Bacterial Biofilms May Play Role in Colorectal Cancer

Roxanne Nelson

December 23, 2014

Researchers have found an association between bacterial biofilms and colorectal cancer, according to a new report.

While it has long been suspected that bacteria contribute to chronic inflammation leading to colorectal cancer, this is the first time that bacterial biofilms have been identified in colorectal cancer, say the study authors.

"Most remarkably," they note, "biofilm presence correlates with bacterial tissue invasion and changes in tissue biology with enhanced cellular proliferation, a basic feature of oncogenic transformation occurring even in colons without evidence of cancer."

Another intriguing discovery was that colon biofilms were almost universally found on right-sided tumors. "What was so striking was that these biofilm-positive samples cluster so dramatically in the right colon," said senior author Cynthia L. Sears, MD, professor of medicine and oncology at the Johns Hopkins University School of Medicine and Bloomberg School of Public Health, Baltimore, Maryland.

"In fact, it's virtually a universal feature of tumors that appear in that section of the colon, although we don't understand why," she commented in a statement.

The study was published online December 8 in the Proceedings of the National Academy of Sciences of the United States of America.

Biofilms are defined as aggregations of microbial communities encased in a polymeric matrix that adhere to biological or nonbiological surfaces. They are associated with many chronic mucosal disease states, including inflammatory bowel diseases, pharyngo-tonsillitis, otitis media, rhinosinusitis, urethritis, and vaginitis.

Dr Sears and colleagues examined healthy and malignant tissue that was obtained from 118 individuals undergoing surgery or colonoscopy. Invasive polymicrobial bacterial biofilms were almost entirely located (89%) on right-sided tumors (13 of 15 cancers, 4 of 4 adenomas), but on only 12% of left-sided tumors (2 of 15 cancers, 0 of 2 adenomas).

The cause of bacterial biofilms in colon, Dr Sears explained, is not yet clear. "At present, we do not understand the striking geographic location of the biofilms in the right colon where the fecal stream is more liquid and one would think bacteria would be less likely to adhere to the mucosa," she told Medscape Medical News. "We hope to get some clues from studies to examine in more detail which bacteria adhere and their signaling as well as host cell signaling. Nonetheless, whether biofilms form in the right or left colon, the biologic changes are the same in both locations, strongly linking biofilms to tissue biology consistent with oncogenesis."

Another surprise was that all patients with biofilm-positive tumors, whether cancers or adenomas, had biofilms on tumor-free mucosa that were distant from the tumor site.

"This suggests that either the tumor allows the biofilm to form, or the biofilm is helping to cause the tumor," commented coauthor Jessica Mark Welch, PhD, a scientist at the Marine Biological Laboratory in Woods Hole, Massachusetts, in a statement. "The breaching of the mucus layer could allow bacteria to come into contact with the host epithelial cells, and that is one thing that could lead to cancer."

The data also show that the formation of biofilms in patients with cancer and healthy controls was associated with reduced or redistributed colonic epithelial cell E-cadherin, a finding consistent with increased epithelial permeability.

This study used a novel method of viewing the bacterial structure, which was developed by Dr Welch and colleagues. Called combinatorial imaging, it uses various colors of fluorescent probes to "light up" different species of bacteria in the biofilm and shows the three-dimensional structure of its microbial community.

With this technology, the authors could see that biofilms associated with ascending colon tumors are composed of many species of bacteria. The species are also diverse, and the part of the biofilm that actually invades the mucosal layer contains a subset of all the bacterial strains in the biofilm, as opposed to there being just one aggressive strain.

This suggests that the biofilm itself, rather than a particular kind of bacteria, may be the cancer-causing trigger, noted Dr Sears.

Thus far, this finding has no immediate actionable clinical implications. "However, we believe the next step is to test whether detection of biofilms in the colon during colonoscopy identifies a patient at increased risk of neoplasia in the colon," said Dr Sears. "This would require biopsies stored in a readily available but not currently routinely used tissue fixative (instead of the usual formalin tissue fixation) plus longitudinal follow-up."

If careful prospective studies show that biofilms identify patients at risk, this could modify current paradigms for use and interpretation of screening colonoscopy, she noted. Other important future work will be to test whether probiotic treatments modify biofilm formation in the colon or the oncogenic signaling that was detected in the study.

"If so, the implication would be that modifying long-term risk of colon neoplasia is possible with simple therapies," Dr Sears explained.

This work was supported by the National Institutes of Health and a grant from the Mérieux Institute. The authors have disclosed no relevant financial relationships.

Proc Natl Acad Sci U S A. Published online December 8, 2014. Abstract

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