This schematic depicts the findings of Abed et al., who identify a host polysaccharide, Gal-GalNAc, and fusobacterial lectin (Fap2) that explicate fusobacteria abundance in colorectal cancer (CRC). Targeting Fap2 or host Gal-GalNAc may provide a means to reduce F. nucleatum potentiation of CRC. [Abed et al./Cell Host & Microbe 2016]
Evidence emerges almost daily in support of the microbiome’s influence on a variety of body systems and disease states. Yet, can it be true that various microbes that constitute the oral microbiota negatively affect colorectal cancer (CRC)? A new study led by researchers at the Harvard T.H. Chan School of Public Health has found evidence strongly suggesting that they can.
While some previous evidence alluded to common mouth bacteria worsening CRC in animals, it had not been clear how these microbes made their way to the gut to exert their adverse effects. In the new study, the Harvard investigators found evidence that microbes called fusobacteria might use the bloodstream to reach colorectal tumors. Moreover, the research team was able to show exactly how these bacteria home in on colorectal tumors—causing them to proliferate and subsequently accelerate colorectal cancer.
“As fusobacteria contribute to colon tumor development, revealing the mechanism that guides them to the tumor and why fusobacteria become abundant there might inform ways of blocking this,” explained co-senior study author Wendy Garrett, M.D., Ph.D., associate professor of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health and the Dana-Farber Cancer Center. “Alternatively, and perhaps more importantly, 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.”
CRC is the third leading cause of cancer-related deaths in the United States, and microbes have recently begun to emerge as key factors influencing the development and progression of the disease. Recent studies have shown that fusobacteria promote the formation of colon tumors in animals and are enriched in human colorectal tumors compared to adjacent normal tissue. But these studies left it unclear how bacteria from the mouth localize to, and become abundant in, colorectal tumors.
The research team had a suspicion that oral microbes might reach colorectal tumors through the bloodstream. To test this idea, the scientists injected fusobacteria into the tail veins of two mouse models with either precancerous or malignant colorectal tumors. Surprisingly, in both types of mice, the fusobacteria became enriched in colorectal tumors compared to adjacent normal tissue. The researchers also detected fusobacteria in the majority of human colorectal cancer metastases tested, but not in most samples taken from tumor-free liver biopsies.
The findings from this study were published recently in Cell Host & Microbe in an article entitled “Fap2 Mediates Fusobacterium nucleatum Colorectal Adenocarcinoma Enrichment by Binding to Tumor-Expressed Gal-GalNAc.”
Using human samples and mouse models, the researchers went on to discover that the Fap2 protein located on the surface of fusobacteria recognizes a sugar called Gal-GalNac, which is abundant on the surface of colorectal tumor cells.
“We identify a host polysaccharide and fusobacterial lectin that explicates fusobacteria abundance in CRC,” the authors wrote. “Gal-GalNAc, which is overexpressed in CRC, is recognized by fusobacterial Fap2, which functions as a Gal-GalNAc lectin.”
Additional experiments showed that Fap2 mediates fusobacterial colonization of colorectal cancer tumors and metastases. Recent studies have demonstrated that this protein also impairs the ability of the host immune system to kill tumor cells. Taken together, the findings suggest that fusobacteria travel through the bloodstream to reach colorectal tumors and then use their Fap2 protein to bind to host cells and proliferate in tumors, thereby accelerating colorectal cancer.
“F. nucleatum binding to clinical adenocarcinomas correlates with Gal-GalNAc expression and is reduced upon O-glycanase treatment,” the authors wrote. “Clinical fusobacteria strains naturally lacking Fap2 or inactivated Fap2 mutants show reduced binding to Gal-GalNAc-expressing CRC cells and established CRCs in mice.”
“The strengths are that the study involved both human samples and mouse models. The weakness is that the available mouse models for colorectal adenocarcinoma do not completely reflect the slowly developing disease in humans,” noted co-senior study author Gilad Bachrach, Ph.D., associate professor in the Institute of Dental Sciences at the Hebrew University of Jerusalem. “Based on our findings, it's too early to say whether we can prevent mouth bacteria from traveling through blood to the colon and promoting tumor formation or if some people are more at risk than others.”
In future studies, the researchers will look to examine further how fusobacteria contribute to the development, growth, and spread of colorectal cancer. “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,” Dr. Garrett concluded.