A new study in mice reveals a particular type of DNA damage that occurs during inflammation gives rise to colon cancer, a disease that eventually develops in nearly one in ten people with inflammatory bowel disease (IBD).
Senior author Leona Samson, professor of biological engineering and biology at Massachusetts Institute of Technology, and colleagues, write about their findings in a paper published earlier this month in the Journal of Clinical Investigation.
The chronic bowel inflammation seen in diseases like IBD, Crohn’s disease and ulcerative colitis, is the result of repeated onslaught by reactive oxygen and nitrogen species, highly destructive molecules released by neutrophils and macrophages in the immune system.
These chemicals kill bacteria and other invading organisms that the immune system identifies as enemies, but if they linger, they can damage DNA and other important molecules in healthy host cells.
In their study, which was funded by the National Institutes of Health, the MIT researchers showed that mice that cannot repair DNA damaged in this way are more likely to develop colon cancer.
They also found three enzymes were key to repairing this kind of damage, and suggest there could be potential for using them as biomarkers of colon cancer risk in humans.
Samson, who is also a member of MIT’s Center for Environmental Health Sciences, told the press that other studies have already established that humans produce one of these enzymes in widely varying amounts, so these findings may explain why some people with IBD go on to develop cancer.
“All other things being equal, if the same inflammatory response is present in the colon of different individuals, but they have differences in DNA-repair capability, they’re probably going to respond differently,” she said.
Four years earlier, Samson’s lab had found mice that lacked an enzyme called AAG were more likely to develop colon cancer following bowel inflammation. They showed that AAG was necessary to repair the DNA damage from the immune system’s reactive molecules, and without it, the damage led to colon cancer.
In this new study, Smason and colleagues tested the effect of two other DNA repair enzymes: ALKBH2 and ALKBH3.
They found that mice with induced colon inflammation that were missing both these enzymes were more likely to develop colon cancer than healthy mice.
And when they tested mice that lacked all three enzymes, they were even more susceptible to colon cancer.
It appears that if at least one of these enzymes is available, tissue repair can proceed almost as normal, but when none of the three is present, the damage remains.
The researchers showed this was the case when they analyzed the tissue samples. They found that while all the mice had the same amount of tissue damage, it was the mice lacking all three enzymes that showed no evidence of tissue repair.
Tissue samples from the mice that had at least one DNA repair enzyme showed that most of the damage had been repaired.
New tissue is made by stem cells. If they suffer DNA damage, then they can’t give rise to new cells.
Samson said what is happening is that the cells required for tissue reconstruction “are presumably being killed off because they can’t repair the DNA damage induced during inflammation”.
The researchers didn’t establish exactly how the three enzymes work together to repair DNA, but Samson suggests AAG probably attaches to the DNA lesion first and then summons the other two to help.
Steven Lipkin, who was not involved in the study, is an associate professor of medicine at New York’s Weill Cornell Medical College. He said the research “elegantly demonstrates” that the repair of DNA damaged by inflammation in the colon involves distinct pathways.
He said the study offers “insights that will help us to understand the precise mechanisms that cause inflammatory bowel disease-associated colorectal cancer, and will open the door to discovering better targeted chemopreventative agents”.
The team now plans to study how the three enzymes respond to inflammation caused by the bacterium Helicobacter pylori, which is linked to stomach cancer.
Colon cancer is the second leading cause of cancer death in the United States.
More than 15% of cancer deaths worldwide are linked to underlying infections or inflammatory conditions, so studies like this one help general understanding of how inflammation leads to cancer, and hopefully improve the chances of finding new ways to prevent and treat it.
Written by Catharine Paddock PhD