Release date: 2017-02-17
In the face of the immune system, cancer cells always try to "hidden their identity" and blind the immune system. Therefore, many scientists believe that a feasible way to overcome cancer is to "use some means to expose cancer cells to the immune system." To this end, they have tried many methods, one of which is the use of bacteria to infect cancerous tissues. This time, researchers have discovered new discoveries in this field. They have confirmed that genetically engineered Salmonella typhimurium can cause a strong immune response, effectively kill tumors and was first discovered to inhibit tumor metastasis [1] ]!
The study was completed by researchers at the National University of South Korea and published in the February 8 issue of Science Translational Medicine. Salmonella typhimurium is a kind of Salmonella. Salmonella belongs to anaerobic bacteria, and the tumor microenvironment happens to be an anoxic environment, which provides feasibility for Salmonella "undercover" cancer tissue. In past studies, under ideal conditions, bacteria played a "very strong" role in the "battle" of coping with tumors. On the one hand, he "rooted" in tumors to breed and use his own toxicity. On the other hand, it also shows its identity as an "invader", attracting the "firepower" of immune cells to fight cancer, and of course, it can't "live".
Salmonella typhimurium
Most of the ideas based on bacterial treatment of cancer are the same, but the reality is often less than ideal. First of all, like Salmonella, we know that it is a pathogen, so in order to ensure safety, the toxicity of bacteria will be artificially weakened, and the effect of bacteria in the tumor causing immune system attack will also be inhibited by the tumor, making treatment not good. Effect. This reality was also confirmed in a previous phase I trial of melanoma. The researchers injected the patient with attenuated Salmonella typhimurium. Although the safety was guaranteed, the treatment was disappointing. No patient. The tumor was eliminated as expected [2].
This new study is also very coincidental. Two professors Jung-Joon Min and Joon Haeng Rhee of the National University of South Korea (the two are the authors of this study) have led their team to work hard to find new ones. Anti-cancer drugs. At the same time, in 2006, crustaceans on the coast of South Korea died of large-scale deaths from vibrio vulnificus, so they also conducted a study to develop a vaccine that inhibits Vibrio vulnificus. In the experiment, they found that a protein in the flagella of Vibrio vulnificus can cause a strong immune response. This protein is called flagellin B (FlaB), and they later published their findings in the 2013 Vaccine. In the magazine [3].
Through this research, they thought, if a relatively safe bacteria also produces FlaB, can it also cause an immune response to fight cancer? So they chose the more mature and used S. typhimurium. The researchers first attenuated it, and then used genetic engineering technology to transfer the coding gene of FlaB, so that it could overexpress and produce FlaB. .
Professor Joon Haeng Rhee (left) and Professor Jung-Joon Min (right)
Next, the researchers transplanted human colon tumors to the mice. Four days later, the mice were given intravenous injections of Salmonella typhimurium. Three days after the start of the treatment, the researchers found that the bacteria in the liver, lungs and spleen of the mice had been cleared, and at the same time, the tumor tissue in the colon "spreads" the Salmonella typhimurium (the picture is too beautiful to imagine). In the following 4 months, 11 of the 20 mice (55%) had completely disappeared tumors and maintained good health with no signs of recurrence.
Then they did a comparative experiment on tumor metastasis. The mice were divided into three groups, one group was injected with Salmonella typhimurium (8) capable of producing FlaB, one group was injected with Salmonella typhimurium (6) transferred to an empty vector, and one group was used as a control, and phosphate buffer was injected. (PBS, 7). After treatment, 3 of the 8 mice in the FlaB group had metastases, but the researchers only found 4 lesions. The other two groups were in a much worse condition, with 26 lesions found in the empty vector group and 91 in the PBS group (although the researchers did not disclose in the two groups) A few have happened to transfer)!
Comparison of tumor metastasis in three groups of mice after treatment
After getting more positive results, the researchers also explored the mechanisms. In the 2013 study we mentioned earlier, in addition to demonstrating that FlaB can effectively activate the immune response, the study also found that this phenomenon is related to the Toll-like receptor 5 (TLR5) signaling pathway. Toll-like receptors (TLRs) are important protein molecules involved in non-specific immunity. When microorganisms break through the "first line of defense" of skin and mucous membranes, TLRs can identify certain molecules in their structure and judge them to be Harmful foreign matter that activates immune cell responses. Different molecules in the TLR family recognize different molecules, and TLR5 recognizes flagellin [4].
But in this study, the researchers found that in addition to TLR5, TLR4 is also associated with inhibition of cancer cells. They knocked out the genes encoding TLR4 and TLR5 in mice, and found that when the genetically engineered Salmonella typhimurium was injected, the therapeutic effect of mice knocked out of TLR4 completely disappeared, and mice knocked out by TLR5 were completely eliminated. The treatment effect has partially disappeared. Therefore, the researchers speculate that TLR4 is a necessary condition for FlaB to activate a non-specific immune response, while the TLR5 signaling pathway plays a role in enhancing the immune response.
Schematic diagram of phagocytic tumors of macrophages (white) after Salmonella typhimurium enters tumor cells
"Science" magazine also reported on the same day of the study. In the email to Science, Jung-Joon Min and Joon Haeng Rhee described their research as follows: FlaB seems to be particularly good at activation. TLR5, it seems to make immune cells more aggressive, just like turning Dr. Jekyll into Mr. Hyde (singularity note: this metaphor comes from the Scottish novelist Robert Louis Stevenson's masterpiece "Dr. In the novel, Dr. Jekyll invented a medicine that allowed him to become Mr. Hyde. Mr. Hyde is actually the "blood-blooded and violent" side of Dr. Jekyll's personality. The editor of Science also believes that "if the technology can replicate in humans, it will be an important step forward in the field of cancer and bacterial therapy."
references:
[1] Two-step enhanced cancer immunotherapy with engineered Salmonella typhimurium secreting heterologous flagellin
[2] Phase I Study of the Intravenous Administration of Attenuated Salmonella typhimurium to Patients With Metastatic Melanoma
[3] Flagellin enhances tumor-specific CD8+ T cell immune responses through TLR5 stimulation in a therapeutic cancer vaccine model
[4] The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5
Source: Singularity Network (WeChat public number: geekheal_com)
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