Health Europa spotlights recent research into the relationship between inflammation and inflammatory bowel cancer and bowel disease.
Inflammatory bowel disease (IBD) is the name given to two long-term conditions – Crohn’s disease and ulcerative colitis – in which areas of the gut become inflamed. It is characterised among other symptoms by diarrhoea, tiredness and fatigue, abdominal pains and cramps, anaemia, and weight loss, and according to World Inflammatory Bowel Disease Day affects an estimated ten million people worldwide. While treatments do exist that can relieve the symptoms and prevent them from returning, there is currently no known cure for inflammatory bowel disease, and many patients with the condition go on to require surgery.
How does ulcerative colitis lead to bowel cancer?
It has been known for some time that people with ulcerative colitis or Crohn’s disease are also at an increased risk of getting bowel (or colorectal) cancer; now, however, a team of scientists at the Medical College of Georgia and Georgia Cancer Center at Augusta University, US, has revealed one way in which ulcerative colitis enables this kind of cancer.
Writing in the journal Cell Reports,1 they describe the pathway to bowel cancer as follows:
- Inflammation causes high levels of myeloid-derived suppressor cells (MDSCs) to accumulate in the colon
- This produces elevated levels of the anti-inflammatory cytokine interleukin 10 (IL-10)
- These high levels cause the function of IL-10 to change: instead of suppressing inflammation, it activates the protein STAT3, which works as a gene regulator
- This, in turn, increases expression of DNMT1 and DNMT3b in the colon
- These two genes alter the DNA of and ultimately silence interferon regulatory factor 8 (IRF8), a tumour suppressor.
“IL-10 has a dual function. It can either be promoting or interfering with an immune response,” explains Dr Kebin Liu, a professor of biochemistry and molecular biology at Augusta. “What we found here is IL-10 promotes colon cancer.”
IL-10 – which influences the behaviour of nearby cells – and IRF8 – a transcription factor that helps to regulate the activity of genes – have no known interaction in a healthy state; however, Liu says that both work in different ways to protect the body against invaders.
The Augusta scientists therefore set out to examine how, if at all, the two are connected in a chronically inflamed colon.
To this end, they created a mouse lacking IRF8 in the epithelial cells which line the colon.
In line with the team’s hypothesis that IRF8 functions as a bowel cancer suppressor, the mice were far more susceptible to chronic inflammation, had less normal cell death in this high-cell turnover area, and developed more tumours.
The team was also able to demonstrate that, in this altered environment, MDSCs and the IL-10 they produce were at elevated levels, as were the two genes that ultimately silence IRF8. The same shifts were identified in human bowel cancer.
Liu believes that a combination of these high levels and timing turn IL-10 from a suppressor of inflammation into a suppressor of IRF8. But more research will be needed to identify an effective way of inhibiting the high expression of IL-10 in the colon.
Does IBD increase the risk of prostate cancer?
Elsewhere, the results of a near 20-year study by Northwestern Medicine, US, has suggested that men with inflammatory bowel disease are not only more prone to bowel cancer but also four to five times more likely to receive a prostate cancer diagnosis.
The study, which has been published in the journal European Urology,2 is the first of its kind to demonstrate that men with inflammatory bowel disease have higher than average PSA (prostate-specific antigen) levels. PSA is a protein produced by both normal cells in the prostate and prostate cancer cells and can be measured via a simple blood test.
According to lead study author Dr Shilajit Kundu, an associate professor of urology at Northwestern University Feinberg School of Medicine, a man with IBD should thus “be screened more carefully than a man without inflammatory bowel disease” as elevated PSA levels can be indicative of prostate cancer.
To arrive at these results, scientists examined more than 1,000 men with inflammatory bowel disease and compared them to a control group of more than 9,000 healthy men.
They then followed both groups of men for 18 years and discovered that those with inflammatory bowel disease were far more likely to have prostate cancer and elevated PSA levels.
The team is now working to understand exactly how gut inflammation leads to prostate cancer.
Could targeting inflammation help treat drug-resistant bowel cancer?
In more positive news, scientists at The Institute of Cancer Research, London (ICR), UK, have found that some treatment-resistant bowel cancers could be re-sensitised using drugs that reduce inflammation.
Their study, which has been published in the journal Oncogene,3 reveals that inflammation-related genes are enriched in bowel cancer cells that do not respond to the drug trametinib, compared to cells that do.
Using the inflammation-reducing compound JQ1, the scientists were successfully able to overcome the resistance.
The scientists came to this conclusion by focusing on cancerous cells with a mutation to their KRAS gene, which account for up to half of bowel cancer cases. They compared the genetics of trametinib-resistant cancer cells with those that respond to treatment, and discovered higher levels of activity in the genes related to inflammation in the resistant cells.
To confirm their results, the team then exposed responsive cells to low levels of trametinib over a period of two months, in order to make them resistant to the drug. They found that the same genes increased in activity.
The scientists therefore turned their attention to bromodomain inhibitors, which reduce inflammation, and successfully suppressed the activity of these genes using JQ1. Tests in mini-tumours derived from patients’ cancers showed that JQ1 and trametinib worked alongside one another to kill cancerous cells.
Trametinib is a targeted therapy used to treat melanoma and had been viewed by many as a promising bowel cancer drug. However, it failed to show a response in most clinical trial patients – thanks to this research, scientists may now have an explanation as to why.
“Our research suggests that by suppressing inflammation, it is possible to overcome resistance to drugs like trametinib, potentially opening up new avenues to treating this disease,” says Dr Steven Whittaker, leader of the Molecular Drug Resistance Team at the ICR, who led the research.
Nonetheless, much more research will be needed if this promising finding is to be successfully translated for patient benefit.
Please note, this article will appear in issue 8 of Health Europa Quarterly, which is available to read now.