Bacteria in Mouth May Promote Colorectal Cancer

August 21, 2013
Anna Azvolinsky

Two separate studies have found direct evidence that F. nucleatum, a bacteria found in the mouth and in periodontal plaques, promotes growth of colorectal tumors.

Studies have previously found a high abundance of the bacteria Fusobacterium nucleatum in colorectal carcinoma tissues but whether this association was circumstantial or whether the bacteria can promote colorectal tumors has not been clear. Now, in two separate studies, researchers from the Case Western Reserve University in Cleveland, Ohio, and Harvard Medical School in Boston, have found direct evidence that F. nucleatum promotes growth of colorectal tumors.

Both studies are published in the journal Cell Host & Microbe. F. nucleatum is a bacteria found in the mouth and in periodontal plaques and has a role in periodontal disease. The bacteria has also been shown to colonize the gut.

“We provide evidence that there is an infectious component to [colorectal cancer],” said Yiping W. Han, PhD, professor at the school of dental medicine and school of medicine at the Case Western Reserve University.

Other types of bacteria have been linked to colorectal cancers associated with inflammatory bowel disease, as antibiotic treatments of mouse colorectal cancer models reduce tumor incidence in colitis-prone mice. But, whether microbes influence the initiation or progression of colorectal cancers not associated with inflammatory bowel diseases was not known.

If further studies confirm the link of F. nucleatum to human colorectal cancer initiation and progression, minimizing F. nucleatum in both the mouth and the gut may lower the risk of those who are at an increased risk of developing colorectal cancer, stated Wendy Garrett, MD PhD, assistant professor of Immunology and infectious diseases, Harvard School of Public Health and Dana-Farber Cancer Institute in Boston, and co-authors in their discussion.

In the first study, Garrett and colleagues used colon tissue and stool samples from patients as well as mouse models. They found F. nucleatum to be enriched not only in colorectal carcinomas but also in colorectal adenomas, the precursor neoplastic lesions to malignant, sporadic colorectal cancers. Of 29 colorectal adenomas, 48% had high levels of the bacteria while adjacent normal colon tissue from the same patients was not colonized by the bacteria. F. nucleatum was also in higher abundance in stool samples from the colorectal adenoma and carcinoma patients but not in samples from 30 healthy control participants.

Using two different colorectal cancer mouse models, Garrett and colleagues introduced the bacteria into mice which resulted in more invasive tumors and more tumors in general compared with mice who were not inoculated with the bacteria. The bacteria also promoted tumor-infiltrating myeloid cells and inflammation that can promote tumor progression. As in human colorectal cancers positive for F. nucleatum, the bacteria-infected mice had a similar pro-inflammatory tumor microenvironment to human fusobacteria-positive colorectal cancers. But F. nucleatum did not exacerbate colitis or other inflammatory bowel conditions.

That F. nucleatum caused progression of colorectal cancer but did not influence colitis is very exciting according to Garrett. It is important that F. nucleatum was not associated with the rare colitis linked colorectal cancer (only 2% of diagnosed colorectal cancers) because it suggests that the bacteria may be important in the vast majority of human colorectal cancers, said Garrett.

In the second paper, Han and colleagues identified a mechanism by which F. nucleatum can potentially promote tumorigenesis using human colon cancer cell lines. The study showed that an adhesion molecule, FadA, found on the surface of the bacterial cell, allows the cell to attach and invade the colorectal neoplasms. FadA was shown to stimulate an inflammatory response in the colon, promoting tumor formation in xenograft mice.

Colon tissue from patients with adenoma and carcinoma had a 10- to 100-fold higher expression levels of the fadA gene which correlated with expression of oncogenic and inflammatory genes compared with healthy controls. The group also identified a synthetic peptide that can prevent the binding of the bacteria to human colorectal cells. The peptide was able to prevent growth of the human colorectal cancer cell line providing preliminary evidence that FadA is a potential therapeutic target.

Both studies provide evidence for a causal link between F. nucleatum and colorectal cancer. “We have known for a while that F. nucleatum can cause inflammation, but its activation of cancer growth genes and signals required for angiogenesis is a new and unexpected finding,” said Han.

Garrett and colleagues postulate in the discussion of their paper that the bacteria likely plays a role downstream of the loss of the tumor suppressor, APC, found in approximately 80% of non-colitis linked colorectal cancers and thought to be a tumor-initiating event. Previous studies have shown that F. nucleatum stimulates the growth of neoplasmic and not healthy colorectal cell lines.

“Our study also shows how data from large human datasets and mouse models can be effectively used to understand, evaluate, and test potential mechanisms of disease,” said Garrett.

These study findings could lead to prevention and early diagnosis strategies for colorectal cancer, but more studies on the mechanism of how F. nucleatum promotes colorectal tumors are needed. Because the fadA gene is unique to F. nucleatum, it could be a good diagnostic marker to identify inviduals at risk for adenomas and carcinomas in the colon. Han and colleagues are working to develop a diagnostic test for presence of the bacteria and is also working on further defining the mechanisms by which F. nucleatum promotes colorectal cancer tumorigenesis.

Because most people have F. nucleatum in their mouths, it is also important to understand whether other factors, including other microorganisms, in the gut facilitate the bacteria’s role in colorectal cancer development.