Microbes and metastases
Bacteria in cancer cells contribute to metastasis
Peter Kazimirov, PCR.news
Chinese scientists have confirmed in experiments on mice that in a cancerous tumor, compared with healthy tissues, the content of bacteria is increased. They live mainly in the cytosol, spread throughout the body along with cancer cells and increase their resistance to mechanical stress in the circulatory system, thereby increasing the potential for metastasis.
In recent years, more and more studies have confirmed the role of tissue microbiota in the development of cancerous tumors. However, the small number of bacteria in the tissues makes it much more difficult to study this problem in detail, so the details of the interaction of microbiota and cancer were not known. A group of scientists from China has shown that bacteria living in cancer cells make them more resistant to mechanical stress and thereby contribute to the spread of metastases.
As a model, the scientists used spontaneous mouse breast cancer (MMTV-PyMT), since it is similar in microbiological composition to human breast cancer. To analyze the number of bacteria in healthy tissues and tumor tissues. For this purpose, a quantitative PCR analysis was used, modified to more accurately account for small amounts of bacteria. The analysis showed that about 10 times more bacteria live in the tumor tissues than in healthy tissues. Next, the scientists analyzed the composition of the microbiota using modified 16S RNA sequencing. It turned out that Proteobacteria group bacteria predominate in healthy tissues, and Firmicutes group prevail in tumor tissues. The overall level of diversity was also lowered in cancer tissues.
To determine exactly where bacteria live in tissues — in cells or in the intercellular space — staining of components characteristic of bacteria and fluorescent labeling were used. The analysis showed that about 97% of bacteria live in the cytosol. These results were also confirmed by an estimate of the number of bacteria in cultured tissues.
Scientists wondered how the destruction of the tissue microbiome and the gastrointestinal microbiome would affect the development of the tumor. Mice received a cocktail of antibiotics with drinking water or through the tail vein. In the first case, the microbiota of both the gastrointestinal tract and tumor tissues was destroyed, in the second only tumor tissues. The destruction of the microbiota of the gastrointestinal tract and tumor tissues slowed down the growth of the tumor and the formation of metastases. When only the microbiota of cancer tissues was destroyed, there was no slowing down of tumor growth, but the formation of metastases decreased.
The authors also checked whether the bacteria contained in the cells spread with them into metastases. To do this, they compared the composition of the microbiota in primary cancer, metastases and healthy tissues. The microbiota of metastases generally corresponded to the microbiota of primary cancer, although it underwent some changes related to conditions in different tissues (for example, there were fewer anaerobic bacteria in lung metastases).
To finally confirm the spread of bacteria in tandem with cancer cells, scientists introduced recombinant bacteria synthesizing fluorescent protein into cancer tissues. In the future, clones of these bacteria were found only in metastases and were absent in healthy tissues.
To study in more detail the effect of bacteria on growth and metastasis, scientists cultured cancer cells together with individual genera of bacteria. The presence of bacteria did not affect the growth rate, however, the introduction of co-cultured cells to mice with pretreated tumors with antibiotics provoked metastasis. The data obtained suggested that bacteria of the genus Staphylococcus and Lactobacillus contributed to the formation of metastases, while Enterococcus and Streptococcus had minimal effect, possibly due to the low efficiency of invasion into cells or organoids.
Finally, scientists tried to find out how bacteria-infected cancer cells gain an advantage in metastasis. When cells enter the circulatory system, they are subjected to severe mechanical stress in the blood stream, which often leads to apoptosis. Scientists have suggested that changes caused by bacteria may help cancer cells to endure this stress. To test this hypothesis, a special installation equipped with a pump was constructed, which simulated various levels of mechanical stress. Indeed, at high levels of stress, the cells carrying the bacteria showed a higher survival rate — apparently due to the reorganization of the actin cytoskeleton in circulating cells.
The authors believe that further research into the interaction of cancer cells and bacteria can contribute to the development of new methods of cancer treatment based on antibiotics.
Article by Fu et al. Tumor-resident intracellular microbiota promotes metastatic colonization in breast cancer published in the journal Cell.
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