Scientists from the Harvard T H Chan School of Public Health and Hebrew University-Hadassah School of Dental Medicine have recently found that certain type of bacteria, known as fusobacteria, which often reside in mouth, are aggravating the tumor metastasis in colorectal cancer. After mixing with the bloodstream, these bacteria travel from the mouth to the colon which is the primary site of damage.
With an annual increase rate of 8%, colorectal cancer is the second most common cancer in the United States. With an estimated new cases of 134,490 in year 2016, colorectal cancer is expected be become a cause of death for 49,190 people in this year. In recent years, a 5-year survival rate was recorded for 65.1% which is likely to improve with the recent developments. The crucial findings of this pioneering study were also recently published in the journal, Cell Host & Microbe.
It was established that this bacterium uses the hematogenous (carried through blood) route to reach colon adenocarcinoma. In addition to this, the role of FAp2 and host epithelial Gal-GalNAc was also demonstrated in mice and humans, pointing at the future possibility of targeting them to reduce the incidence rate of colorectal cancer.
Previously, certain fusobacterial strains were associated with worsening of colorectal cancer in animal subjects. This finding was led by the Garrett Lab at Harvard Chan School. Complementing these findings, the new pioneering study for humans has further validated this previously established association which has a great potential for treating colorectal cancer in future.
Over the years, diseases have been studied in reference with the presences of microbes in the human system. Interestingly, the effects of microbes on our health are much more than mere infections. With emerging findings in the field of microbiology and immunology, the role of microbiome is becoming increasingly important in understanding disease progression. And now, concrete evidence has been added to the pool of research which indicates a role of microbes in exacerbating tumors.
How Do The Oral Bacteria Reach Colon And Stick To Tumor Cells?
Fusobacterium nucleatum sticks to a sugar-binding protein Gal-GalNAc which is found in abundance in colorectal cancer patients. These bacteria possess an outer membrane protein Fap2, it functions as a Gal-GalNAc lectin which acts as a liaison to establish an interaction between the bacterial molecule and adenocarcinomas.
Interestingly, earlier studies have also pointed out the galactose sensitivity of fasubacterium nucleatum interactions. In was found that the sugar sensitive interactions help the bacterial cells to adhere to the host cells. When further investigation was carried to understand the interaction minutely, it was observed that the presence on Fap2 outer membrane protein played a vital role in mediating this interaction first to the sugar molecule and then to the host cells. Thereby, fusobacterial Fap2 is said to function as a Gal-GalNAc lectin.
Lectins are proteins which recognize and bind a particular sugar sequences in a carbohydrate molecule. Known also as peanut agglutinin (PNA), the Gal-GalNAc lectin binds to the carbohydrate sequence Gal-GalNAC and has a highly specific affinity to it.
This study quantified the Gal-GalNAc expression levels on healthy human colorectal tissues, human colonic adenomas (benign tumors) and human colorectal adenocarcinomas by straining them with fluorescently labeled Gal-GalNAc specific lactic. It was found that the Gal-GalNAc expression was highest in the adenocarcinoma epithelial cells, while the intensity varied in villous and tubular adenomas.
Upon studying Fap2 medicated response in detail, it was found that the role of Fap2 protein was central and no adherence mediation could have taken place if the genes encoding Fap2 were mutated. Binding to the red blood cells, the route of this oral bacterium through bloodstream was confirmed. The immune suppressing role was about found to be present in the bacterium which inhibits the protective role of immune cells. The anti-tumor immunity and tumor killing through innate immunity method by the natural killer (NK) cells was specifically suppressed by the bacteria leading to tumor metastasis and failure of immune therapy to contain the malignant cancer.
The researchers suggested that it is not possible to completely get rid of the oral bacteria and that it would be premature to comment on how the bacterial travel to the gut can be prevented.
The researchers were optimistic about the future implications of their findings as senior study co-author Wendy Garret said, “…more importantly, our findings suggest that drugs targeting the same or similar mechanisms of bacterial sugar-binding proteins could potentially prevent these bacteria from exacerbating colorectal cancer.”
With this striking development, it is hoped that therapeutics will be formulated to specifically target Fap2 proteins on the bacterial cell walls to inhibit their activity. While sugar binding proteins (Gal-GalNAc) are required to keep the normal physiological functions of the body running smoothly, a more complex mechanism will have to be adopted to limit its interaction with Fap2 to avoid any detrimental effects.