One of the biggest risk factors for liver, colon or stomach cancer is chronic inflammation of those organs, often caused by viral or bacterial infections. A new study from MIT offers the most comprehensive look yet at how such infections provoke tissues into becoming cancerous.
The study, which is appearing in the online edition of Proceedings of the National Academy of Sciences the week of June 11, tracked a variety of genetic and chemical changes in the livers and colons of mice infected with Helicobacter hepaticus, a bacterium similar to Helicobacter pylori, which causes stomach ulcers and cancer in humans.
The findings could help researchers develop ways to predict the health consequences of chronic inflammation, and design drugs to halt such inflammation.
"If you understand the mechanism, then you can design interventions," says Peter Dedon, an MIT professor of biological engineering. "For example, what if we develop ways to block or interrupt the toxic effects of the chronic inflammation?"
Dedon is one of four senior authors of the paper, along with Steven Tannenbaum, a professor of biological engineering and chemistry; James Fox, a professor of biological engineering and director of the Department of Comparative Medicine; and Gerald Wogan, a professor of biological engineering and chemistry. Lead author is Aswin Mangerich, a former MIT postdoc now at the University of Konstanz in Germany.
Too much of a good thing
For the past 30 years, Tannenbaum has led a group of MIT researchers dedicated to studying the link between chronic inflammation and cancer. Inflammation is the body's normal reaction to any kind of infection or damage, but when it goes on for too long, tissues can be damaged.
When the body's immune system detects pathogens or cell damage, it activates an influx of cells called macrophages and neutrophils. These cells' job is to engulf bacteria, dead cells and debris: proteins, nucleic acids and other molecules released by dead or damaged cells. As part of this process, the cells produce highly reactive chemicals that help degrade the bacteria.
"In doing this, in engulfing the bacteria and dumping these reactive chemicals on them, the chemicals also diffuse out into the tissue, and that's where the problem comes in," Dedon says.
If sustained over a long period, that inflammation can eventually lead to cancer. A recent study published in the journal The Lancet found that infections account for about 16 percent of new cancer cases worldwide.
In the new MIT study, the researchers analyzed mice that were infected with H. hepaticus, which causes them to develop a condition similar to inflammatory bowel disease in humans. Over the course of 20 weeks, the mice developed chronic infections of the liver and colon, with some of the mice developing colon cancer.
Throughout the 20-week period, the researchers measured about a dozen different types of damage to DNA, RNA and proteins. They also examined tissue damage and measured which genes were turned on and off as the infection progressed. One of their key findings was that the liver and colon responded differently to infection.
In the colon, but not the liver, neutrophils secreted hypochlorous acid (also found in household bleach), which significantly damages proteins, DNA and RNA by adding a chlorine atom to them. The hypochlorous acid is meant to kill bacteria, but it also leaks into surrounding tissue and damages the epithelial cells of the colon.
The researchers found that levels of one of the chlorine-damage products in DNA and RNA, chlorocytosine, correlated well with the severity of the inflammation, which could allow them to predict the risk of chronic inflammation in patients with infections of the colon, liver or stomach. Tannenbaum recently identified another chlorine-damage product in proteins: chlorotyrosine, which correlates with inflammation. While these results point to an important role for neutrophils in inflammation and cancer, "we don't know yet if we can predict the risk for cancer from these damaged molecules," Dedon says.
Another difference the researchers found between the colon and the liver was that DNA repair systems became more active in the liver but less active in the colon, even though both were experiencing DNA damage. "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," Dedon says.
The researchers also identified several previously unknown types of damage to DNA in mice and humans, one of which involves oxidation of guanine, a building block of DNA, to two new products, spiroiminodihydantoin and guanidinohydanotoin.
In future studies, the MIT team plans to investigate the mechanisms of cancer development in more detail, including looking at why cells experience an increase in some types of DNA damage but not others.
The research was funded by the National Cancer Institute.
Written by Anne Trafton, MIT News Office
Anne Trafton | EurekAlert!
Penn vet research identifies new target for taming Ebola
12.01.2017 | University of Pennsylvania
The strange double life of Dab2
10.01.2017 | University of Miami Miller School of Medicine
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
17.01.2017 | Earth Sciences
17.01.2017 | Materials Sciences
17.01.2017 | Architecture and Construction