The results were published on June 9 in Discovery of cancerand may reveal another troublesome role for this microbe, which causes approximately 500,000 infections per year in the United States. – many of which prove incredibly difficult to clean.
“The increase in the number of people under the age of 50 being diagnosed with colorectal cancer in recent years is shocking. We found that this bacterium appears to be a very unexpected contributor to colon malignancy, the process by which normal cells become cancerous,” says Cynthia Sears, MDBloomberg~Kimmel Professor of Cancer Immunotherapy and Professor of Medicine at Johns Hopkins University School of Medicine.
Several years ago, Sears Lab researchers found that more than half of colorectal cancer patients had bacterial biofilms – dense collections of bacteria on the surface of the colon – while 10-15% of healthy patients health without tumor showed biofilms. However, when researchers infected mice with samples of biofilm from people with colorectal cancer, one sample caught their attention because it significantly increased colorectal tumors in mice. While in most controls, less than 5% develop tumors, this slurry induced tumors in 85% of mice.
In additional work, the team identified a patient sample without biofilm that similarly increased colorectal tumors in mice. Although several bacterial species have been associated with colorectal cancer, including enterotoxigenic Bacteroides fragilis, Nucleated Fusobacteria and a specific strain of Escherichia coli — these microbes were either absent in the tumors of these two patients (B.fragilis and E.coli) or failed to colonize mice (F.nucleatum), suggesting that other bacteria were responsible for promoting the colorectal cancer cascade.
To determine which bacteria can cause tumors in mice, Sears, along with study co-authors Julia Drewes, Ph.D., assistant professor of medicine, Jie (Angela) Chen, Ph.D., Jada Domingue, Ph.D., of Johns Hopkins, and colleagues performed additional experiments to see if a single bacterial species or community of bacteria favored tumor formation in mice. They noted that toxigenic It’s hard, the type of It’s hard that causes diarrhea, was absent in samples that did not cause tumors, but was present in samples that caused tumors in mice. When researchers added this bacterium to samples that did not originally cause tumors, it induced colon tumors in mice. Further tests have shown that It’s hard alone was sufficient to induce tumor formation in animal models.
Additional experiments by co-author Nicholas Markham, MD, Ph.D., assistant professor of medicine at Vanderbilt University Medical Center, and study co-leads Franck Housseau, Ph.D.associate professor of oncology at Johns Hopkins, and Ken Lau, Ph.D., associate professor of cell and developmental biology and surgery at Vanderbilt University School of Medicine, have shown that It’s hard caused a series of changes in colon cells that made them vulnerable to cancer.
Cells exposed to this bacterium turned on cancer-causing genes and turned off cancer-protective genes. These cells produced reactive oxygen species, unstable molecules that can damage DNA, and they also caused immune activity associated with harmful inflammation.
A toxin produced by this bacterium – known as TcdB – appears to be driving most of this activity, the researchers said. When they used genetically modified products It’s hard strains containing inactivated toxin genes and/or releasing a It’s hard toxin called TcdA, mice infected with TcdB-inactivated microbes produced significantly fewer tumors than those with TcdB-activated microbes, while TcdA made by It’s hard was not sufficient to induce tumours.
To date, says Drewes, there is little epidemiological data linking It’s hard with colorectal cancer in men, but if further research shows a link, it could lead to screening for latent cancer It’s hard infection or previous infection as a risk factor for cancer. Since long exposures to TcdB can increase the risk of colorectal cancer, a major prevention effort could include increased efforts to quickly and effectively eradicate this pathogen, which reproduces – often repeatedly – in 15% to 30% patients infected after initial treatment, including pediatric patients .
“While this link between It’s hard and colorectal cancer needs to be confirmed in prospective longitudinal cohorts, developing better strategies and therapeutics to reduce the risk of It’s hard primary infection and recurrence could both spare patients the immediate consequences of severe diarrhea and potentially limit the risk of colorectal cancer later,” says Drewes.
Other Johns Hopkins researchers who contributed to this study include Reece J. Knippel, Ada J. Tam, June L. Chan, Lana Kim, Madison McMann, Courtney Stevens, Christine M. Dejea, John Michel, Fuad Mohammad, Victoria L. Campodonico, Xinqun Wu, Shaoguang Wu, Hua Ding, Patricia Simner, Karen Carroll, Robert A. Anders, and Fengyi Wan.
This research was funded by National Institutes of Health grants (R01CA196845, R00CA230192, U2CCA233291, R01CA203891, R01DK103831, P50CA236733, R35CA197570, P30DK089502, S10OD016374, T32 GM136577, R01DK073338), the Bloomberg~Kimmel Institute for Immunotherapy, the Cancer Grand Challenges OPTIMISTICC team grant (A27140) funded by Cancer Research UK, Johns Hopkins University Department of Medicine, Johns Hopkins Kimmel Cancer Center Core and Department of Veterans Affairs grant (BX005699-01).