Effects of serum from breast cancer surgery patients receiving perioperative dexmedetomidine on breast cancer cell malignancy: A prospective randomized controlled trial

Yan Liu, Jiaxin Sun, Tong Wu, Xiaoying Lu, Yueyao Du, Hongwei Duan, Weifeng Yu, Diansan Su, Jinsong Lu, Jie Tian, Yan Liu, Jiaxin Sun, Tong Wu, Xiaoying Lu, Yueyao Du, Hongwei Duan, Weifeng Yu, Diansan Su, Jinsong Lu, Jie Tian

Abstract

Adrenergic receptors (ARs) have gained attention for their involvement in breast cancer (BC) progression. Dexmedetomidine, a selective α2 -AR agonist, has been reported to increase the malignancy of BC cells in vitro or stimulate tumor growth in mice. However, clinical evidence is lacking. Clinical research in this area is important as dexmedetomidine is widely used in BC surgery patients. Here we allocated 24 women with primary BC to the dexmedetomidine group (who received a total dose of 2 μg kg-1 dexmedetomidine perioperatively) or to the control group (who received the same volume of normal saline). Venous blood was obtained from all patients immediately upon entering the operating room and 24 hours postoperatively. Serum was then exposed to MCF-7 cells at a concentration of 10% for 24 hours. Cell proliferation, migration, and invasion were analyzed using EdU, Transwell, and Matrigel methods, respectively. We found that postoperative serum from those who received dexmedetomidine was associated with significantly increased cell proliferation, migration, and invasion compared with preoperative serum when used to culture MCF-7 cells. The mean percentage change from post to preoperative values in these cell functions was significantly larger in the dexmedetomidine group than in the control group (proliferation, 30.44% vs 8.45%, P = .0024; migration, 15.90% vs 3.25%, P = .0015; invasion, 8.17% vs 2.13%, P = .04). In conclusion, these findings suggest that in patients undergoing surgery for primary BC, perioperative administration of dexmedetomidine might influence the serum milieu in a way that favors the malignancy of MCF-7 cells. Clinical trial registration: NCT03108937.

Keywords: breast cancer; cell malignancy; dexmedetomidine; general anesthesia.

Conflict of interest statement

The authors declare that they have no conflict of interest.

© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Trial flow diagram. A total of 29 patients were recruited and randomized to the control group or Dex group. Twenty‐four patients were finally included in the analysis, 11 in the control group, and 13 in the Dex group
Figure 2
Figure 2
Serum from patients receiving dexmedetomidine increased the proliferation of human MCF‐7 breast cancer cell line. A, Serum from the control group, preoperatively; B, serum from the control group, 24 h postoperatively; C, serum from the Dex group, preoperatively; D, serum from the Dex group, 24 h postoperatively. a, Nuclei were counterstained with Hoechst 33 342 (blue); b, proliferative cells were stained with EdU (green); c, Merge. Original magnification, 100×. E, Graphical representation of EdU positive cell proportion of the four groups. The value obtained with preoperative serum of control patients was considered 1.0, and the ratios relative to this are shown. F, Graphical representation of the mean percentage change from post to preoperative values in EdU positive cells in the Dex group vs the control group. Values were expressed as mean ± SD. n = 11 in the control group. n = 13 in the Dex group. **, P < .01. Dex = dexmedetomidine
Figure 3
Figure 3
Serum from the dexmedetomidine group promoted the migration of human MCF‐7 breast cancer cell line. A, Serum from the control group, preoperatively; B, serum from the control group, 24 h postoperatively; C, serum from the Dex group, preoperatively; D, serum from the Dex group, 24 h postoperatively. Original magnification, 100×. E, Graphical representation of cells migrated to the lower surface of the four groups. The value obtained with preoperative serum of control patients was considered 1.0 and the ratios relative to this are shown. F, Graphical representation of the mean percentage change from post to preoperative values in migrated cell numbers in the Dex group vs the control group. Values were expressed as mean ± SD. n = 11 in the control group. n = 13 in the Dex group. **, P < .01. Dex = dexmedetomidine
Figure 4
Figure 4
Serum from the dexmedetomidine group facilitated the cell invasion of MCF‐7. A, Serum from the control group, preoperatively; B, serum from the control group, 24 h postoperatively; C, serum from the Dex group, preoperatively; D, serum from the Dex group, 24 h postoperatively. Original magnification, 100×. E, Graphical representation of cells that invaded the lower surface of the four groups. The value obtained with preoperative serum of control patients was considered 1.0 and the ratios relative to this are shown. F, Graphical representation of the mean percentage change from post to preoperative values in invaded cell numbers in the Dex group vs the control group. Values were expressed as mean ± SD. n = 11 in the control group. n = 13 in the Dex group. *, P < .05; **, P < .01. Dex = dexmedetomidine

References

    1. McGuire A, Brown J, Malone C, McLaughlin R, Kerin M. Effects of age on the detection and management of breast cancer. Cancers (Basel). 2015;7:908‐929.
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7‐30.
    1. Ferlay J, Colombet M, Soerjomataram I, et al. GLOBOCAN sources and methods. Int J Cancer. 2018;2019(144):1941‐1953.
    1. Vazquez SM, Mladovan AG, Perez C, et al. Human breast cell lines exhibit functional alpha2‐adrenoceptors. Cancer Chemother Pharmacol. 2006;58:50‐61.
    1. Powe DG, Voss MJ, Habashy HO, et al. Alpha‐ and beta‐adrenergic receptor (AR) protein expression is associated with poor clinical outcome in breast cancer: an immunohistochemical study. Breast Cancer Res Treat. 2011;130:457‐463.
    1. Shkurnikov MY, Galatenko VV, Lebedev AE, Podol'skii VE, Tonevitskii EA, Mal'tseva DV. On statistical relationship between ADRA2A expression and the risk of breast cancer relapse. Bull Exp Biol Med. 2014;157:454‐458.
    1. Bruzzone A, Pinero CP, Castillo LF, et al. Alpha2‐adrenoceptor action on cell proliferation and mammary tumour growth in mice. Br J Pharmacol. 2008;155:494‐504.
    1. Bruzzone A, Pinero CP, Rojas P, et al. Alpha(2)‐Adrenoceptors enhance cell proliferation and mammary tumor growth acting through both the stroma and the tumor cells. Curr Cancer Drug Targets. 2011;11:763‐774.
    1. Perez Pinero C, Bruzzone A, Sarappa MG, et al. Involvement of alpha2‐ and beta2‐adrenoceptors on breast cancer cell proliferation and tumour growth regulation. Br J Pharmacol. 2012;166:721‐736.
    1. Chaplin DJ, Durand RE, Olive PL. Cell selection from a murine tumour using the fluorescent probe Hoechst 33342. Br J Cancer. 1985;51:569‐572.
    1. Inada T, Shirane A, Hamano N, Yamada M, Kambara T, Shingu K. Effect of subhypnotic doses of dexmedetomidine on antitumor immunity in mice. Immunopharmacol Immunotoxicol. 2005;27:357‐369.
    1. Xia M, Ji NN, Duan ML, et al. Dexmedetomidine regulate the malignancy of breast cancer cells by activating alpha2‐adrenoceptor/ERK signaling pathway. Eur Rev Med Pharmacol Sci. 2016;20:3500‐3506.
    1. Lambert AW, Pattabiraman DR, Weinberg RA. Emerging biological principles of metastasis. Cell. 2017;168:670‐691.
    1. Virtanen R, Savola J, Saano V, et al. Characterization of the selectivity, specificity and potency of medetomidine as an alpha 2‐adrenoceptor agonist. Eur J Pharmacol. 1988;150:9‐14.
    1. Das R, Das RajatKumar, Sahoo S, Nanda S. Role of dexmedetomidine as an anaesthetic adjuvant in breast cancer surgery as a day‐care procedure: a randomised controlled study. Indian J Anaesth. 2018;62:182‐187.
    1. Fan W, Xue H, Sun Y, et al. Dexmedetomidine improves postoperative patient‐controlled analgesia following radical mastectomy. Front Pharmacol. 2017;8:250.
    1. Szpunar M, Burke K, Dawes R, et al. The antidepressant desipramine and α2‐adrenergic receptor activation promote breast tumor progression in association with altered collagen structure. Cancer Prev Res (Phila). 2013;6:1262‐1272.
    1. Lavon H, Matzner P, Benbenishty A, et al. Dexmedetomidine promotes metastasis in rodent models of breast, lung, and colon cancers. Br J Anaesth. 2018;120:188‐196.
    1. Buggy DJ, Borgeat A, Cata J, et al. Consensus statement from the BJA Workshop on Cancer and Anaesthesia. Br J Anaesth. 2015;114:2‐3.
    1. Cata JuanP, Singh V, Lee BrendaM, et al. Intraoperative use of dexmedetomidine is associated with decreased overall survival after lung cancer surgery. J Anaesthesiol Clin Pharmacol. 2017;33:317‐323.
    1. Xu YJ, Chen WK, Zhu Y, Wang SL, Miao CH. Effect of thoracic epidural anaesthesia on serum vascular endothelial growth factor C and cytokines in patients undergoing anaesthesia and surgery for colon cancer. Br J Anaesth. 2014;113(Suppl 1):i49‐55.
    1. Lim J‐A, Oh C‐S, Yoon T‐G, et al. The effect of propofol and sevoflurane on cancer cell, natural killer cell, and cytotoxic T lymphocyte function in patients undergoing breast cancer surgery: an in vitro analysis. BMC Cancer. 2018;18:159.
    1. Hart CD, Migliaccio I, Malorni L, Guarducci C, Biganzoli L, Di Leo A. Challenges in the management of advanced, ER‐positive, HER2‐negative breast cancer. Nat Rev Clin Oncol. 2015;12:541‐552.
    1. Hanahan D, Weinberg R. Hallmarks of cancer: the next generation. Cell. 2011;144:646‐674.
    1. Friedl P, Wolf K. Tumour‐cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer. 2003;3:362‐374.
    1. Ueshima H, Inada T, Shingu K. Suppression of phagosome proteolysis and Matrigel migration with the α2‐adrenergic receptor agonist dexmedetomidine in murine dendritic cells. Immunopharmacol Immunotoxicol. 2013;35:558‐566.
    1. Chen G, Le Y, Zhou L, et al. Dexmedetomidine inhibits maturation and function of human cord blood‐derived dendritic cells by interfering with synthesis and secretion of IL‐12 and IL‐23. PLoS ONE. 2016;11:e0153288.
    1. Liu Y. Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity. Cell. 2001;106:259‐262.
    1. Spengler R, Allen R, Remick D, et al. Stimulation of alpha‐adrenergic receptor augments the production of macrophage‐derived tumor necrosis factor. J Immunol. 1990;145:1430‐1434.
    1. Weatherby K, Zwilling B, Lafuse W. Resistance of macrophages to Mycobacterium avium is induced by alpha2‐adrenergic stimulation. Infect Immun. 2003;71:22‐29.
    1. Kang B, Lee S, Kim T. Stimulation of interleukin‐12 production in mouse macrophages via activation of p38 mitogen‐activated protein kinase by alpha2‐adrenoceptor agonists. Eur J Pharmacol. 2003;467:223‐231.
    1. Wu R‐C, Wu K‐C, Huang C‐C, et al. Different cellular responses of dexmedetomidine at infected site and peripheral blood of emdotoxemic BALB/c mice. Environ Toxicol. 2015;30:1416‐1422.
    1. Balkwill F, Joffroy C. TNF: a tumor‐suppressing factor or a tumor‐promoting factor? Future Oncol. 2010;6:1833‐1836.
    1. Hamaguchi T, Wakabayashi H, Matsumine A, Sudo A, Uchida A. TNF inhibitor suppresses bone metastasis in a breast cancer cell line. Biochem Biophys Res Commun. 2011;407:525‐530.
    1. Schioppa T, Moore R, Thompson R, et al. B regulatory cells and the tumor‐promoting actions of TNF‐α during squamous carcinogenesis. Proc Natl Acad Sci USA. 2011;108:10662‐10667.
    1. Popa C, Netea M, van Riel P, et al. The role of TNF‐alpha in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. J Lipid Res. 2007;48:751‐762.
    1. Lo H‐M, Lai T‐H, Li C‐H, Wu W‐B. TNF‐α induces CXCL1 chemokine expression and release in human vascular endothelial cells in vitro via two distinct signaling pathways. Acta Pharmacol Sin. 2014;35:339‐350.
    1. Sheng W, Hu S, Ni H, et al. TNF‐alpha‐induced chemokine production and apoptosis in human neural precursor cells. J Leukoc Biol. 2005;78:1233‐1241.
    1. King S. Matrix metalloproteinases: new directions toward inhibition in the fight against cancers. Future Med Chem. 2016;8:297‐309.
    1. Vandooren J, Van den Steen P, Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase‐9 (MMP‐9): the next decade. Crit Rev Biochem Mol Biol. 2013;48:222‐272.
    1. Herrera‐García AM, Domínguez‐Luis MJ, Arce‐Franco M, et al. Prevention of neutrophil extravasation by α2‐adrenoceptor‐mediated endothelial stabilization. J Immunol. 2014;193:3023‐3035.
    1. Sud R, Spengler R, Nader N, et al. Antinociception occurs with a reversal in alpha 2‐adrenoceptor regulation of TNF production by peripheral monocytes/macrophages from pro‐ to anti‐inflammatory. Eur J Pharmacol. 2008;588:217‐231.
    1. Benjamin DJ, Berger JO, Johannesson M, et al. Redefine statistical significance. Nat Hum Behav. 2018;2:6‐10.
    1. The IJ. Proposal to lower P value thresholds to.005. JAMA. 2018;319:1429‐1430.
    1. Wei Y, Chen F. Lowering the P value threshold. JAMA. 2018;320:934‐935.
    1. Hernandez I, Gellad WF, Good CB. Lowering the P value threshold. JAMA. 2018;320:935.

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