A series of laboratory findings showed that fusobacteria, commonly found in the mouth, travels through the bloodstream and enriches colorectal cancer cells, a process mediated by the Fap2 protein’s ability to recognize a sugar called Gal-GalNAc. In the future, either Fap2 or Gal-GalNAc could represent therapeutic targets for colorectal cancer.
“If we know how fusobacteria localize and become enriched in colon tumors, hopefully we can utilize the same or similar mechanisms to guide and deliver cancer therapeutics to colon tumors,” said co-senior author Wendy Garrett, MD, PhD, of the Harvard T.H. Chan School of Public Health in Boston, in a press release. The paper was published in Cell Host & Microbe.
The new work involved both mouse models and human tissue samples. First, researchers injected fusobacteria (specifically, Fusobacterium nucleatum) into tail veins of mice with precancerous or malignant colorectal tumors, and found that the tumor cells became enriched with fusobacteria compared with adjacent tissue. The bacteria were also detected in most human colorectal cancer metastases tested, and not in tumor-free liver tissue.
Further testing then showed that Fap2, on the surface of the bacteria in question, recognizes the polysaccharide molecule Gal-GalNAc. They found that Fap2 mediates the colonization of colorectal cancer cells via binding with Gal-GalNAc. The protein also has been shown in earlier work to play a role in suppressing host immunity, thus allowing colorectal cancer to proliferate. Fap2 binds to an immunoregulatory signaling receptor found in T cells and natural killer cells called TIGIT, an interaction that reduces the killing of tumor cells.
Taken all together, these findings paint a picture of just how a mouth bacterium actually works to worsen and accelerate colorectal cancer. The bacterium travels via the bloodstream to reach colorectal tumors, at which point the Fap2 protein binds to the host cells via the Gal-GalNAc molecule, and simultaneously suppresses immune response in the area to allow the tumor to grow.
“Although it may not be possible to prevent oral microbes from entering the bloodstream and reaching colorectal tumors, our findings suggest that drugs targeting either Fap2 or Gal-GalNAc could potentially prevent these bacteria from exacerbating colorectal cancer,” Garrett said.