Data collected by researchers at the Johns Hopkins Kimmel Cancer Center and the Bloomberg ~ Kimmel Institute for Cancer Immunotherapy suggest that Clostridioides difficult, o C. diff, a bacterial species known to cause severe diarrheal infections, can also cause colorectal cancer.
The findings were published June 9 in Cancer Discovery and may expose another problematic role for this microbe, which causes approximately 500,000 infections a year in the U.S., many of which are incredibly difficult to eliminate.
The increase in people under the age of 50 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 turn into cancer. “
Cynthia Sears, MD, Bloomberg Professor ~ Kimmel of Cancer Immunotherapy and Professor of Medicine at Johns Hopkins University School of Medicine
A few 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 between 10% and 15% of healthy patients without tumors showed biofilms. However, when the researchers infected mice with biofilm samples derived from individuals 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 linked to colorectal cancer, such as enterotoxigenic Bacteroides fragilis, Fusobacterium nucleatum, and a specific strain of Escherichia coli, these microbes were absent in the tumors of these two patients (B. fragilis and E. coli) or not. successfully colonize mice (F. nucleatum), suggesting that other bacteria were responsible for promoting the colorectal cancer cascade.
To determine which bacteria may be causing tumors in mice, Sears, along with co-authors of the study, Julia Drewes, Ph.D., adjunct professor of medicine, Jie (Angela) Chen, Ph.D., Jada Domingue, Ph.D. .D. ., by Johns Hopkins, and colleagues conducted additional experiments to see if a single bacterial species or community of bacteria encouraged tumor formation in mice. They noted that the toxic C. difficile, the type of C. difficile that causes diarrhea, was absent in samples that did not cause tumors, but was present in samples that caused tumors in mice. When the researchers added this bacterium to samples that did not originally cause tumors, it induced colon tumors in mice. Subsequent tests showed that C. difficile was only sufficient to cause tumor formation in animal models.
Additional experiments led by co-author Nicholas Markham, MD, Ph.D., adjunct professor of medicine at Vanderbilt University Medical Center and study co-leaders Franck Housseau, Ph.D., associate professor of oncology at Johns Hopkins and Ken Lau, Ph.D., associate professor of cell biology and surgery and development at Vanderbilt University School of Medicine, showed that C. difficile caused a number of changes in cells. Colon cells that made them vulnerable to cancer.
Cells exposed to this bacterium activated the genes that drive cancer and turned off the genes that protect against cancer. These cells produced reactive oxygen species, unstable molecules that can damage DNA, and also triggered immune activity associated with harmful inflammation.
According to the researchers, a toxin produced by this bacterium, known as TcdB, appears to cause most of this activity. When they used genetically modified C. difficile strains that contained inactivated toxin genes and / or released a related C. difficile toxin called TcdA, mice infected with TcdB-inactivated microbes produced far fewer tumors than those with the active ones. by TcdB, while TcdA used. for C. difficile was not sufficient to cause tumors.
To date, Drewes says, there are limited epidemiological data linking C. difficile to colorectal cancer in humans, but if further research shows a connection exists, it could lead to the detection of latent C. difficile infection or a previous infection such as to cancer risk factor. Since long exposures to TcdB may increase the risk of colorectal cancer, a major prevention effort could include intensified efforts to eradicate this pathogen quickly and effectively, which is repeated, often repeatedly, in 15% -30% of patients. infected after initial treatment, including pediatric patients. .
“While this link between C. difficile and colorectal cancer needs to be confirmed in prospective and longitudinal cohorts, the development of better strategies and therapies to reduce the risk of primary infection and recurrence of C. difficile could save patients the immediate consequences of severe diarrhea and potentially limit the risk of colorectal cancer later on, ”says Drewes.
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Magazine reference:
Drewes, JL, et al. (2022) Clostridioides difficile strains derived from human colon cancer drive colon tumorigenesis in mice. Discovery of cancer. doi.org/10.1158/2159-8290.CD-21-1273.