Can surgery induce cancer recurrence or metastasis? Revisiting the relationship between anesthetic selection and outcomes in cancer surgery

Dear Editor,

The significance of surgery in the management of solid tumours cannot be overstated, as complete resection through surgery has the potential to offer a complete cure. After surgery, there is a notable occurrence of locoregional recurrence and distant metastasis, which pose substantial risks of morbidity and mortality. Surgical procedures and surgical stress may create a permissive environment for tumour growth and recurrence by modulating tumour immunity, shedding of cancer cells into lymphatic and blood circulation (micrometastasis), enhancing cancer cell adhesion in remote organs and activation of inflammatory and neuroendocrine stress pathways¹. For instance, in a well-established animal model examining the impact of surgical stress and metastases, it implicated the suppression of natural killer (NK) cells induced by surgery in the development of postoperative metastases. Approximately 45% of cancer patients undergo surgical procedures to remove the cancerous tumour, and with over 60% of patients require anaesthesia². The pharmacological impact of anaesthesia drugs may inadvertently facilitate disease recurrence or the advancement of metastatic disease. For example, volatile anaesthetics elevates HIF levels in tumour cells contributing to its protumorogenic ability and cytoprotection³. In humans, opioid analgesics inhibited humoral and cellular immune response and in rodents it promoted breast cancer growth. Apart from this, there are subtle differences in anaesthetic agents on its effect on cancer cells. Some promote cancer growth proving to be detrimental and others may be beneficial to patients. Colon cancer surgery shows improved survival rates when utilising propofol-based total intravenous anaesthesia compared to desflurane anaesthesia⁴. However, the molecular mechanisms behind such modulatory role of various anaesthetic agents are yet to be delineated.

In the early immune defence against cancer, NK cells play a vital role whose activation is essential for targeting cancer cells. Inhalational anaesthetics, in specific propofol is known to supress NK cell functions, macrophage recruitment and polarisation, and DC cells activation. In contrast, it promoted NK cell activity in breast cancer patients and enhanced the NK cells activity from colon cancer patients through increased expression of activated p30 and p44 receptors and reduced the inhibitory receptor 158b expression. Similarly, propofol increased Tc cells activity and has shown to inhibit cyclooxygenease-2 and PGE2 levels thereby exerting anti-inflammatory properties⁵. So it is clear that immune cells responsive to various anaesthetics and their functions are greatly altered, which could govern the cancer surgery outcomes.

The next question of is whether anaesthetic agents could alter gene expression in the body? Sakamoto et al.⁶, utilised microarray analysis and identified that inhalational anaesthetics affects the expression of 10 000 genes in various organs. Anaesthetics have the potential to impact cancer surgical outcomes by inducing changes in microRNA (miRNA) expression, which are single-stranded and noncoding RNA molecules consisting of 20–25 nucleotides. These miRNAs play a role in post-transcriptional gene regulation by influencing mRNA degradation and translational repression. The effect of anaesthetics on miRNA expression can have both beneficial and detrimental effects on cancer surgical outcomes. Sevoflurane and propofol was found to alter several miRNA’s and specific expression patterns in the brain, liver and lung. miR-142-3p, miR-29a and miR-378 expression in mice liver including 43 other miRNAs were altered in response to propofol and sevoflurane exposure. Similarly, in mice lung, following sevoflurane exposure the expression pattern of 16 miRNA were altered compared to controls⁶. However, only miRNAs were altered in the hippocampus of the mouse brain following propofol and sevoflurane exposure. Thus, it is clear that anaesthetics alters specific miRNA expression in different organs concluding its signature patterns.

Next, comparing the role of intravenous and inhalational anaesthetics, the latter is known to promote cancer cells proliferation and migration. Glioma stem cells proliferation was promoted and increasing the postsurgical recurrence following sevoflurane exposure, elevated levels of the HIF-1alpha and VEGF expression were found to be behind this role⁷. The growing body of information suggests that anaesthetic drugs may profoundly affect cancer growth by altering miRNAs. These results demonstrate that propofol, the most widely used anaesthetic, affects the expression of miRNAs important in regulating signalling pathways including AKT, Wnt/-catenin, NF-KB and MMPs in various tumours, hence preventing the growth of these malignancies. Additionally, several studies have shown that FOX proteins (FOXM1 and FOXO1/3) are the unique target of miRNAs modulated by propofol in lung cancer⁸. In contrast, propofol suppresses the growth, migration and invasiveness of hepatocarcinoma cells while facilitating programmed cell death by reducing the levels of miR-374a. It also inhibited NF-kB pathways and reduced MMP levels in breast cancer. Propofol upregulated miR-218 expression in gastric cancer and miR-451 in glioblastoma there by inhibiting cell proliferation and apoptosis induction⁹. Sevoflurane promoted miR-203 expression in breast cancer and exerted antiproliferative role. Therefore, it is clear that anaesthetics exert anti-cancer and procancerous effects based on the cancer type by regulating various miRNAs.

Overall, only limited studies are available in relating the role of anaesthetics and cancer surgery outcomes. In-depth molecular mechanisms and clinical relevance is still at infancy. Therefore, further studies are essential to integrate the choice of anaesthetics for specific cancer surgeries. The following are the possible questions that could be answered to bridge the gap between choice of anaesthesia and surgical outcomes.

1. What type of cancer cells are regulated (inhibited/promoted) by various commonly used anaesthetics?

2. Whether the type of anaesthetics regulated immune cell functions in governing its antitumor functions?

3. Which mode of anaesthetics is preferable for surgeries to excise various types of cancer?

4. What are the molecular mechanisms including miRNA’s role in regulating the pro and antitumor roles of anaesthetics?

The answer to these questions will provide us a standard guidelines in selecting anaesthetics to improve clinical outcomes following cancer surgeries and supportive molecular therapeutics (miRNA mimics/inhibitors) that could be provided during peri and postoperative period. In conclusion, it is important for anaesthesiologists to stay updated with the latest research and guidelines regarding the indirect role of anaesthesia in cancer recurrence. By being aware of these factors, anaesthesiologists can contribute to optimising patient outcomes and reducing the potential for cancer recurrence or metastasis after surgery.

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No funding was supported.

Author contribution

S.S., S.V., D.G., and R.S. devised the concept, performed the literature search and draughted the letter.

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No conflict of interest.

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The submission is a correspondence. No new study was performed. All authors accept full responsibility for the submitted letter.

Data statement

The correspondence is based exclusively on resources that are publicly available on the internet and duly cited in the ‘References’ section.

No primary data was generated and reported in this manuscript. Therefore, data has not become available to any academic repository.