Washington: Colorectal cancer is caused by lingering inflammation in the colon. Now scientists have reported a way inflammation enables this sort of cancer.
While inflammation is a short-term response to an infection or other irritant in the body that is essential to eliminating it, when it persists, it can contribute to a number of common conditions, from cancer to cardiovascular disease.
In their quest towards determining how chronic inflammation of our large intestines, or colon, enables cancers, a research team, led by Dr. Kebin Liu at the Medical College of Georgia and Georgia Cancer Center at Augusta University found it turns one more protective mechanism against us and silences another.
According to the study, as published in the journal Cell Reports, the chronic inflammation of ulcerative colitis prompts high levels of myeloid-derived suppressor cells, or MDSCs, to accumulate in the colon.
The study further added, high levels of MDSCs, in turn, produce higher levels of IL-10, a cytokine known to suppress inflammation. But at this high level, the function of IL-10, like the environment in the colon, changes. IL-10 instead activates STAT3, a protein that works as a gene regulator, which in turn increases expression of two genes – DNMT1 and DNMT3b – in the colon.
These genes alter the DNA of and ultimately silence a tumor suppressor called interferon regulator factor 8, or IRF8.
According to Liu, the pathway they found that ends with silencing IRF8, likely is not a factor for non-colitis associated colon cancer.
The next step included finding ways to inhibit high expression of IL-10 in the colon.
Speaking about it, Liu said, “IL-10 has a dual function. It can either be promoting or interfering with an immune response.”
Liu further added, “What we found here is IL-10 promotes colon cancer.”
In a healthy state, IL-10 and IRF8 have no known interaction but both work in different ways to protect against invaders, Liu, a cancer immunologist in the MCG Department of Biochemistry and Molecular Biology, said.
The scientists set out to look at whether and how the two are connected in a chronically inflamed colon and test the hypothesis that IRF8 functions as a colorectal cancer suppressor.
The scientists created a mouse missing IRF8 in the epithelial cells that line the colon and found that mice were much more susceptible to chronic inflammation, had less normal cell death in this high-cell turnover area and got more tumors. They also found that in the face of chronic inflammation, IRF8 is silenced, and that in human cancer, IRF8 is downregulated compared to normal colon tissues.
Meanwhile, they showed that in this altered environment, MDSCs and the IL-10 they produce were at higher levels and so were the two genes that ultimately silence IRF8. They found the same shifts in human colon cancer.
Liu says it’s likely the high levels and timing that transform the role of IL-10 from suppressor of inflammation to suppressor of IRF8.
Colorectal cancer is among the top five common cancers and causes of cancer death in men and women in the United States, according to the Centers for Disease Control and Prevention.