According to data from the World Health Organization, among the new cancers in the world in 2020, breast cancer has become the world's largest cancer, and the incidence of breast cancer in the mainland is also rising year by year. As one of the most common malignancies in women, the factors influencing breast cancer progression are complex and unclear, and scientists have been working to find the driving force that leads to breast cancer's progression, hoping to find a corresponding solution.
Cai Shang's team from the School of Life Sciences of Westlake University published a latest research paper online in Cell on the 7th, confirming for the first time in the world that a variety of unique "intracellular bacteria" exist in breast cancer tissues are crucial in the process of tumor metastasis and colonization. This concept is a major breakthrough in the traditional theory of tumor metastasis, and provides a new idea for in-depth understanding of tumor metastasis and clinical treatment of breast cancer.
Screenshot of the paper
Finding unproven "adversaries"
Traditional belief is that because of the presence of the immune system, the vast majority of tissues and organs (except the intestines, mouth, and skin) of the human body are sterile inside, as is tumor tissue.
But around 2020, Israeli and American scientists found that bacteria are also a component of cancer itself, and it is present in a wider range of cancer types outside of colorectal cancer, such as pancreatic cancer, lung cancer, breast cancer, etc. The vast majority of these bacteria are found in the cytoplasm and are called "intracellular bacteria".
Scientists speculate that it is precisely because the intracellular bacteria are located inside tumor cells that they have escaped the attack of the human immune system and survived.
So, what role do intracellular bacteria play in the process of tumorigenesis and development? Is it a dispensable bystander, or a participant in the tumor progression?
Previous studies have suggested that the gut microbiota can regulate the progression of cancer indirectly by modulating the immune system or by producing metabolites, but there is no evidence that tumor bacteria can be directly involved in the development of cancer. In particular, the small number of bacteria detected in tumors makes people more skeptical that such a low biomass of tumor microorganisms can have a significant impact on tumor progression.
Cai Shang has been focusing on breast cancer research. "The original idea came from a discussion I had when I was a postdoc at Stanford: What genes influence the development of breast cancer tumors. When constructing a mouse model of the induced knockout gene, I was surprised to find that there was no need to knock out the gene, just the addition of an inducer (an antibiotic), and the metastasis of the tumor would be affected. I find it incomprehensible. ”
In 2016, during the experiment, antibiotics once again attracted the attention of Cai Shang. He was acutely aware that the metastasis of tumors could be related to the ability of antibiotics to kill bacteria. He boldly assumed that bacteria were likely to be present in the tumor.
"At the time, it seemed like this assumption was a bit 'crazy'. But scientists always have to have a bit of an 'adventurous' spirit. In 2017, Cai Shang, who had just returned to China to join Westlake University, immediately launched a special study on this issue. Based on the classic mouse spontaneous breast cancer model, Cai Shang led the research team to build a rigorous tumor microbiota research system to explore the role of tumor microorganisms in tumor progression.
At that time, the "intracellular bacteria" was still an unproven conjecture, and their first task was to find "opponents". Looking back at the choice at that time, Cai Shang still had palpitations, "This topic is very risky, full of unknowns, when I decided to start the study, even whether the tumor microbiota really existed was extremely controversial." ”
Intracellular bacteria can promote tumor cell metastasis
The content of "intracellular bacteria" in tumor cells is very low, and the research team has continuously improved the detection and staining methods to improve the sensitivity, signal-to-noise ratio and accuracy, and finally observed the bacterial localization in mouse tumors, and clearly saw the bacteria present in the cytoplasm through high-resolution electron microscopy.
Intracellular bacteria are present in mouse models of spontaneous breast cancer
Exploring the function of these bacteria became the focus of Cai Shang's team.
A simple idea is to clear these bacteria and see what happens to the tumor. The conventional method of elimination is the use of antibiotics. But how do you ensure that antibiotics only remove tumor bacteria?
Without precedent and no experience to follow, he led the team members of Westlake University, from the research system to the experimental method, from the cultivation and transmission of mouse models, to the improvement of antibiotic use methods, everything started from scratch, built from scratch, continuously optimized the treatment method of antibiotics, adjusted the combination of antibiotic combination types and injection methods, and finally achieved the purpose of "targeted" removal of tumor flora.
The results showed that after the removal of the tumor flora, the tumor weight was not affected, but the lung metastasis decreased significantly. This suggests that the tumor flora is likely to influence not the growth of the tumor, but the metastasis process.
Antibiotic clearance experiments prove that tumor flora is very important for tumor metastasis
Based on this finding, the team hypothesized that intracellular bacteria in tumor tissue would migrate with tumor cells to distant organs and affect metastasis. That is, the bacteria in the tumor run along with the tumor cells to other parts of the body.
To test this hypothesis, Cai Shang's team sequenced bacterial 16S for in situ tumors, visible lung metastases, lung tissue containing tiny metastases, and normal lung and breast tissue. The analysis results showed that the bacteria that metastasized in the early lung may still have the characteristics of the microflora of the tumor in situ, and as the tumor grows and spreads, it gradually begins to be affected by the lung microenvironment.
By isolating and staining circulating tumor cells, the research team saw that circulating tumor cells can "run" to the distal organs with intracellular bacteria; and by transfusing these intracellular bacteria into tumor cells, it can be seen that tumor cells are "more viable during running" in the human body, and even breast cancers that are not easy to metastasize also begin to metastasize after the input of intracellular bacteria.
This is a powerful demonstration that intracellular bacteria can promote the metastasis of tumor cells.
Provides a new perspective for clinical control of tumor metastasis
So why can intracellular bacteria promote tumor cell metastasis? Cai Shang explained that during metastasis, cancer cells are not as "powerful" as we think, and blood pressure (flow pressure) in the blood vessels can cause damage to it. But they found that when endocytocci invade tumor cells, they remodel the cytoskeleton through specific signaling pathways (RhoA-ROCK) to help tumor cells resist pressure in blood vessels and avoid damage during metastasis.
This perfectly explains why tumor cells with intracellular bacteria have a greater ability to run to distant organs.
The invasion of intracellular bacteria reshapes the cytoskeleton of tumor cells as a pattern diagram to resist fluid pressure.
Finally, the research team returned to the human body from mice, collected the tumor tissue, paracancer and lymph node tissue of the paired breast cancer patients, and quantitatively and qualitatively analyzed the composition of the respective microbiota with qPCR combined with 16S sequencing. The results showed that mouse breast cancer tissue and human breast cancer tissue had the same microbial profile and dynamic changes, suggesting that the human breast cancer microbiota may play a similar role in the occurrence and progression of human cancer.
Over the past 5 years, from conjecture, hypothesis to step by step confirmation, the research of Cai Shang's team has identified new components that have been neglected for a long time in the tumor microenvironment, revealed new factors affecting tumor metastasis, opened up new directions for tumor research, and provided a new perspective for clinical control of tumor metastasis.
"This field is just emerging, there are still many unsolved mysteries, the clinical use of antibiotics is also full of complexity, how to use this discovery to guide clinical treatment is still a complex and urgent scientific problem, requiring more researchers to do a lot of basic and solid work." In Cai Shang's view, this achievement only opens a small window in the field of breast cancer research, and as for the scenery outside the window, I hope that more latecomers will look at it together.
(Guangming Daily all-media reporter Jin Haotian correspondent Zhang Chi)
Source: Guangming Daily all-media reporter Jin Haotian correspondent Zhang Chi
Photo: Westlake University official website
Editor-in-charge: Zhang Yongqun
Editor: Wu Yaqi Wang Yuanfang