Researchers at St. Jude Children’s Research Hospital recently published in the journal Cell the discovery of a protective gene against colorectal cancer which may open alternative avenues towards novel therapeutic strategies. The study is entitled “Critical Role for the DNA Sensor AIM2 in Stem Cell Proliferation and Cancer”.
Colorectal cancer is a common malignancy that usually develops from abnormal growths (polyps) in the inner walls of the large intestine. Screening and polyp removal can prevent the disease. Colorectal cancer corresponds to the third leading cause of cancer death in the United States and it is estimated that in 2015, 49,700 Americans will die from the disease.
Colorectal cancer patients often have mutations in a gene called AIM2 (absent in melanoma 2), however, the role played by AIM2 in colon tumorigenesis is not clear. AIM2 encodes an innate immune sensor protein that is able to detect invading pathogens like viruses and bacteria triggering an immune defense response.
“When we found that the intestine expressed high levels of AIM2, we hypothesized that this gene may also play a role in regulating gut health,” explained one of the study’s lead co-authors Dr. Si Ming Man in a news release. “This was how we became interested in AIM2 and colorectal cancer.”
In the study, researchers used mice models of colorectal cancer and found that the animals had a drastically reduced AIM2 function; in addition, AIM2-deficient mice had considerably more colonic tumors in comparison to normal mice. Researchers found that AIM2, besides its role in immunity, also plays an important role in suppressing abnormal expansion of intestinal stem cell populations, undifferentiated cells that have the potential to differentiate into several specialized cell types, in this case intestinal cells. Dysfunction of AIM2 results in uncontrolled intestinal stem cell proliferation.
“Many previous studies have indicated that AIM2 contributes to the immune system by acting as a pathogen sensor,” noted Dr. Man. “However, our work is the first to identify AIM2’s role in controlling proliferation of intestinal stem cells. This work is truly exciting to us because we have found a new role for AIM2 in regulating colorectal cancer, and it does so by inhibiting excessive proliferation of stem cells in the large intestine.”
The team then hypothesized that AIM2’s protective role against colorectal cancer could involve gut bacteria, and found that in fact, gut bacteria were different between normal and AIM2-deficient mice. Researchers housed normal and AIM2-deficient mice together to allow the exchange of gut bacteria between the animals. Remarkably, the team observed a significant reduction in colon tumors in AIM2-deficient mice and an increase in tumors in normal mice, indicating that AIM2 can influence gut bacteria by favouring the proliferation of bacteria that have protective properties against colorectal cancer.
“What this might suggest is that transfer of some of the ‘good’ microbiota from wild-type mice to replace the ‘bad’ microbiota from mice lacking AIM2 offers increased protection against colorectal cancer,” said Dr. Man. “We believe that this finding has important clinical relevance because we can potentially prevent or decelerate the progression of colorectal cancer in humans, especially in those who have mutations in the AIM2 gene, by simply giving them ‘good’ microbiota.”
The team believes that it might be possible to prevent colorectal cancer or reduce its risk by giving healthy donor bacteria to susceptible patients and by increasing their AIM2 activity. “In people who already have colorectal cancer, therapies that boost the expression of AIM2, such as interferons, might reduce tumor progression. Also, transferring healthy microbiota or a group of ‘good’ bacteria to patients with colorectal cancer at the early stage of disease may prolong survival,” said the study’s senior author Dr. Thirumala-Devi Kanneganti.
Some questions still remain to be addressed though, “We have only scratched the surface of the role of AIM2 in controlling stem cell proliferation and the maintenance of a healthy gut microbiota,” noted Dr. Kanneganti. “How exactly AIM2 does both of these functions is an exciting research area to pursue.”
