The effect of anesthetic technique on µ-opioid receptor expression and immune cell infiltration in breast cancer

Kirk J Levins, S Prendeville, S Conlon, D J Buggy, Kirk J Levins, S Prendeville, S Conlon, D J Buggy

Abstract

Background: Clinical histological studies demonstrate that the distribution of natural killer (NK) cells, other immune cells and μ-opioid receptors (MOR) within cancer tissue can predict cancer prognosis. No clinical study has evaluated whether anesthetic technique influences immune cell and MOR expression within human breast cancer.

Methods: Excised preoperative biopsies and intraoperative breast cancer specimens from 20 patients randomly chosen from patients previously enrolled in an ongoing, prospective, randomized trial (NCT00418457) investigating the effect of anesthetic technique on long-term breast cancer outcome were immunohistochemically stained and microscopically examined by two independent investigators, masked to randomization, to quantify MOR and immune cell infiltration: CD56, CD57 (NK cells), CD4 (T helper cells), CD8 (cytotoxic T cells) and CD68 (macrophages). Patients had been randomized to receive either a propofol-paravertebral anesthetic with continuing analgesia (PPA, n = 10) or balanced general anesthetic with opioid analgesia (GA, n = 10).

Results: There were no differences between the groups in staining intensity in preoperative biopsy specimens. Expression intensity values (median 25-75%) for MOR in intraoperative resected biopsy were higher in GA 8.5 (3-17) versus PPA 1 (0-10), p = 0.04. The numbers of MOR-positive cells were also higher in GA patients. Expression and absolute numbers of CD56, CD57, CD4 and CD68 were similar in resected tumor in both groups.

Conclusion: General anesthesia with opioid analgesia increased resected tumor MOR expression compared with propofol-paravertebral anesthetic technique, but the anesthetic technique did not significantly influence the expression of immune cell markers.

Keywords: Anesthesia; Breast cancer metastasis; Cancer; Regional anesthesia; µ-Opioid receptor in cancer.

References

    1. Neeman E, Ben-Eliyahu S. The perioperative period and promotion of cancer metastasis: New outlooks on mediating mechanisms and immune involvement. Brain Behav Immun. 2013;30(Suppl):32–40. doi: 10.1016/j.bbi.2012.03.006.
    1. Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology. 2006;105(4):660–664. doi: 10.1097/00000542-200610000-00008.
    1. Singleton PA, Mirzapoiazova T, Hasina R, Salgia R, Moss J. Increased µ-opioid receptor expression in metastatic lung cancer Br. J Anaesth. 2014;113(suppl 1):i103–i108. doi: 10.1093/bja/aeu165.
    1. Zylla D, Gourley BL, Vang D, Jackson S, Boatman S, Lindgren B, Kuskowski MA, Le C, Gupta K, Gupta P. Opioid requirement, opioid receptor expression, and clinical outcomes in patients with advanced prostate cancer. Cancer. 2013;119(23):4103–4110. doi: 10.1002/cncr.28345.
    1. Yao YS, Yao RY, Zhuang LK, Qi WW, Lv J, Zhou F, Qiu WS, Lu Y. MOR1 expression in gastric cancer: a biomarker associated with poor outcome. Clin Transl Sci. 2015;8(2):137–142. doi: 10.1111/cts.12246.
    1. Schlagenhauff B, Ellwanger U, Breuninger H, Stroebel W, Rassner G, Garbe C. Prognostic impact of the type of anesthesia used during the excision of primary cutaneous melanoma. Melanoma Res. 2000;10:165–169. doi: 10.1097/00008390-200004000-00009.
    1. Boehncke S, Hardt K, Schadendorf D, Henschler R, Boehncke WH, Duthey B. Endogenous µ-opioid peptides modulate immune responsetowards malignant melanoma. Exp Dermatol. 2011;20:24–28. doi: 10.1111/j.1600-0625.2010.01158.x.
    1. Frances E, Lennon PhD, Mirzapoiazova T, Mambetsariev B, Salgia R, Moss J, Singleton PA. Overexpression of the µ-opioid receptor in human non-small cell lung cancer promotes Akt and mTOR activation, tumor growth, and metastasis. Anesthesiology. 2012;116(4):857–867. doi: 10.1097/ALN.0b013e31824.
    1. Singleton PA, Lingen MW, Fekete MJ, Garcia JG, Moss J. Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: Role of receptor transactivation. Microvasc Res. 2006;72:3–11. doi: 10.1016/j.mvr.2006.04.004.
    1. Dushyanthen S, Beavis PA, Savas P, Teo ZL, Zhou C, Mansour M, Phillip KD, Loi S. Relevance of tumor-infiltrating lymphocytes in breast cancer. BMC Med. 2015;13:202. doi: 10.1186/s12916-015-0431-3.
    1. Geng Y, Shao Y, He W, Hu W, Xu Y, Chen J, Wu C, Jiang J. Prognostic role of tumor-infiltrating lymphocytes in lung cancer: a meta-analysis. Cell Physiol Biochem. 2015;37:1560–1571. doi: 10.1159/000438523.
    1. Ishigami S, Natsugoe S, Uenosono Y, Hata Y, Nakajo A, Miyazono F, Matsumoto M, Hokita S, Aikou T. Infiltration of antitumor immunocytes into the sentinel node in gastric cancer. J Gastrointest Surg. 2003;7:735. doi: 10.1016/S1091-255X(03)00076-3.
    1. Zlobec I, Lugli A. Invasive front of colorectal cancer: dynamic interface of pro-/anti-tumor factors. World J Gastroenterol. 2009;15(47):5898–5906. doi: 10.3748/wjg.15.5898.
    1. Fiona Desmond J, McCormack N, Mulligan M, Stokes, Donal JB. Effect of anesthetic technique on immune cell infiltrationin breast cancer: a follow-up pilot analysis of a prospective, randomised, investigator-masked study. Anticancer Res. 2015;35(3):1311–1319.
    1. Desmond F, McCormack J, Mulligan N, Stokes M, Buggy DJ. Effect of anesthetic technique on immune cell infiltration in breast cancer: a follow-up pilot analysis of a prospective, randomised, investigator-masked study. Anticancer Res. 2015;35(3):1311–1319.
    1. Shavit Y, Martin FC, Yirmiya R, Ben-Eliyahu S, Terman GW, Weiner H, Gale RP, Liebeskind JC. Effects of a single administration of morphine or footshock stress on natural killer cell cytotoxicity. Brain Behav Immun. 1987;1:318–328. doi: 10.1016/0889-1591(87)90034-1.
    1. Schäfer M, Shaaban A, Mousa Opioid therapy and tumorprogression. Adv Pall Med. 2009;8(2):53–56.
    1. Carr DJJ, Scott M, Brockunier LL, Bagely JR, France CP. The effect of novel opioids on natural killer activity and tumor surveillance in vivo. In: Friedman H, Eisenstein TK, Madden J, Sharp BM, editors. AIDS, drugs of abuse, and the neuroimmune axis. Advances in Experimental Medicine and Biology. Boston: Springer; 1996.
    1. Lennon FE, Mirzapoiazova T, Mambetsariev B, Salgia R, Moss J, Singleton PA. Overexpression of the µ-opioid receptor in human non-small cell lung cancer promotes Akt and mTOR activation, tumor growth, and metastasis. Anesthesiology. 2012;116:857–867. doi: 10.1097/ALN.0b013e31824babe2.
    1. Gach K, Piestrzeniewicz M, Fichna J, Stefanska B, Szemraj J, Janecka A. Opioid-induced regulation of µ-opioid receptor gene expression in the MCF-7 breast cancer cell line. Biochem Cell Biol. 2008;86:217–226. doi: 10.1139/O08-001.
    1. Zylla D, Gourley BL, Vang D, Jackson S, Boatman S, Lindgren B, et al. Opioid requirement, opioid receptor expression, and clinical outcomes in patients with advanced prostate cancer. Cancer. 2013;119:4103–4110. doi: 10.1002/cncr.28345.
    1. Ecimovic P, Murray D, Doran P, McDonald J, Lambert DG, Buggy DJ. Direct effect of morphine on breast cancer cell function in vitro: role of the NET1 gene. Br J Anaesth. 2011;107(6):916–923. doi: 10.1093/bja/aer259.
    1. Conrick-Martin I, Kell MR, Buggy DJ. Meta-analysis of the effect of central neuraxial regional anesthesia compared with general anesthesia on postoperative natural killer T lymphocyte function. J Clin Anesth. 2012;24:324. doi: 10.1016/j.jclinane.2011.09.001.
    1. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008;9(5):503–510. doi: 10.1038/ni1582.
    1. Anfossi N, André P, Guia S, Falk CS, Roetynck S, Stewart CA, Breso V, Frassati C, Reviron D, Middleton D, Romagné F, Ugolini S, Vivier E. Human NK cell education by inhibitory receptors for MHC class I. Immunity. 2006;25:331–342. doi: 10.1016/j.immuni.2006.06.013.

Source: PubMed

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