Dangerous microbe
Intestinal bacteria contributes to the development of colorectal cancer
Peter Kazimirov, PCR.news
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in the world. Associations of individual intestinal microbiota taxa with the development of cancer have already been shown. In a new paper, an international team of scientists has shown that Fusobacterium nucleatum provokes faster cancer development and described the molecular mechanisms of this process.
First of all, the scientists analyzed the composition of the intestinal microbiota of patients with CRC (63 people) using 16S RNA sequencing and compared it with the microbiota of healthy controls (52 people). The authors also analyzed the composition of the microbiota of cancer tissues according to previously published data. The results of the analysis showed that from a sample of bacteria associated with CRC, Fusobacterium nucleatum (Fn) it is also present in cancer tissues, so the authors focused further research on this particular bacterium. Database analysis showed that Fn is associated with two of the four CRC subtypes.
To study in more detail the effect of Fn on cancer development, the researchers cultured cancer cells together with bacteria. During cultivation, they found significant changes in gene expression profiles in tumor cells, which included activation of signaling pathways associated with the AhR aromatic hydrocarbon receptor. This receptor regulates enzymes that promote the metabolism of xenobiotics.
At the next stage, the authors used a mathematical model to predict metabolic changes in the interaction of bacteria with cancer cells. The results of the analysis showed that in the joint culture, the metabolism of Fusobacterium shifts towards more active formate production.
After that, the authors returned to an in vitro experiment in which the presence of formate in a joint culture provoked activation of signaling pathways associated with cancer cell invasion. Since the formation of metastases has previously been associated with stem cancer cells, scientists analyzed typical markers associated with stemness. Indeed, the analysis showed an increase in the activity of these markers in cancer cells when co-cultured with bacteria. The scientists confirmed the results obtained by treating cancer cells with pure formate, as well as introducing formate-treated cancer cells to mice. In both cases, an increase in invasive activity and stem cell activity was observed.
Since the signaling pathway associated with the AhR receptor was most strongly activated when CRC cells were co-cultured with Fn, scientists assumed that it was through it that the increase in invasive activity occurred. Indeed, blocking this signaling pathway leveled the effects of formate on the development of cancer cells.
Finally, scientists confirmed the effect of Fn on the development of CRC in vivo by injecting Fn orally to mice with cancer that do not have their own microbiota. With the introduction of bacteria, the number of metastases increased, as well as the number of immune cells associated with inflammation increased.
Thus, the researchers described the role of the microbiota in the development of colorectal cancer, and also showed that formate is a metabolite that significantly affects the development of cancer.
Ternes et al. The gut microbial metabolite formate exacerbates colorectal cancer progression is published in the journal Nature Metabolism.
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