Tumor-generating bacteria collaborate to trigger colon cancer

Two species of bacteria work together to drive tumor formation in hereditary colon cancer syndrome and sporadic colon cancer, according to researchers at the Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD.

In a study published in Science, researchers revealed that patients with familial adenomatous polyposis (FAP)—a hereditary syndrome that precedes colon cancer—harbor two bacterial species (Bacteroides fragilis and Escherichia coli) that collaborate to encourage development of the disease. The same species have been found in patients with sporadic colorectal cancer.

In a related study published in Cell Host & Microbe, the same researchers used a mouse model to describe a possible mechanism in which B. fragilis spurs an interleukin-17 mucosal immune response that promotes—rather than inhibits—the formation of malignant tumors.

“FAP is a devastating disease that ultimately results in surgical removal of the colon, and our findings could point us to new and less invasive ways to prevent colon cancer from developing,” said lead investigator Cynthia Sears, MD, professor of oncology, Johns Hopkins University School of Medicine, and researcher, Bloomberg~Kimmel Institute for Cancer Immunotherapy.

Bacterial biofilms

In previous studies, Dr. Sears and coauthors were the first to demonstrate that bacterial biofilms in the colon are associated with colorectal cancers. These bacterial biofilms form colonies that can penetrate the protective mucosal lining to reach the colonic epithelium, which induces chronic inflammation and subsequent DNA damage that supports tumor formation.

In this current research, the authors further investigated the relationship between the bacterial biofilms and the formation of colon cancer. To do so, they analyzed the bacteria in the mucosa of six patients with FAP. In roughly 70% of these patients, the researchers found patchy sections of biofilms throughout the length of the colon. Notably, they determined that E. coli and B. fragilis were the predominant biofilm strains that were in direct contact with the host colon epithelial cells.

Culture tests on 25 additional colon samples from FAP patients identified that the B. fragilis strain was a subtype, called enterotoxigenic B. fragilis (ETBF), that triggers oncogenic pathways in colon epithelial cells and causes colon inflammation. The researchers also found that the E. coli strain produces colibactin—a genotoxin that promotes colon tumor growth by causing DNA mutations.

Next, they tested these bacteria in a mouse model of colon cancer and found that few or no tumors developed in mice with colons colonized with just one of these strains. But, when colonized with both strains simultaneously, the mice developed many tumors in the colon, with not only faster tumor onset but also greater mortality. Dr. Sears and colleagues concluded that the two bacterial strains cooperate to promote enhanced carcinogenesis.

“It is the combination of these effects, requiring coexistence of these two bacteria, that creates the ‘perfect storm’ to drive colon cancer development,” Dr. Sears said.

Detection and prevention

She and her coauthors also noted that these two strains commonly colonize young children worldwide. Their results suggest that persistent co-colonization in the colon mucosa from a young age may contribute to the pathogenesis of FAP and even sporadic colon cancer in young people.

However, if further research shows that biofilms develop before the characteristic polyps appear in FAP patients, then biofilm evaluation or stool identification of particular bacteria could allow for earlier, nonsurgical intervention to rid the bacteria from the colon, and therefore prevent cases of colorectal cancer, Dr. Sears predicted.

In the meantime, these findings may impact current cancer detection measures in patients with both bacteria.

“More frequent colon cancer screening than the currently recommended once every 10 years should be considered,” said study coauthor Drew Pardoll, MD, PhD, director, Bloomberg~Kimmel Institute.

Dr. Sears, Dr. Pardoll, and two other coauthors are inventors on a patent application submitted by Johns Hopkins University that covers use of biofilm formation to define risk for colon cancer.