| Backgrounds: China is the country with the largest number of cancer cases and deaths in the world,and cancer will bring a heavy medical burden to our country.A growing number of studies have found that anesthetic methods and drugs can affect the growth,recurrence and metastasis of tumors.However,there are still many doubts and controversies about the influence and potential mechanisms of opioids on tumor development.Objective: To investigate whether opioids can promote proliferation,invasion and migration of bladder cancer cells,and whether they can promote epithelial-mesenchymal transformation and circulating tumor cell formation of bladder cancer cells,the cellular and animal model levels were studied.Through this study,we further explore whether opioids can accelerate tumor metastasis by promoting epithelial mesenchymal transformation and circulating tumor cell formation of bladder cancer cells.Methods: In part 1,the effect of morphine on the formation of CTCs and metastatic was proved by in situ bladder cancer mouse model,subcutaneous tumor mouse model and hematogenous metastasis mouse model.Different mouse models were performed and treated with morphine or not as protocols.Then,mice were sacrificed at the specified time points,and the whole blood was acquired from the apex of the heart for CTCs detection(except for the hematogenesis metastasis model),and the bladder,lung and liver were taken for statistics of the number of metastasis and metastasis rate.In part 2,the pathway changes of morphine-treated bladder cancer cells were investigated by full transcriptome gene sequencing.Through F actin cytoskeleton protein staining,living cells time-lapse photography,and scanning electron microscopy to prove the morphology change of MB49 and T24 cell;The changes of invasion and migration ability of MB49 and T24 cells were demonstrated by cell scratch-healing experiment,Transwell migration experiment and invasion experiment.Western blotting,QPCR and immunofluorescence staining were used for detecting changes of epithelial molecules(e-cadherin and ck-19),interstitial molecules(n-cadherin,Vimentin)and related transcription factor(Slug)in morphine-treated bladder cancer cells.In part 3,in vitro cell experiments,the expression of Slug gene was inhibited by sh RNA and the morphological changes,invasion and migration ability of cells,and expression of epithelial and interstitial molecules were detected successively.Results: In part 1,The experimental results of subcutaneous tumor model indicated that morphine treatment did not promote tumor growth,but the number of epithelial CTC significantly increased in the morphine treatment group.The results of the in situ bladder cancer model showed that the number of mesenchymal-CTC and lung metastasis increased significantly in morphine-treated mice when compared with the control group.The results of the hematogenous metastasis model suggested that morphine-treated mice developed tumor metastasis earlier and had significantly worse overall survival.In part 2,The results of whole transcriptome gene sequencing indicated that many pathways of cytoskeleton construction,cell invasion and migration and EMT were significantly changed.The results of f-actin skeleton protein staining and other experiments also showed significant morphological changes on the morphine-treated bladder cancer cells.Western blotting,QPCR and immunofluorescence staining also showed significant changes of EMT-related proteins.In part 3,Western blotting results indicated that the PI3K-AKT-Slug signaling pathway was significantly activated in morphine-treated bladder cancer cells,while the EMT process was reversed after Slug gene expression was knocked down,and the cell invasion and migration capacity was significantly decreased as well.Conclusion: Opioid agonists could activate the PI3K/AKT pathway,upregulate the expression of the transcription factor Slug,and promote the EMT process of bladder cancer cells.As a result,tumor cells invaded into the blood and the formation of CTCs increase,and the metastasis of bladder cancer was accelerated.Backgrounds: Tumor recurrence involves multiple causes and anesthesia methods and anesthetics used have drawn much attention recently.Studies have shown that anesthesia choices may influence the prognosis of tumor patients.However,some other studies held the opposite opinion.Whether anesthesia methods affect the prognosis of tumor patients is controversial.Purpose:No data have previously been presented that compare tumor recurrence in patients having thermal ablation(TA)surgery under general anesthesia(GA)or local anesthesia(LA).With the aim of comparing the effects of GA and LA in primary hepatocellular carcinoma(HCC)patients presenting for elective TA surgeries,a multiple center retrospective cohort study was designed and implemented.Methods:Patients who received elective TA surgery under GA or LA from Jan.2014 to Dec.2016 and met the eligibility criteria were included.Survival analysis was used to identify the influence of anesthesia methods on recurrence-free survival(RFS)and overall survival(OS).Propensity score matching(PSM)was used to minimize the bias between the GA group and the LA group.Results:A total of 244 patients with GA and 245 with LA were eligible for analysis.After PSM,178 patients remained in each group.In the matched groups,GA showed a significantly higher recurrence rate compared with LA by both the Kaplan-Meier survival analyses(P=0.011)and multivariable Cox regression analyses(P=0.002).The multivariable Cox regression model also revealed that GA had a hazard ratio(HR)of 1.746(P=0.036)for death compared with the LA group.Conclusion:GA is associated with decreased RFS and OS after surgery compared with LA in HCC patients undergoing TA surgery.Prospective trials exploring the effects of different anesthetic methods on cancer outcome in these patients are warranted. |
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