Background: Surgery plays a significant role in the comprehensive treatment of breast cancer, and opioids are often the first-choice analgesics in the perioperative period. However, recent studies showed that opioids may enhance the angiogenesis of breast cancer and the recurrence and metastasis of tumor cells. Objectives: We aim to investigate the influence of opioids on recurrence and metastasis of breast cancer in nude mice. Methods: Forty female nude mice with breast tumor were randomly divided into 4 groups (n = 10). They were treated with (i) normal saline (10 mL/kg), (ii) morphine (10 mg/kg), (iii) morphine plus naloxone (10 + 4 mg/kg), and (iv) naloxone (4 mg/kg) for 2 weeks. Four groups of MDA-MB-231 cells were administered (i) Dulbecco’s Modified Eagle’s Medium, (ii) morphine (10 μmol/mL), (iii) morphine plus naloxone (10 + 10 μmol/mL), and (iv) naloxone (10 μmol/mL). The influence of morphine in each treated group was evaluated by immunocytochemistry and Western blotting. Results: Mice in the morphine group had higher rates of Ki67-positive cells, lower rates of apoptotic index, and a significant increase in the microvessels density of the tumor as evidenced by CD31 staining (p < 0.05). Furthermore, the MDA-MB-231 cells in the morphine group showed an increase in p-Akt, c-Myc, and thrombosponin-1 expression. Conclusion: In the current study, we found that morphine promotes the angiogenesis of the recurrent postoperative tumors of nude mice with breast cancer and the proliferation of tumor cells and such promotion may be related to the PI3K-c-Myc signaling pathway.

Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, et al. A pooled analysis of bone marrow micrometastasis in breast cancer.
N Engl J Med
. 2005 Aug;353(8):793–802.
Xenidis N, Perraki M, Kafousi M, Apostolaki S, Bolonaki I, Stathopoulou A, et al. Predictive and prognostic value of peripheral blood cytokeratin-19 mRNA-positive cells detected by real-time polymerase chain reaction in node-negative breast cancer patients.
J Clin Oncol
. 2006 Aug;24(23):3756–62.
Banys M, Hartkopf AD, Krawczyk N, Kaiser T, Meier-Stiegen F, Fehm T, et al. Dormancy in breast cancer.
Breast Cancer (Dove Med Press)
. 2012 Dec;4:183–91.
Bovill JG; JG B. Surgery for cancer: does anesthesia matter?
Anesth Analg
. 2010 Jun;110(6):1524–6.
Gottschalk A, Sharma S, Ford J, Durieux ME, Tiouririne M. Review article: the role of the perioperative period in recurrence after cancer surgery.
Anesth Analg
. 2010 Jun;110(6):1636–43.
Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis?
. 2006 Oct;105(4):660–4.
Nguyen J, Luk K, Vang D, Soto W, Vincent L, Robiner S, et al. Morphine stimulates cancer progression and mast cell activation and impairs survival in transgenic mice with breast cancer.
Br J Anaesth
. 2014 Jul;113 Suppl 1:i4–13.
Bimonte S, Barbieri A, Rea D, Palma G, Luciano A, Cuomo A, et al. Morphine Promotes Tumor Angiogenesis and Increases Breast Cancer Progression.
BioMed Res Int
. 2015;2015:161508.
Gupta K, Kshirsagar S, Chang L, Schwartz R, Law PY, Yee D, et al. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth.
Cancer Res
. 2002 Aug;62(15):4491–8.
Kuroki H, Hayashi H, Nakagawa S, Sakamoto K, Higashi T, Nitta H, et al. Effect of LSKL peptide on thrombospondin 1-mediated transforming growth factor β signal activation and liver regeneration after hepatectomy in an experimental model.
Br J Surg
. 2015 Jun;102(7):813–25.
Guba M, Cernaianu G, Koehl G, Geissler EK, Jauch KW, Anthuber M, et al. A primary tumor promotes dormancy of solitary tumor cells before inhibiting angiogenesis.
Cancer Res
. 2001 Jul;61(14):5575–9.
Röcken M. Early tumor dissemination, but late metastasis: insights into tumor dormancy.
J Clin Invest
. 2010 Jun;120(6):1800–3.
Naumov GN, MacDonald IC, Weinmeister PM, Kerkvliet N, Nadkarni KV, Wilson SM, et al. Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy.
Cancer Res
. 2002 Apr;62(7):2162–8.
Naumov GN, Bender E, Zurakowski D, Kang SY, Sampson D, Flynn E, et al. A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype.
J Natl Cancer Inst
. 2006 Mar;98(5):316–25.
Indraccolo S, Favaro E, Amadori A. Dormant tumors awaken by a short-term angiogenic burst: the spike hypothesis.
Cell Cycle
. 2006 Aug;5(16):1751–5.
Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases.
. 2000 Sep;407(6801):249–57.
Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion.
. 2005 May;121(3):335–48.
Indraccolo S, Stievano L, Minuzzo S, Tosello V, Esposito G, Piovan E, et al. Interruption of tumor dormancy by a transient angiogenic burst within the tumor microenvironment.
Proc Natl Acad Sci USA
. 2006 Mar;103(11):4216–21.
Mackey JR, Kerbel RS, Gelmon KA, McLeod DM, Chia SK, Rayson D, et al. Controlling angiogenesis in breast cancer: a systematic review of anti-angiogenic trials.
Cancer Treat Rev
. 2012 Oct;38(6):673–88.
Baba M, Gomyo I. [Case of non-cancer abdominal pain successfully treated by a large amount of oral morphine].
. 2011 Feb;60(2):254–7.
Afsharimani B, Cabot P, Parat MO. Morphine and tumor growth and metastasis.
Cancer Metastasis Rev
. 2011 Jun;30(2):225–38.
Sueoka E, Sueoka N, Kai Y, Okabe S, Suganuma M, Kanematsu K, et al. Anticancer activity of morphine and its synthetic derivative, KT-90, mediated through apoptosis and inhibition of NF-kappaB activation.
Biochem Biophys Res Commun
. 1998 Nov;252(3):566–70.
Sueoka N, Sueoka E, Okabe S, Fujiki H. Anti-cancer effects of morphine through inhibition of tumour necrosis factor-alpha release and mRNA expression.
. 1996 Nov;17(11):2337–41.
Koodie L, Yuan H, Pumper JA, Yu H, Charboneau R, Ramkrishnan S, et al. Morphine inhibits migration of tumor-infiltrating leukocytes and suppresses angiogenesis associated with tumor growth in mice.
Am J Pathol
. 2014 Apr;184(4):1073–84.
Cadet P, Rasmussen M, Zhu W, Tonnesen E, Mantione KJ, Stefano GB. Endogenous morphinergic signaling and tumor growth.
Front Biosci
. 2004 Sep;9(1-3):3176–86.
Balasubramanian S, Ramakrishnan S, Charboneau R, Wang J, Barke RA, Roy S. Morphine sulfate inhibits hypoxia-induced vascular endothelial growth factor expression in endothelial cells and cardiac myocytes.
J Mol Cell Cardiol
. 2001 Dec;33(12):2179–87.
Roy S, Balasubramanian S, Wang J, Chandrashekhar Y, Charboneau R, Barke R. Morphine inhibits VEGF expression in myocardial ischemia.
. 2003 Aug;134(2):336–44.
Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers
. Rockville (MD): US Food and Drug Administration; 2005.
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 Dec;107(6):916–23.
Tsai WB, Aiba I, Long Y, Lin HK, Feun L, Savaraj N, et al. Activation of Ras/PI3K/ERK pathway induces c-Myc stabilization to upregulate argininosuccinate synthetase, leading to arginine deiminase resistance in melanoma cells.
Cancer Res
. 2012 May;72(10):2622–33.
Gomis RR, Gawrzak S. Tumor cell dormancy.
Mol Oncol
. 2017 Jan;11(1):62–78.
Balz LM, Bartkowiak K, Andreas A, Pantel K, Niggemann B, Zänker KS, et al. The interplay of HER2/HER3/PI3K and EGFR/HER2/PLC-γ1 signalling in breast cancer cell migration and dissemination.
J Pathol
. 2012 Jun;227(2):234–44.
Yin D, Woodruff M, Zhang Y, Whaley S, Miao J, Ferslew K, et al. Morphine promotes Jurkat cell apoptosis through pro-apoptotic FADD/P53 and anti-apoptotic PI3K/Akt/NF-kappaB pathways.
J Neuroimmunol
. 2006 May;174(1-2):101–7.
Bentley AA, Adams JC. The evolution of thrombospondins and their ligand-binding activities.
Mol Biol Evol
. 2010 Sep;27(9):2187–97.
Volpert OV, Alani RM. Wiring the angiogenic switch: Ras, Myc, and Thrombospondin-1.
Cancer Cell
. 2003 Mar;3(3):199–200.
Ndishabandi D, Duquette C, Billah GE, Reyes M, Duquette M, Lawler J, et al. Thrombospondin-1 Modulates Actin -Filament Remodeling and Cell Motility in Mouse Mammary Tumor cells in Vitro. 
Discoveries (Craiova)
. 2014 Oct-Dec;2(4):2.
Straume O, Akslen LA. Expresson of vascular endothelial growth factor, its receptors (FLT-1, KDR) and TSP-1 related to microvessel density and patient outcome in vertical growth phase melanomas.
Am J Pathol
. 2001 Jul;159(1):223–35.
Bujak E, Pretto F, Ritz D, Gualandi L, Wulhfard S, Neri D. Monoclonal antibodies to murine thrombospondin-1 and thrombospondin-2 reveal differential expression patterns in cancer and low antigen expression in normal tissues.
Exp Cell Res
. 2014 Sep;327(1):135–45.
Lin XD, Chen SQ, Qi YL, Zhu JW, Tang Y, Lin JY. Overexpression of thrombospondin-1 in stromal myofibroblasts is associated with tumor growth and nodal metastasis in gastric carcinoma.
J Surg Oncol
. 2012 Jul;106(1):94–100.
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