April 16, 2018 Colon cancer is one of the most common cancers in Germany. Since the upswing in microbiome research, physicians are also looking for risk factors in the gut itself. They came across Fusobacterium nucleatum. Is the bacterium the cause of colon cancer?
Will the emergence of the colon carcinoma favored or even caused by bacterial infections? The Canadian geneticist Dr. Robert Holt. It is now well known that bacterial or viral infections may be a risk factor for some cancers. The most prominent example is the bacterium Helicobacter pylori , The infection often results in a chronic atrophic Gastritis, which may result from adenocarcinoma can develop. Does it therefore make sense to search for potential risk factors for colon carcinoma directly in the gut?
On the other end
In search of a possible cause of colon carcinoma in the microbiome, Dr. Brings an amazing find in 2011. He and his team investigated the genetic material of eleven tumor samples from different patients. They analyzed the DNA instead of the DNA RNA to find out which microorganisms were active in the samples. The RNA, in contrast to the DNA, shows which genes of the genome were actually transcribed at the time of sampling.
In the analysis of the microbial genome, the researchers came across 415 different bacterial species. One species was in the tumor cells especially present : Fusobacterium nucleatum , Compared with the samples of the healthy colon cells, Fusobacterium nucleatum was detected on average 79 times more frequently in the samples of the tumor cells.
Independent of Dr. Holt’s discovery, at the same time announced the research group around Dr. Matthew Meyerson from the Dana-Faber Cancer Institute in Boston similar findings , The team initially studied nine samples, but then extended the study to a cohort of 95 subjects. Although they did not analyze microbial RNA but DNA, they came to the same conclusion. They also found a surprisingly high number of F. nucleatum in colon carcinoma cells. The special feature: F. nucleatum normally does not inhabit the intestine in large numbers. It mainly colonizes the oral cavity.
The periodontitis problem
F. nucleatum is a gram-negative , obligatory anaerobic bacillus that in the emergence of periodontitis , The bacterial infection of the periodontium, plays a central role. Also in the healthy Parodont This bacterium is found in such low concentrations that it can be controlled by the immune system.
Accumulating plaque on the gum line, for example due to poor oral hygiene, irritates the sensitive gums here. The consequence is an immune response, in addition to a gingivitis also leads to the formation of periodontal pockets. In these pathological depressions, the anaerobic bacteria find good living conditions. Through their metabolism, F. nucleatum creates a livelihood for other highly pathogenic anaerobic bacteria. Periodontitis progresses without medical intervention.
Not only for dental problems of importance
However, F. nucleatum does not only seem to play a role in periodontitis: it has been associated with adverse pregnancies for years, such as premature birth and stillbirth connected. The bacterium is to pass through the hematogenous transmission of the maternal oral cavity into the uterus and there the chorioamnionitis trigger. Also in atherosclerotic plaques It is often detected and associated with cardiovascular disease connected. It is assumed that parodonthopathogenic bacteria migrate through small injuries in the blood vessels, trigger immune reactions there and lead to vascular damage.
So does F. nucleatum now also fit into the risk factors for colon carcinomas? Or is it just an excellent way to live as an anaerobic bacterium in the tumor environment? “One hypothesis for colonizing Fusobacteria in the gut would be to create a suitable environment through components of the intestinal flora, or even through the tumor itself,” Dr. Jan Liese, senior physician at the Institute of Medical Microbiology and Hospital Hygiene at the University Hospital Tübingen. He assumes that the germ does not come into question as the sole cause of colon cancer: “The mechanisms in which the pathogen favors tumor growth could include influencing the tumor response of the immune system or promoting cell adhesion and invasion by bacterial metabolites.”
Also Dr. Niels Halama is convinced that Fusobacteria act more as modulators of disease-promoting processes. He is Senior Physician at the University Hospital in Heidelberg and Group Leader in the Department of Medical Oncology at the National Center for Tumor Diseases (NCT) Heidelberg. “The acidic environment in the microenvironment of the tumor creates a suitable livelihood for Fusobacteria, where they presumably play the role of an immunomodulator,” Dr. Halama. “By intervening in signaling cascades of the immune response, for example, Fusobacteria contribute to chemoresistant resistance in colon carcinoma.”
Fusobacteria modulate the immune response
An American study shows in that F. nucleatum prevents the programmed cell death (apoptosis) of tumor cells during chemotherapy. By expressing the expression of two microRNAs Suppressed, it indirectly activates the process of autophagy. This cell’s own cytosolic material is degraded as misfolded proteins or damaged cell organelles. By activating the autophagy pathway, the tumor cells escape cell death.
A research team led by Gilad Bachrach of the University of Jerusalem also devoted to possible mechanisms of immunomodulation. You too found out in that the bacterium protects tumor cells from an immune response. The Fap2 membrane protein of F. nucleatum interacts directly with the inhibitory TIGIT receptor on natural killer cells ( NK cells ). These cytotoxic lymphocytes have the ability to target their target cells, for example, tumor cells, apoptosis trigger. Occupation of the TIGIT receptor with Fap2 inhibits the cytotoxic activity of NK cells. The tumor cells can therefore no longer be eliminated by the immune system.
A bacterium traveling
Using these mechanisms, F. nucleatum could provide for very good living conditions – and not give them up so quickly. A recently published study By Meyerson shows: Once the tumor tissue is infected, the pathogen seems to be an integral part of the tumor. The researchers found that F. nucleatum even “travels” when the cancer metastasizes. Meyerson examined infected colon carcinomas that had spread to the liver. F. nucleatum was also found in these liver tumors. According to study authors, these were not newly acquired infections. In liver tumors, which resulted from uninfected colon carcinomas, no bacteria could be detected. They also looked for F. nucleatum in primary liver tumors – it was not found.
In another experiment, Meyerson’s team transplanted human colon carcinoma cells into mice, where they continued to grow. The xenotransplantation was maintained over four generations of mice. F. nucleatum remained true to the tumors. The researchers treated the mice with metronidazole , an antibiotic that kills fusobacteria, the tumor grew much more slowly. The control was erythromycin, whereas these bacteria are resistant. In this case, tumor growth was unaffected.
Antibiotics for everyone?
The study raises hope for therapeutic measures. After all, colon cancer is with over 73,000 new cases and about 27,000 deaths per year in Germany one of the most common malignant tumors. So, could patients with Fusobacterium-associated colon carcinoma benefit from simple antibiotic treatment in the future? “Although animal model studies provide initial indications that these mechanisms of action could also affect humans,” Dr. Halama “but as with all animal model studies, the problem is that the results can not be directly applied to humans.”
Dr. Jan Liese explains: “The experimental work on the influence of Fusobacteria on the genesis of colon carcinomas naturally suggests an additional antibiotic therapy, especially since this would be relatively low side effects compared to the ‘conventional’ tumor therapies. The targeted eradication of individual pathogens from a bacterial flora, however, is hardly possible, because it is also influenced by other antibiotics always other components of normal flora. “In addition, lacked clinical studies, the advantage of such a therapy on the development, progression and prognosis of the disease could show.