Chronic inflammation of the liver, stomach or colon, often as a result of infection by viruses and bacteria, is one of the biggest risk factors for cancer of these organs. Scientists at the Massachusetts Institute of Technology (MIT) in the US have been researching this for over three decades, and now in a new paper published online this week they offer the most comprehensive clues so far about the potential underlying molecular mechanisms.
A bacterium called Helicobacter pylori causes stomach ulcers and cancer in humans. Helicobacter hepaticus has a similar effect in mice, so the researchers used it as a model to study how such a bacterial infection alters genes and chemicals in the liver and colon.
They write about their findings in a paper that appeared online in the 11 June issue of the Proceedings of the National Academy of Sciences, PNAS.
One of the four senior authors of the paper is Peter Dedon, a professor of biological engineering at MIT. Biological engineering is where molecular life scientists work with engineers to discover how biological systems function; the resulting knowledge can be used to develop new medical technologies.
Dedon and his co-authors hope their findings will help other researchers develop ways to predict the health problems caused by chronic inflammation and design drugs to stop it.
“If you understand the mechanism, then you can design interventions,” he said in a statement. “For example, what if we develop ways to block or interrupt the toxic effects of the chronic inflammation?”
Inflammation is a natural body reaction to an infection or wound, but if the inflammation persists too long, it can damage healthy tissue.
A study published recently in The Lancet found that inflammation caused by infections account for around 16% of new cancer cases worldwide.
Inflammation begins when the immune system detects cell damage or pathogens: both of these are potential threats to health. This triggers a surge of immune cells called macrophages and neutrophils that come along to clean up and remove the threat. They engulf the invading organisms, dead cells, debris and materials released by dead or damaged cells, such as proteins, nucleic acids and other molecules.
As well as removing these materials, the immune cells produce highly reactive chemicals to break down the bacteria. And it appears that it is this part of the process that is linked to cancer risk, because, as Dedon explained, “in engulfing the bacteria and dumping these reactive chemicals on them, the chemicals also diffuse out into the tissue”.
If the inflammation persists, the tissue is constantly bathed in the reactive chemicals.
For the new study, which was funded by the National Cancer Institute, Dedon and colleagues studied mice infected with H. hepaticus for 20 weeks. After 10 weeks, the mice developed severe colitis and hepatitis, and at 20 weeks, some had also developed colon cancer.
Over the 20 weeks they examined the tissue damage in the mice, and assessed damage to DNA, RNA and proteins. They also identified which genes were switched on and off.
They found that levels of one of the damaged products in DNA and RNA, chlorocytosine, correlated well with the severity of the inflammation. This could serve as a marker to predict the risk chronic inflammation in patients with infections in the colon, liver or stomach, said the researchers.
But Dedon said this does not necessarily mean you could use such a marker to predict the risk for cancer from these damaged molecules.
The researchers also noticed that the liver responded differently to the colon.
When DNA of healthy tissue comes under attack, it triggers a mechanism that attempts to repair the DNA. The researchers found that DNA repair was more active in the liver than in the colon, even though both experienced DNA damage.
Another difference was that in the colon, but not the liver, neutrophils released hypochlorous acid (a constituent of household bleach). This acid causes significant damage to molecules like DNA, RNA and proteins by attaching a chlorine atom. It is an effective way to kill bacteria, but if the acid leaks into surrounding tissue, it can cause similar damage to the epithelial cells in the lining of the colon.
“It’s possible that we have kind of a double whammy [in the colon]. You have this bacterium that suppresses DNA repair, at the same time that you have all this DNA damage happening in the tissue as a result of the immune response to the bacterium.”
The team also identified two other unknown types of DNA damage, the molecules spiroiminodihydantoin and guanidinohydanotoin, which result from oxidation of guanine, a building block of DNA.
They now plan to look at the mechanisms more closely, for instance to find out why some types of DNA damage are more frequent than others.
Written by Catharine Paddock PhD