New research suggests some gut bacteria that cause gastric upsets may also create an ideal “incubating” environment for tumor development, by preventing routine mechanisms that repair damaged DNA.
Researchers from the Wistar Institute, a National Cancer Institute designated research center in Philadelphia, PA, presented their findings at the 2014 American Association for Cancer Research Annual Meeting in San Diego, CA.
Senior investigator Frank Rauscher, III, a professor in the Wistar Institute, says:
“There is a drastic, unmet need to look at new ways to define exactly how colon cancer forms in the gut and what triggers its progression into a lethal form. We suggest that some bacterial proteins can promote genetic changes that create conditions in the gut that would favor the progression of colon cancer.”
Colorectal or colon cancer develops because changes or mutations in the genes of healthy cells in the gut lining (the epithelium) accumulate, causing them to become progressively cancerous and form polyps that can eventually become malignant tumors.
Like many cells, the epithelial cells that form the gut lining, produce proteins that attempt to repair the DNA damage. This latest study suggests that proteins produced by some of the bacteria in the gut actively suppress the gut cells’ DNA repair proteins, and this contributes to the accumulation of mutations that lead to cancer.
The researchers suggest their findings introduce the idea that treatments that alter the mix of bacteria in the gut could be a way to reduce the chance of developing colon cancer in people who have a higher risk of the disease.
While colon cancer incidence is falling among Americans, and falling sharply among older Americans, most likely due to increased screening, rates of survival are not. The American Cancer Society estimates that the disease will claim around 50,000 lives this year.
Prof. Rauscher says while we have learned a lot about the gene mutations in the cells lining the gut, this knowledge hasn’t really helped us increase the overall survival.
The microenvironment of the gut is something scientists are only just beginning to understand. In it, human cells nestle among 10 trillion – mostly unknown – bacteria. Many of the microbes that inhabit the human gut are ‘friendly’ bacteria that provide important benefits such as helping to digest food and crowding out disease-causing species.
However, studies are starting to show that both friendly and disease-causing bacteria produce proteins that actively reduce inflammation, an important mechanism that the human innate immune system uses to heal and prevent infection from spreading.
This was the area that Prof. Rauscher and colleagues set out to investigate. They injected anti-inflammatory proteins produced by a strain of bacteria called Enteropathogenic Escherichia coli (EPEC) into colon epithelial cells. One of these proteins, called NLEE, blocks a specific gut cell protein called TAB2. Without TAB2, a number of inflammatory processes in the gut cannot function.
The team then wondered if NLEE targets any other human gut cell proteins. They found to their surprise that it did – it blocks another protein called ZRANB3 which is important for repairing cellular DNA, thus indirectly helping mutations that promote cancer to accumulate in the gut lining.
In further work with a team led by Dr. Feng Shao at the National Institute of Biological Sciences in Beijing, China, Prof. Rauscher and colleagues found that NLEE seems to attack a structure on TAB2 and ZRANB3 known as a “zinc finger,” which is a common feature of many proteins.
When they investigated the structure of NLEE they found it contained a deep cleft that fits a specific zinc finger. And when they looked at EPEC-infected colon cells they found this same zinc finger pattern in at least three DNA repair enzymes, suggesting NLEE can block a number of mechanisms that would otherwise prevent cancer, as Prof. Rauscher explains:
“Our results suggest that some infective intestinal bacteria, which normally can simply cause gastric distress, have the capability of inducing genetic changes (by limiting repair) in our intestinal cells which could lead to tumor development.”
He says perhaps reducing the amount of this bacteria in the gut could be a way to protect it from the genetic changes that collect over time and lead to cancer.
The researchers wonder if the microenvironment of the gut behaves like an “incubator” for colon cancer, depending on the mix of bacteria present. They are about to test this idea on a new project.
Meanwhile, Medical News Today recently learned how another team of researchers also found that a person’s particular mix of gut microbes may help the development of colon cancer by interacting with genes and inflammatory responses.