Nat Comm . . . The whole drug affects breast cancer metastasis in animal models through the IL-6 pathway.

Enzyme aesthetic surgery is one of the most commonly used treatments for solid organ tumors. It is often used for cancer prevention, diagnosis, staging and radical resection.more than 80% of patients with malignant tumors will receive at least one operation.however, for highly malignant tumors such as triple negative breast cancer, even if the tumor and its involved local areas are completely removed, the cancer will still relapse or metastasize, which is the main cause of death.in recent years, more and more studies have shown that perioperative medication and treatment can increase the number of circulating tumor cells and enhance the invasive ability.during the operation, the neuroendocrine system is activated to release a large number of immunosuppressive factors, resulting in persistent cell-mediated immunosuppression.all of these factors contribute to the metastasis of tumor cells to distant organs, thus affecting the prognosis of cancer patients.anesthetics are the most commonly used drugs in surgery. General anesthesia mainly includes volatile anesthetics such as sevoflurane and intravenous anesthetics such as propofol.in 2016, Wigmore et al. Published a large retrospective study to analyze the long-term (three-year) survival rate of more than 7000 cancer patients undergoing tumor resection under inhalation or intravenous anesthesia.after matching control, 2607 patients were enrolled in the inhalation anesthesia group and intravenous anesthesia group (597 cases died in the inhalation anesthesia group, the mortality rate was 22.8%; in the intravenous anesthesia group, 407 cases died, the mortality rate was 15.6%).multivariate analysis of known confounding factors in the matching groups of the two anesthesia methods showed that the risk of death was significantly increased in the inhalation anesthesia group (HR 1.46; 95% CI: 1.29-1.66). However, some other retrospective studies suggested that anesthesia did not affect the survival rate and tumor recurrence rate of cancer patients.recently, a large multicenter prospective study found that compared with general anesthesia with sevoflurane and opioid analgesia, regional anesthesia analgesia (paraspinal block and propofol) did not reduce postoperative recurrence of breast cancer.however, it should be noted that all patients in this study were primary breast cancer (stage I to III), excluding patients with inflammatory breast cancer, and no distinction was made between breast conserving surgery and radical mastectomy.in view of the diversity of patients and the complexity of breast cancer, local anesthesia analgesia and intravenous anesthesia may be more beneficial to the prognosis of patients with malignant breast cancer.in addition, for breast cancer patients, the most common is breast conserving surgery with less trauma, so the intensity of body stress response caused by surgery may also lead to differences in research results.although narcotic drugs have been used in modern medical treatment for more than 100 years, the mechanism of action of commonly used narcotic drugs such as sevoflurane and propofol is very limited, and the role of narcotic drugs in tumor metastasis is even less understood.therefore, Lin Jun, a professor at the school of medicine at State University of New York at Stony Brook, used a mouse model to study the effects of different anesthetics on cancer metastasis and further reveal their mechanisms.this work was published in nature communications, entitled: distinct effects of general anesthetics on lung metastasis mediated by IL-6 / JAK / STAT3 pathway in mouse models (first author: Dr. Li Ru, Dr. Huang Yujie).the team used two mouse models for tumor resection to study the effects of different anesthetics: 4T1 syngeneic mouse model and MDA-MB-231 xenograft mouse model.in these two mouse models, tumor cells were inoculated in situ.when the tumor in situ grows to a certain size, simulate the clinical operation and remove the tumor in situ under the effect of different anesthetic drugs.then, after a period of observation, the metastasis of tumor cells to the lung was finally evaluated.studies have shown that sevoflurane anesthesia during surgery significantly increased the number of postoperative lung metastases compared with those anesthetized with propofol.this result was confirmed by two mouse models.in order to further reveal the mechanism of action of anesthetics and find potential targets to eliminate the role of anesthetics in promoting tumor metastasis, they screened for changes in cytokines and cytokines in blood and lung tissues within a short period of time (i.e., three hours after surgery and one day after surgery).the results showed that several proinflammatory cytokines related to tumor metastasis were increased in mice anesthetized with sevoflurane.ELISA was used to further detect the changes of IL-6 and VEGF to verify the screening results.ELISA showed that the level of IL-6 in serum of mice in sevoflurane group was significantly higher than that in propofol group three hours after operation.one day after operation, the serum level of IL-6 in sevoflurane group was twice as much as that in propofol group.there was no significant change in the amount of IL-6 in lung tissue.similar to the results of IL-6, the serum VEGF level in sevoflurane group was higher than that in propofol group one day after operation, but the change of VEGF was not as significant as that of IL-6.based on the above results and the important role of IL-6 in tumor metastasis, they further studied the changes of IL-6 related signaling pathways under the action of anesthetics.after IL-6 binds to its receptor, JAK kinase activates JAK kinase, and JAK kinase catalyzes the phosphorylation of STAT3 protein (a transcription factor) bound to the receptor. The modified STAT3 protein enters the nucleus in the form of dimer and binds to the targeted gene to promote cell proliferation and differentiation.the level of p-STAT3 (p-tyr705) in lung tissue of mice in sevoflurane anesthesia group was significantly higher than that in propofol group within 3 hours to 1 day after operation. to further confirm the role of IL-6 / JAK / STAT3 signaling pathway in the process of sevoflurane induced tumor metastasis, azd1480, a JAK kinase inhibitor, was introduced into a 4T1 homologous transplantation mouse model. in this animal experiment, mice were given azd1480 or its excipients orally as control on the day of operation, and were administered daily after operation until the end of the experiment. azd1480 significantly reduced the number of lung metastases and the level of p-STAT3 (p-tyr705) in sevoflurane anesthesia group. the tumor microenvironment of lung tissue includes many different stromal cells, among which CD11b + myeloid cells can effectively promote the formation of a microenvironment suitable for cancer cell metastasis. in 4T1 homologous transplantation mice, immunofluorescence staining showed that CD11b + myeloid cells in lung tissue of sevoflurane anesthesia group was significantly higher than that of propofol group within one day after operation. this phenomenon has also been confirmed in MDA-MB-231 xenotransplantation model. in addition, azd1480 can effectively reduce the infiltration of CD11b + myeloid cells into lung tissue. in conclusion, sevoflurane can activate IL-6 / JAK / STAT3 signaling pathway by increasing the expression of IL-6 during surgery, and induce CD11b + myeloid cells to accumulate in lung tissue, thus promoting tumor cell metastasis to the lung. compared with directly acting on tumor cells, anesthetics affect tumor metastasis mainly by changing tumor microenvironment, and this effect is carried out under surgical trauma. different anesthetics have different effects on different types of tumors and even different subtypes of the same kind of tumors, which needs to be further confirmed by prospective clinical studies with a large number of samples. At the same time, animal models are of great benefit to the study of the mechanism of action of narcotic drugs in tumor metastasis, and also provide reference for clinical drug selection, and find potential targets to overcome the side effects of narcotic drugs. original link: plate maker: 11