Anesthesiology. 2013 Jun 14. [Epub ahead of print]
Isoflurane, a Commonly Used Volatile Anesthetic, Enhances Renal Cancer Growth and Malignant Potential via the Hypoxia-inducible Factor Cellular Signaling Pathway In Vitro.
Benzonana LL, Perry NJ, Watts HR, Yang B, Perry IA, Coombes C, Takata M, Ma D.
Source* Research Fellow, † Foundation Year Doctor, ‡ Postdoctoral Fellow, § Medical Student, ‖ Student, ** Professor, Section of Anesthetics, Pain Medicine, and Intensive Care, Division of Surgery, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom. # Professor, Division of Oncology, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, London, United Kingdom. †† Reader, Section of Anesthetics, Pain Medicine, and Intensive Care, Division of Surgery, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, and Department of Anesthesiology, Hubei University of Medicine, Hubei, China.
Abstract
BACKGROUND:: Growing evidence indicates that perioperative factors, including choice of anesthetic, affect cancer recurrence after surgery although little is known about the effect of anesthetics on cancer cells themselves. Certain anesthetics are known to affect hypoxia cell signaling mechanisms in healthy cells by up-regulating hypoxia-inducible factors (HIFs). HIFs are also heavily implicated in tumorigenesis and high levels correlate with poor prognosis.
METHODS:: Renal cell carcinoma (RCC4) cells were exposed to isoflurane for 2h at various concentrations (0.5-2%). HIF-1α, HIF-2α, phospho-Akt, and vascular endothelial growth factor A levels were measured by immunoblotting at various time points (0-24h). Cell migration was measured across various components of extracellular matrix, and immunocytochemistry was used to analyze proliferation rate and cytoskeletal changes.
RESULTS:: Isoflurane up-regulated levels of HIF-1α and HIF-2α and intensified expression of vascular endothelial growth factor A. Exposed cultures contained significantly more cells (1.81 ± 0.25 vs. 1.00 of control; P = 0.03) and actively proliferating cells (89.4 ± 2.80 vs. 64.74 ± 7.09% of control; P = 0.016) than controls. These effects were abrogated when cells were pretreated with the Akt inhibitor, LY294002. Exposed cells also exhibited greater migration on tissue culture-coated (F = 16.89; P = 0.0008), collagen-coated (F = 20.99; P = 0.0003), and fibronectin-coated wells (F = 8.21; P = 0.011) as along with dramatic cytoskeletal rearrangement, with changes to both filamentous actin and α-tubulin.
CONCLUSIONS:: These results provide evidence that a frequently used anesthetic can exert a protumorigenic effect on a human cancer cell line. This may represent an important contributory factor to high recurrence rates observed after surgery.
PMID:23774231[PubMed - as supplied by publisher]作者: huabin 时间: 2013-8-6 18:23 曲 度:关于这篇文章评论及在DXY网上一位站友的观点
Isoflurane, a Commonly Used Volatile Anesthetic, Enhances Renal Cancer Growth and Malignant Potential via the Hypoxia-inducible Factor Cellular Signaling Pathway In Vitro.
What We Already Know about This Topic
? Hypoxia-inducible factor signaling is heavily implicated in cancer growth
? Enhancing the signaling of these transcription factors may increase metastatic potential
? Whether anesthetics exert promoting effects on cancer cells via modulation of this pathway remains uncertain
What This Article Tells Us That Is New
? Exposure of human renal cancer cells to isoflurane (0.5–2% for 2 h) resulted in up-regulation of levels of hypoxia-inducible factor-1α and -2α along with enhanced cell migration and cytoskeleton rearrangements
? Isoflurane promotes cancer cell growth and migration in vitro and hence enhances malignant potential
Benzonana, Laura L. B.Sc., M.Res., Ph.D. *; Perry, Nicholas J. S. M.B.B.S., B.Sc. +; Watts, Helena R. Ph.D. ++; Yang, Bob B.Sc. ; Perry, Iain A. B.Sc. ||; Coombes, Charles M.B.B.S. #; Takata, Masao M.D., Ph.D. **; Ma, Daqing M.D., Ph.D. ++
Miscellaneous
Background: Growing evidence indicates that perioperative factors, including choice of anesthetic, affect cancer recurrence after surgery although little is known about the effect of anesthetics on cancer cells themselves. Certain anesthetics are known to affect hypoxia cell signaling mechanisms in healthy cells by up-regulating hypoxia-inducible factors (HIFs). HIFs are also heavily implicated in tumorigenesis and high levels correlate with poor prognosis.
Methods: Renal cell carcinoma (RCC4) cells were exposed to isoflurane for 2h at various concentrations (0.5-2%). HIF-1[alpha], HIF-2[alpha], phospho-Akt, and vascular endothelial growth factor A levels were measured by immunoblotting at various time points (0-24h). Cell migration was measured across various components of extracellular matrix, and immunocytochemistry was used to analyze proliferation rate and cytoskeletal changes.
Results: Isoflurane up-regulated levels of HIF-1[alpha] and HIF-2[alpha] and intensified expression of vascular endothelial growth factor A. Exposed cultures contained significantly more cells (1.81 +/- 0.25 vs. 1.00 of control; P = 0.03) and actively proliferating cells (89.4 +/- 2.80 vs. 64.74 +/- 7.09% of control; P = 0.016) than controls. These effects were abrogated when cells were pretreated with the Akt inhibitor, LY294002. Exposed cells also exhibited greater migration on tissue culture-coated (F = 16.89; P = 0.0008), collagen-coated (F = 20.99; P = 0.0003), and fibronectin-coated wells (F = 8.21; P = 0.011) as along with dramatic cytoskeletal rearrangement, with changes to both filamentous actin and [alpha]-tubulin.
Conclusions: These results provide evidence that a frequently used anesthetic can exert a protumorigenic effect on a human cancer cell line. This may represent an important contributory factor to high recurrence rates observed after surgery.
(C) 2013 American Society of Anesthesiologists, Inc.
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Cancer Prognosis : Can Anesthesia Play a Role?
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-----------------------------Collectively, these findings suggest that isoflurane could promote a cellular mechanism (HIFs), which is implicated
in tumorigenesis, and isoflurane might enhance the cellular activities that are associated with a malignant phenotype in
the cells. Note that isoflurane has been shown to induce cell death, rather than increase growth of cells, in other studies.Therefore, as suggested by other studies, it is possible that isoflurane may have a dual effect on cell death, which is dependent on specific cell lines, various treatment time, and different concentrations.16,17
Nevertheless, the well designed and wellperformed study by Dr. Daqing Ma’s group is a timely and welcome startingpoint, grounded in sound and reasoned biochemistry at the cellular level, which could direct and focus the endeavors of much-needed in vivo and clinical follow-up work. The clinical evidence on the subject is limited to small-scale, often
retrospective studies and is, at times, conflicting, with regard to how true or sizeable this concern is or how much of a
difference that an anesthetic technique can make toward a patients’ long-term disease-free survival. Of course, what is
sorely missing at this moment is a good number of randomized controlled trials that have adequate power and followup, but such are the number of variables in the perioperative period and such is the heterogeneity of “cancer” as a disease that accounting for each of these will be a difficult and costly challenge. Basic science studies such as the one by Benzonana et al. published in the current issue of Anesthesiology are essential for more in vitro and in vivo studies with different cancer cell lines and different anesthetics to be launched in this field. The current and future research findings would ultimately help to design clinical trials to explore good anesthetics/ anesthetic technique for cancer patients.
Zhongcong Xie, M.D., Ph.D.,
Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts. [email protected]
英国Chelsea and Westminster 医院一组麻醉师与外科医师在一篇近期发表论文中的观点:
Surgery is of paramount importance in the management of solid tumors as definitive resection can be totally curative.
Nonetheless, metastatic recurrence after surgery remains a major cause of morbidity and mortality. Interest in the impact of the perioperative period on cancer recurrence is now growing rapidly, with recent research suggesting that some anesthetics or anesthetic techniques may influence the pathophysiology of postoperative metastatic spread.
Our review examines the most widely postulated mechanisms for this, including the impact of anesthesia on neuroendocrine and immune function. We also consider evidence for a direct impact on tumor cell signaling pathways based on findings from organ protection research.
These studies have demonstrated that certain volatile anaesthetics confer cytoprotective properties to exposed cells and lead to significant upregulation of Hypoxia Inducible Factor-1α (HIF-1α). This ubiquitous transcription factor exerts many effects in cancer: its activity has been linked with more aggressive phenotypes and poorer clinical prognosis.
It is proposed that such an upregulation of HIFs in tumor cells by these anesthetics may contribute to a tumor's recurrence by stimulating cytoprotective or protumorigenic behavior in residual cells. Conversely, other anesthetic agents appear to downregulate HIFs or cause negligible effect and thus may prove more suitable for use in cancer surgery. As anesthetic drugs are given at a point of potentially high vulnerability in terms of dissemination and establishment of metastases, there is an urgent need to determine the most appropriate anesthetic strategy for surgical oncology so that the optimal techniques are used to maximize long-term survival.作者: huabin 时间: 2013-8-8 15:51
贵坛太麻烦了,同一专业性主题内容,有些贴不审,有些贴不审,让一个主题内容无法连接,无所适从.
能否改进?作者: huabin 时间: 2013-8-15 18:38 曲 度:全身麻醉原罪--某些麻醉剂与措施在临床上有促代谢紊乱效应(该论点支持证据之一)