Studies suggest that the oral microbe Fusobacterium nucleatum creates a proinflammatory microenvironment and promotes colorectal carcinogenesis by binding to and modulating E-cadherin and activating β-catenin signaling.
Scientists have long known that the oral microbe Fusobacterium nucleatum plays a role in plaque formation and various periodontal diseases, but it isn't confined to the mouth. The bacterium is prevalent in intrauterine infections that can cause complications during pregnancy. In addition, separate research teams reported in 2012 that levels of F. nucleatum and other Fusobacterium species were higher in malignant colorectal tumors than in surrounding tissues. What wasn't clear, however, was whether the microbe was a cause or a consequence of cancer.
Now, two studies published in Cell Host & Microbe suggest that F. nucleatum creates a proinflammatory microenvironment and promotes colorectal carcinogenesis through E-cadherin and β-catenin signaling.
“Fusobacteria may provide not only a new way to group or describe colon cancers, but also, more importantly, a new perspective on how to target pathways to halt tumor growth and spread,” says Wendy Garrett, MD, PhD. Garrett is an assistant professor of immunology and infectious disease and medicine at Harvard School of Public Health, Harvard Medical School, and Dana-Farber Cancer Institute, all in Boston, MA, and senior author of one of the studies (Cell Host Microbe 2013;14:207–15).
Building on the earlier research, Garrett's team examined colonic adenomas and normal tissue from 29 patients. They found an increased abundance of Fusobacteria sp. in adenomas compared with normal tissue, suggesting that the microorganism is involved in the initiation or progression of neoplasms. They also examined stool samples from healthy controls as well as patients with colorectal adenomas and carcinomas and found that levels of the bacteria increased as disease progressed.
Additionally, in a mouse model of intestinal tumorigenesis, the researchers found that F. nucleatum potentiated tumor development and recruited differentiated myeloid cells—including dendritic cells, myeloid-derived suppressor cells, and macrophages—that promote angiogenesis and tumor progression.
In the other study, a team led by Yiping Han, PhD, a microbiologist who has studied F. nucleatum for more than a decade and a professor of periodontics at Case Western Reserve University School of Dental Medicine in Cleveland, OH, showed that a small molecule called FadA on the surface of F. nucleatum binds to and modulates E-cadherin, a tumor suppressor, on colorectal epithelial cells (Cell Host Microbe 2013;14:195–206). β-catenin signaling is then activated, leading to the increased expression of transcription factors, oncogenes, Wnt genes, and inflammatory genes, and stimulating the growth of cancer cells.
Han's team also found specific fadA gene copy levels in normal colorectal tissue, adenomas, and carcinomas, with a 10-fold jump between each tissue type. “The differences were very clear,” she says. “There was very little overlap between the three groups, and no overlap between normal and carcinoma.”
Because fadA is unique to F. nucleatum, its expression could be used to diagnose colorectal cancer and identify people at risk for the disease, Han suggests. It could also be used to guide and assess possible treatments. “If FadA levels are reduced after treatment, perhaps it is an effective treatment,” she says. “If it doesn't reduce the levels, perhaps the danger is still there.”
As part of the research, Han's lab derived a synthetic peptide from a region of E-cadherin. Tested in mice, the peptide prevented F. nucleatum from binding to and invading cells, inhibiting tumor growth and inflammatory responses. Although the researchers didn't test the compound against other disorders related to F. nucleatum, she says there could be value in doing so.
“If we could block systemic proliferation of Fusobacterium nucleatum,” Han suggests, “we could kill many birds with one stone.”
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