Common infection could be one driver of colorectal cancer rise in younger adults, according to findings from members of the team taking on our Microbiome challenge.
Data collected by researchers at the Johns Hopkins Kimmel Cancer Center and the Bloomberg~Kimmel Institute for Cancer Immunotherapy suggest that Clostridioides difficile, or C. diff, a bacterial species well known for causing serious diarrheal infections, may also drive colorectal cancer.
The findings published in Cancer Discovery may expose another troublesome role for this microbe, which causes approximately 500,000 infections a year in the US — many of which prove incredibly difficult to clear.
Clues in biofilms
“The uptick of individuals under age 50 being diagnosed with colorectal cancer in recent years has been shocking. We found that this bacterium appears to be a very unexpected contributor to colon malignancy, the process by which normal cells become cancer,” says Cancer Grand Challenges OPTIMISTICC team co-investigator Cynthia Sears MD, Bloomberg~Kimmel Professor of Cancer Immunotherapy and professor of medicine at the Johns Hopkins University School of Medicine.
Several years ago, researchers in the Sears Lab discovered that more than half of patients with colorectal cancer had bacterial biofilms — dense collections of bacteria on the colon surface — whereas 10% to 15% of healthy patients without tumours displayed biofilms.
However, when the researchers infected mice with biofilm samples derived from individual people with colorectal cancer, one sample caught their attention because it markedly increased colorectal tumours in the mice. Whereas in most controls, less than 5% develop tumours, this slurry induced tumours in 85% of mice. In additional work, the team identified a patient sample without a biofilm that similarly increased colorectal tumours in the mice.
Although several bacterial species have been linked with colorectal cancer — including enterotoxigenic Bacteroides fragilis, Fusobacterium nucleatum and a specific strain of Escherichia coli — these microbes were either absent in the tumours of these two patients (B. fragilis and E. coli) or did not successfully colonize the mice (F. nucleatum), suggesting that other bacteria were responsible for promoting the colorectal cancer cascade.
Infection with toxigenic C diff makes mouse colon cells vulnerable to cancer
To determine which bacteria may be causing tumours in the mice, Sears, along with study co-authors Julia Drewes PhD, Jie (Angela) Chen PhD, Jada Domingue PhD, all of Johns Hopkins, and colleagues performed additional experiments to see if a single bacterial species or a community of bacteria were promoting tumour formation in the mice.
They noted that toxigenic C. diff (the type of C. diff that causes diarrhoea) was absent in the samples that did not cause tumours, but was present in the samples that caused tumours in mice. When toxigenic C. diff was added to the samples that originally did not cause tumours, it induced colon tumours in the mice.
Further testing showed that toxingenic C. diff alone was sufficient to prompt tumour formation in the animal models. This is due to the way the bacterium brings about a range of changes within colon cells, making them vulnerable to cancer, according to additional experiments led by co-author Nicholas Markham MD PhD (Vanderbilt University Medical Center) and study co-leaders Franck Housseau PhD (Johns Hopkins) and Ken Lau PhD (Vanderbilt University School of Medicine).
Cells exposed to toxigenic C. diff turned on genes that drive cancer and turned off genes that protect against cancer. These cells produced reactive oxygen species, unstable molecules that can damage DNA, and they also prompted immune activity associated with harmful inflammation. Most of this activity appears to be caused by a toxin produced by this strain of C. diff, known as TcdB.
Bridging the gap from animal studies to epidemiology
There is limited epidemiological data linking C. diff with colorectal cancer in humans, according to Drewes.
But if further research shows that a connection exists, it could lead to screening for latent C. diff infection or previous infection as a risk factor for cancer. Since lengthy exposures to TcdB may increase colorectal cancer risk, an important prevention effort could include heightened efforts to eradicate this pathogen quickly and effectively — which recurs, often repeatedly, in 15%–30% of infected patients after initial treatment, including in paediatric patients.
“While this link between C. diff and colorectal cancer needs to be confirmed in prospective, longitudinal cohorts, developing better strategies and therapeutics to reduce the risk of C. diff primary infection and recurrence could both spare patients the immediate consequences of severe diarrhoea and potentially limit colorectal cancer risk later on,” Drewes says.
This article is adapted from a news release from Johns Hopkins Newsroom.
Other Cancer Grand Challenges researchers and collaborators who contributed to this study include Reece Knippel, Jada Domingue and June Chan (Johns Hopkins University School of Medicine).
This research was funded by National Institutes of Health, the Bloomberg~Kimmel Institute for Immunotherapy, the Cancer Grand Challenges OPTIMISTICC team grant funded by Cancer Research UK, the Johns Hopkins University Department of Medicine, the Johns Hopkins Kimmel Cancer Center Core and a Department of Veterans Affairs grant.