Anesthesia for Treating Neurological Tumors

For patients with excisable neurological tumors, surgery is often the first line of treatment. However, the perioperative period may present events which can influence cancer recurrence or worsen side effects. There is a growing recognition of the potential impact of anesthesia on neurological tumors, malignancies in general, and cancer progression [1]. Theoretically, all anesthetics affect immune system response by depressing bone marrow activity, altering phagocytosis and ultimately inducing immunosuppression. These effects, while different for each anesthetic agent, will also be variable for tumor type [2]. Additionally, preconditioning with xenon is shown to upregulate cellular signaling pathways, importantly, the hypoxia-inducing factor (HIF) pathway [3].

HIFs are transcription factors that influence the expression of genes important to aspects of cancer progression, including cell proliferation. High HIF levels have been repeatedly linked to tumorigenesis and treatment resistance against radiation and chemotherapy [1]. Using renal carcinoma cell cultures, researchers found the volatile anesthetic isoflurane induces HIF expression in both time- and dose-dependent measures. The in vitro assessment found significant increases in HIF-1α protein levels at 4, 8 (highest difference with the strongest significance), and 24 hours postexposure, but not at 0 or 2 hours, suggesting an optimal time frame for the effect of isoflurane. Dose-dependent up-regulation of HIF levels differed for HIF-1α and HIF-2α, with significant increases in cultures dosed with higher isoflurane concentrations (2%) for the former but not the latter [1]. In all samples, evidence was found of increased cellular proliferation, cytoskeletal rearrangement, and higher levels of the proangiogenic vascular endothelial growth factor A, a gene known to increase cellular migration and invasion into the surrounding tissue [4]. In addition, exposure of human glioblastoma stem cells (stem cells from an aggressive type of neurological tumor) to clinically relevant levels of isoflurane (1.5 or 2%) resulted in increased proliferation and decreased apoptosis, as well as increased migratory capacity both in vitro and in vivo, perhaps due to isoflurane’s ability to increase HIF expression [5].

Certain intravenous agents such as propofol have shown tumor-suppressive effects in various types of cancer cells, including human glioma cells. MicroRNAs (miRNA) are a class of small, noncoding RNAs, of which miRNA-218 has been linked to cancer cell survival. When abundant, they down-regulate matrix mellanoproteinase-2 (MMP-2), a molecule with the ability to degrade extracellular matrices and also heavily expressed in human glioma, a neurological tumor originating from non-neuronal cells [6]. In U373 human glioma cells, propofol stimulated the expression of miRNA-218, preventing proliferation and invasion, while also inducing cell apoptosis [6]. It is also suggested propofol’s anti-tumor effects are due to its mediating effect on increased nuclear factor-kappa В (NF-κВ), a chief transcription factor known to regulate vital processes such as cell proliferation, inflammatory responses, metastasis, and angiogenesis. Fischer rats injected with 9L gliosarcoma cells and later with a mixture of genistein (a phytochemical frequently found in leguminous plants) and propofol showed improved tumor survival time [7].

A key benefit of propofol’s effects on cancer progression is its degree of specificity, shown by its ability to induce cell cycle arrest in the G2/M phase in human glioblastoma cells but not healthy astrocytes. Reactive oxygen species (ROS) signaling pathways often play a critical role in current cancer treatments which aim to induce cytotoxicity in tumor cells. After propofol administration, ROS intracellular levels are increased in the 8401 glioblastoma cell line but were preserved in normal astrocytes [8].

A systematic review shows patients undergoing an awake craniotomy to remove tumors had shorter postoperative hospital stays and fewer neurological impairments than patients undergoing a traditional craniotomy with general anesthesia [9]. While more research is being done on the long-term outcome comparison of awake and conventional surgical methods for neurological tumors, assessing the anesthesia approach that creates the lowest degree of harm and the highest degree of benefit is crucial.

References

1. Benzonana, L. L., Perry, N. J., Watts, H. R., Yang, B., Perry, I. A., Coombes, C., … & Ma, D. (2013). Isoflurane, a commonly used volatile anesthetic, enhances renal cancer growth and malignant potential via the hypoxia-inducible factor cellular signaling pathway in vitro. Anesthesiology, 119(3), 593-605. https://doi.org/10.1097/ALN.0b013e31829e47fd
2. Lin, L., Liu, C., Tan, H., Ouyang, H., Zhang, Y., & Zeng, W. (2011). Anaesthetic technique may affect prognosis for ovarian serous adenocarcinoma: a retrospective analysis. British journal of anaesthesia, 106(6), 814-822. https://doi.org/10.1093/bja/aer055
3. Ma, D., Lim, T., Xu, J., Tang, H., Wan, Y., Zhao, H., … & Maze, M. (2009). Xenon preconditioning protects against renal ischemic-reperfusion injury via HIF-1α activation. Journal of the American Society of Nephrology, 20(4), 713-720. https://doi.org/10.1681/ASN.2008070712
4. Claesson‐Welsh, L., & Welsh, M. (2013). VEGFA and tumour angiogenesis. Journal of internal medicine, 273(2), 114-127. https://doi.org/10.1111/joim.12019
5. Zhu, M., Li, M., Zhou, Y., Dangelmajer, S., Kahlert, U. D., Xie, R., … & Lei, T. (2016). Isoflurane enhances the malignant potential of glioblastoma stem cells by promoting their viability, mobility in vitro and migratory capacity in vivo. British journal of anaesthesia, 116(6), 870-877. https://doi.org/10.1093/bja/aew124
6. Xu, J., Xu, W., & Zhu, J. (2015). Propofol suppresses proliferation and invasion of glioma cells by upregulating microRNA-218 expression. Molecular medicine reports, 12(4), 4815-4820. https://doi.org/10.3892/mmr.2015.4014
7. Zheng, Y., Liu, H., & Liang, Y. (2017). Genistein exerts potent antitumour effects alongside anaesthetic, propofol, by suppressing cell proliferation and nuclear factor-κB-mediated signalling and through upregulating microRNA-218 expression in an intracranial rat brain tumour model. Journal of Pharmacy and Pharmacology, 69(11), 1565-1577. https://doi.org/10.1111/jphp.12781
8. Hsu, S. S., Jan, C. R., & Liang, W. Z. (2017). Evaluation of cytotoxicity of propofol and its related mechanism in glioblastoma cells and astrocytes. Environmental toxicology, 32(12), 2440-2454. https://doi.org/10.1002/tox.22458
9. Brown, T., Shah, A. H., Bregy, A., Shah, N. H., Thambuswamy, M., Barbarite, E., … & Komotar, R. J. (2013). Awake craniotomy for brain tumor resection: the rule rather than the exception?. Journal of neurosurgical anesthesiology, 25(3), 240-247. https://doi.org/10.1097/ANA.0b013e318290c230