You may not think that the tumor, the "fierce" guy, still has bacteria in the cells. Moreover, this unique intracellular bacteria control the behavior of tumor cells and play an important role in cancer metastasis.
At 23:00 beijing time on April 7, 2022, The research group of Cai Shang, a professor at the School of Life Sciences of Westlake University, published a paper in Cell, which proved for the first time that the presence of intracellular bacteria in breast cancer tissue is crucial to tumor metastasis and colonization under physiological conditions.
The study identifies new components that have been neglected for a long time in the tumor microenvironment, reveals the genetic and extra-episcopic factors that affect tumor metastasis, and opens up new directions for tumor research, providing a new perspective for clinical control of tumor metastasis.
Accidental discovery of tumor intracellular bacteria
"It was a coincidence that the discovery of intracellular bacteria was indeed a coincidence." Cai Shang told China Science Daily, "We didn't start to think 'on a whim' that there were bacteria inside the tumor. ”
Like most researchers, Cai Shang believes that the inside of the tumor is similar to the human tissue and is a sterile environment.
Five or six years ago, when Cai Shang was doing postdoctoral research at Stanford University, when he explored the role of a tumor gene on tumor development, he made a mouse model - using antibiotics to induce, knock out a gene, and use this to find out the role of the gene in tumor development.
"At that time, we found that using antibiotic induction to knock out this gene did inhibit the metastasis of the tumor." Cai Shang added, "But curiously, if antibiotics are used, tumor metastasis can also be found to be affected in the control group that did not induce gene knockout." ”
That is to say, there seems to be some kind of correlation between antibiotics and tumor metastasis. This phenomenon puzzled Cai Shang because there were other research targets at the time and the problem was not pursued deeply.
After that, Cai Shang went to consult the relevant literature and found that the early literature did report that antibiotics had the effect of killing tumor cells.
"But in the experiment, we only saw that lung metastases were affected by antibiotics, and the tumor growth of the primary lesion was not actually affected." Cai Shang said, "I suddenly thought, will there also be bacteria inside the tumor?" However, due to various factors such as cognitive limitations and technical level, there was no solid conclusion on this issue at that time. ”
In 2017, Cai Shang came to Westlake University and began to study whether bacteria may exist in the tumor and whether it has a role if it exists.
After unremitting efforts, Cai Shang's team confirmed the existence of tumor intracellular bacteria with experiments.
Figure: Presence of intracellular bacteria in mouse models of spontaneous breast cancer
Deepen your understanding of the nature of tumors
To prove the presence of tumor intracellular bacteria, the next more important work is to explore the function of tumor microbiota.
Cai Shang's team innovatively adopted a variety of antibiotics and a variety of strategies to specifically remove tumor flora, so as to conduct tumor microbiota function studies. The results showed that the use of tail vein injection of ATBx compound antibiotics and Doxycline water only removed the tumor flora, which did not affect the tumor weight, but the lung metastasis was significantly reduced.
"This was also demonstrated using a germ-free mouse model, which shows that the tumor flora has a biological function of promoting tumor metastasis." Cai Shang said.
Figure: Antibiotic clearance experiments prove that tumor flora is very important for tumor metastasis
Because most of the identified bacteria are intracellular bacteria, and considering that metastasis is a multi-step process, including migration from in situ into blood vessels, circulating tumor cells through the blood to reach the distal organs, and distal colonization and growth. The researchers assumed that the intracellular bacteria in the tumor tissue would migrate with the tumor cells to the distal organs and affect metastasis, and studied the bacteria by staining, transmission electron microscopy observation, and 16S library sequencing of the bacteria.
"The results of bioinformatics data analysis suggest that bacteria metastatic in the early stages of the lung may still carry the flora characteristics of the tumor in situ, and as the tumor progresses, it begins to be affected by the lung microenvironment." Fu Aikun, co-first author of the paper and a postdoctoral fellow at the School of Life Sciences at Westlake University, told China Science News.
Figured: Tumor cells carry bacteria to distant organs and promote metastasis
Through experiments, the researchers saw that circulating tumor cells can carry tumor flora to the distal organs, and the infusion of these tumor flora does not affect the growth of tumors in situ, but significantly promotes tumor metastasis, and even weakly metastasized tumor types can also metastasize in large quantities.
"Combined with antibiotic clearance experiments, we demonstrated the function of tumor flora in promoting metastasis in the physiological state." Fu Aikun said.
Potential direction of tumor treatment
Tumor cells experience "flow shear" pressure during metastasis, especially in the circulatory system, which can easily cause cell death.
"Tumor cell metastasis must enter the blood system, but there is a 'fluid pressure' in the blood flow system (a wonderful anti-metastasis mechanism in the body), which causes more than 99% of tumor fine deaths." Cai Shang said.
To further explore the mechanism of tumor microbiota in promoting tumor cell metastasis, the team used single-cell sequencing analysis to find a specific shear pressure pathway after bacteria invaded tumor cells. The construction of the fluid flow pressure system in vitro and the in vivo tail vein return experiment proved that after experiencing stress, the invading bacteria cells had a higher viability than the cells in the control group.
Experiments have shown that if bacteria invade tumor cells, it can provide strong protection for tumor cells. When tumor cells are exposed to fluid pressure, their viability is increased by 5 to 10 times, and their remote survival chances are greatly improved.
"Bacteria invade and reshape the cytoskeleton of tumor cells to resist flow pressure." Cai Shang explains, "These bacteria are actually helpful for tumors, and can help tumors spread and metastasize. ”
The research team also collected tumor tissue, paracancertic tissue and lymph node tissue from paired breast cancer patients and analyzed the composition of the microbiota by sequencing. The results showed that mouse breast cancer tissue and human breast cancer tissue had similar microbial profiles and dynamic changes. That is, "the human breast cancer flora may play a similar role in the occurrence and progression of cancer."
Cai Shang believes that in addition to the well-known genetic, epigenetic and matrix microenvironmental factors, the host microbiome, as a non-negligible component of the body, is also a vital medium in regulating cancer susceptibility and tumor progression, "their presence adds another layer of complexity to cancer biology research."
According to the reviewers, "this study is very timely and critical, answering important questions in the field." The use of antibiotics specifically clears the tumor flora, significantly reduces tumor metastasis but does not affect tumor growth. It is shown mechanically that intracellular bacteria can regulate the skeleton of host cells, resist the fluid pressure of host cells in the circulatory system, and thus promote the survival of cancer cells, providing new insights for in-depth understanding of tumor metastasis, and opening up new ideas for the clinical treatment of breast cancer.
"It's an emerging field, and what we're finding may be just the tip of the iceberg." Cai Shang said, "This deepens the understanding of the nature of tumors, and at the same time will attract more researchers to pay attention to this direction." If people can regulate these flora, it will provide a potential way to treat tumors. ”
Related paper information:
https://doi.org/10.1016/j.cell.2022.02.027
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