
MMR: MMR pathway can repair these mismatches as well. but when they are not repaired, the transversion mutation will occur. Such as (A:G) which is a mismatche of purine and pyrimide
MMR system recognize & repair DNA mutations and damages but when this system is defective, it cannot recognize or repair those mutations or errors which result in cancer
When MMR is not present in a cell, cells are at risk of oxidative damage.
Lack of MMR causes mutation and causes neoplasia
8-oxyguanine DNA glycosylase
(enzyme) for when ROS leads to guanine oxidation forming C:8-oxoG pairs (C:G)
neutralizing ROS with antioxidants might reduce CRC
one clinical trial found that vitamin C (VitC) reduces oxidative stress in IBD patients14, and hence might be effective at neutralizing DNA damage caused by ROS and reducing CAC.
the therapeutic reduction of ROS- or RNI-induced genetic lesions would be sufficient to prevent cancer initiation in the inflamed colon
Because the MMR system repairs 8-oxoG, we test whether oxidative DNA damage is a mediator of carcinogenesis in a Lynch syndrome colon cancer model
we examine the interplay between microbiota, genetics, and inflammation, to dissect the mechanism by which gut microbiota induce CRC
sing IL10−/− mice, we find that infection with E. coli NC101, ETBF, or Helicobacter species, or tissue damage caused by dextran sodium sulfate (DSS) leads to inflammation, which generates an accumulation of oxidative DNA damage in colonic tissue.