Distinct effects of general anesthetics on lung metastasis mediated by IL-6/JAK/STAT3 pathway in mouse models
Ru Li1, Yujie Huang1,2, Jun Lin3
1Department of Anesthesiology, Stony Brook University Health Science Center, Stony Brook, NY, 11794-8480, USA.
Abstract:
Metastasis can occur following surgical resection of solid tumors and metastasis is the main cause of cancer death. The role of anesthetics used during surgery in cancer metastasis and the underlying mechanism remains largely unknown. Here we show that surgical dissection of primary tumors in mice under anesthesia with sevoflurane leads to significantly more lung metastasis than with propofol in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. Sevoflurane increases the level of serum IL-6, which activates STAT3 and the infiltration of CD11b+ myeloid cells into the lung. Interruption of IL-6/JAK/STAT3 pathway by a JAK inhibitor AZD1480 reverses the pro-metastatic effect of sevoflurane and the associated increase of both activated STAT3 and infiltrated CD11b+ cells in 4T1 model. Our study provides the preclinical evidence informing the distinct effects of anesthetics on metastasis of breast cancers through change of cytokines and the tumor microenvironment.
Insights
Sevoflurane anesthesia increases breast cancer metastasis more than propofol by raising IL-6 levels. Blocking the IL-6/STAT3 pathway reverses this effect, impacting cancer spread.
Area of Science:
- Oncology
- Anesthesiology
- Immunology
Background:
- Cancer metastasis is a primary cause of cancer-related mortality.
- The influence of anesthetic agents on cancer metastasis remains poorly understood.
- Understanding anesthetic effects on metastasis is crucial for improving surgical outcomes.
Purpose of the Study:
- To investigate the differential effects of sevoflurane and propofol on breast cancer metastasis.
- To elucidate the underlying mechanisms by which anesthetics influence cancer spread.
- To evaluate the potential of targeting specific molecular pathways to mitigate anesthetic-induced metastasis.
Main Methods:
- Utilized syngeneic 4T1 and xenograft MDA-MB-231 murine breast cancer models.
- Administered anesthesia using sevoflurane or propofol during surgical tumor resection.
- Measured lung metastasis, serum IL-6 levels, STAT3 activation, and CD11b+ myeloid cell infiltration.
- Investigated the effect of a JAK inhibitor (AZD1480) on sevoflurane-induced pro-metastatic effects.
Main Results:
- Sevoflurane anesthesia significantly increased lung metastasis compared to propofol in both breast cancer models.
- Sevoflurane elevated serum IL-6 levels, promoting STAT3 activation and CD11b+ myeloid cell infiltration in the lungs.
- Inhibition of the IL-6/JAK/STAT3 pathway with AZD1480 reversed the pro-metastatic effects of sevoflurane.
Conclusions:
- Anesthetic choice significantly impacts breast cancer metastasis, with sevoflurane promoting metastasis more than propofol.
- The IL-6/STAT3 signaling pathway and myeloid cell infiltration are key mechanisms mediating sevoflurane's pro-metastatic effects.
- Targeting the IL-6/JAK/STAT3 pathway represents a potential strategy to counteract anesthetic-induced cancer metastasis.
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