4. Discussion
tumor, colorectal cancer, bladder carcinoma, cancer, colon cancer, EV-associated, bladder cancer, colon carcinoma, urinary bladder carcinoma
RECURRENCES, TUMOR, COLORECTAL CANCER, CANCER PROGRESSION, CARCINOGENESIS, RESIDUAL TUMOR, BLADDER CARCINOMA, CANCER, URINARY BLADDER CARCINOMA, COLON CANCER, TUMOR PROGRESSION, BLADDER CANCER, COLON CARCINOMA, METASTASES
EVs are signal mediators involved in numerous processes of carcinogenesis and appear to be differentially affected by anesthetics. For bladder carcinoma patients, anesthetic effects on EVs have not yet been investigated in depth. This work investigated the influence of Propofol and Sevoflurane on EVs and associated miRNA signatures of bladder carcinoma patients undergoing radical cystectomy.We were able to demonstrate an increase in particle size and concentration during surgery with Propofol anesthesia, whereas in the Sevoflurane group, there was only an initial increase and a significant decrease in particle concentration at suture. In agreement with our findings, Buschmann et al. showed a decrease in particle concentration postoperatively in colon cancer patients, although this had only been significant in the Sevoflurane anesthesia patients [It remains to be discussed what influence the increased EV concentrations in the Propofol group of the present study exert on tumor tissue and the development of micrometastases. It has already been shown that incubation of colon carcinoma cells with sera from colon carcinoma patients who received Propofol anesthesia increased the apoptosis rate compared to Sevoflurane anesthesia [Since surgical stress promotes inflammatory and proangiogenic signaling pathways that favor growth and settlement as metastases of residual tumor cells, and EVs are involved in this process [To further analyze the potential role of EVs on tumor progression, EV-dependent miRNAs were subsequently investigated. Buschmann et al. already found in a non-randomized pilot study of colorectal cancer patients that EV-associated miRNAs are differentially regulated depending on the anesthetic regime [Array analyses showed expression of different miRNAs expressed by bladder cancer patients during surgery (To test whether EV-miRNA expression changes during surgery, four specific tumor-associated miRNAs [For miR-451a, Propofol resulted in expression changes after induction of anesthesia while Sevoflurane anesthesia had no effect, although Propofol was used for anesthesia induction in both groups (Overexpression of miR-451a in urinary bladder carcinoma cells showed antiproliferative and invasion inhibitory effects in vitro, suggesting that miR-451a acts as a tumor suppressor for urothelial cells and reduces their cell viability [Additional research of the effects of Propofol on miR-451a in bladder carcinoma cell lines and cell viability will be needed to further elucidate the results. In the future, knowledge of mechanisms of action of anesthetics on tumor-associated miRNAs may provide mechanistic insights into potential anesthetic-dependent outcome differences.If the choice of anesthesia affects tumor-inhibitory signaling pathways in patients that could prevent the development of metastases and recurrences via EVs and associated miRNAs, this possible therapeutic potential should be exploited and explored further. EVs themselves are already being explored as potential drug delivery vehicles for cancer therapy [Our results suggest that an increased concentration of EVs as well as elevated levels of tumor-suppressive miR-451a may be an explanation for reduced tumor cell viability after the use of Propofol. As this study was an observational study, we cannot surely distinguish whether an increased count of extracellular vesicles or the altered miRNA expression itself is responsible for tumor progression. As altered miRNA expression also depends on the amount of circulating EVs, and EVs have been shown to play a crucial role in tumor progression [To elucidate our results further, in vitro and in vivo studies are needed to validate the effect of EVs after Propofol on bladder cancer cells. Additionally, pathway analyses of found miRNAs may give a better explanation of the influence on tumor cell growth.Various interactions between anesthetics and cancer progress through regulation of associated miRNAs and their controlling signaling pathways are already known. While Propofol seems to have antitumor effects and Sevoflurane enhances tumor progress, it is important to mention that effects of anesthetics on cancer progression through miRNA regulation are dependent on cancer cell type. The idea of analyzing miRNA profiles of special miRNA clusters with a bioinformatic pathway analysis may enhance the knowledge of different anesthetics that have been used during surgery [This was a monocenter study in which, despite of randomization, more women were included in the Sevoflurane group than in the Propofol group. Both groups received Propofol for induction of anesthesia, which could possibly influence the effects of Sevoflurane. Therefore, the use of Propofol for induction of anesthesia in the Sevoflurane group may have potentially influenced particle size and concentration at this time point. Since Propofol contains lipids, it could be considered a confounder for particle size and concentration measurements. However, particle sizes of Propofol were shown to be clearly above the size range of exosomes [