Sevoflurane depletes macrophages from the melanoma microenvironment

Abstract

BackgroundWith more than 18 million annual new cases, cancer belongs to the major challenges of modern healthcare. Surgical resection of solid tumours under general anaesthesia is the prime therapy. Different aspects of anaesthesia are under discussion to independently influence the long-term outcome of cancer patients. Most recently, the commonly used volatile anaesthetics like sevoflurane have entered the spotlight, as retrospective studies suggest a detrimental outcome in certain cancer aetiologies with sparse mechanistic understanding. Our objective was to investigate this concept in a murine melanoma model, herein comparing the consequence of inhalative and injection anesthesia on tumour composition and growth. MethodsWe used a murine model of malignant melanoma in male, adult C57BL/6 mice (n = 92), induced by the subcutaneous injection of B16-F10 cells. We either exposed the melanoma cells to sevoflurane before implantation or subjected the animals to single or double anaesthesia with either volatile or injection drugs. After a maximum follow-up of 4 weeks, leucocytes within the tumour microenvironment (TME) were comprehensively analysed by flow cytometry with focus on tumor-associated macrophages (TAM). ResultsWe found that exposure of melanoma cells to sevoflurane before implantation induced longlasting transcriptome changes and aggravated tumour growth, without extensive changes of the TME. Contrastingly, both a single and double anaesthesia with sevoflurane led to a significant reduction of TAMs (injection vs. sevoflurane: 2,0 vs. 0.3% and 1.2 vs. 0.6%, respectively), whilst increasing PD-L1 expression on the remaining cells (mean fluorescent intensity injection vs. sevoflurane: 3,804 vs. 7,143 and 9,090 vs. 32,228, respectively). No changes in tumour growth were observed in these groups.

Sevoflurane Induces Ferroptosis of Glioma Cells Through Activating the ATF4-CHAC1 Pathway

“…Sevoflurane (Sev) as a volatile anesthetic which is commonly used in clinical operations has been recently reported to exert antitumor physiologic effects in several tumors, including breast cancer ( 18 ), lung cancer ( 19 ), and colon cancer ( 20 ). Accumulating evidence has indicated that Sev exerts suppressive effects on the proliferation and metastasis of glioma cells in different molecular mechanisms, including suppressing Rac1/paxillin/FAK and Ras/Akt/mTOR in several tumor cells ( 21 ), regulating the ANRIL/let-7b-5p axis ( 22 ), and depleting macrophages from the melanoma microenvironment ( 23 ). Sev could also inhibit glioma cell proliferation and metastasis through the miRNA-124-3p/ROCK1 axis ( 24 ), KCNQ1OT1/miR-146b-5p/STC1 axis ( 25 ), miR-34a-5p/MMP-2 axis ( 26 ), and circ_0002755/miR-628-5p/MAGT1 axis ( 27 ).…”

Effects of propofol on macrophage activation and function in diseases

“…However, the regulation of macrophages by anesthetics is not always beneficial to the body in disease progression. The use of sevoflurane is associated with reduced Tumor-associated macrophages (TAMs) and tumor growth in some cancer models ( Sztwiertnia et al, 2020 ).…”

“…Dexmedetomidine and propofol inhibit the expression of lipopolysaccharide (LPS)-stimulated high mobility group box 1 (HMGB1) in macrophages ( Chang et al, 2013 ; Jia et al, 2017 ). The volatile anesthetic sevoflurane modulates macrophage recruitment, polarization, differentiation, apoptosis and pyroptosis by regulating the caspase-1, reactive oxygen species (ROS), forkhead box O1 (FoxO1), p21, and glycogen synthase kinase-3 (GSK-3β)/nuclear factor-E2-related factor 2 (Nrf2) pathways, which are involved in local immunity and tumor growth ( Jin et al, 2013 ; Fu et al, 2020 ; Sztwiertnia et al, 2020 ; Cai et al, 2021a ). Opioids, such as morphine, also inhibit the phagocytosis of macrophages and are associated with the reduction of macrophage colony-stimulating factor-induced proliferation and differentiation ( Sacerdote et al, 2003 ).…”

Effect of Inhalation Anesthetics on Tumor Metastasis

“…They found isoflurane treatment did not upregulate HIF-1α and HIF-2α expression in RCC4-EV cells under 20% O 2 conditions, and further studies confirmed that isoflurane also did not affect the expression of genes associated with cancer hallmarks. 72 Therefore, the inhibitory effect of isoflurane on tumor angiogenesis still needs to be verified in different tumor types.…”