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Morphine and tumor growth and metastasis

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Abstract

Morphine is an analgesic widely used to alleviate cancer pain. In addition, the perioperative management of pain in cancer surgery patients most often includes opioids. However, there are reports that these drugs may alter cancer recurrence or metastasis. Several mechanisms have been proposed, such as the modulation of the immune response or cellular pathways that control the survival and migratory behavior of cancer cells. The published literature, however, presents some discrepancies, with reports suggesting that opioids may either promote or prevent the spread of cancer. It is of great importance to determine whether opioids, in particular the most widely used, morphine, may increase the risk of metastasis when used in cancer surgery. This review examines the available data on the effects of morphine which influence cancer metastasis or recurrence, including immunomodulation, tumor cell aggressiveness, and angiogenesis, with special emphasis on recently published clinical and laboratory based studies. We further discuss the parameters that may explain the difference between reports on the effects of morphine on cancer.

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References

  1. Sobel, H., & Bonorris, G. (1962). Effect of morphine on rats bearing Walker carcinosarcoma 256. Nature, 196, 896–897.

    PubMed  CAS  Google Scholar 

  2. Kerros, C., Cavey, T., Sola, B., Jauzac, P., & Allouche, S. (2009). Somatostatin and opioid receptors do not regulate proliferation or apoptosis of the human multiple myeloma U266 cells. Journal of Experimental and Clinical Cancer Research, 28, 77.

    Google Scholar 

  3. Biji, M., Lennon, F., Siegler, J., Mirzapoiazova, T., Mambetsariev, N., Sammani, S. et al. (2011). The novel role of the mu opioid receptor in lung cancer progression: A laboratory investigation. Anesthesia and Analgesia (in press).

  4. Nylund, G., Pettersson, A., Bengtsson, C., Khorram-Manesh, A., Nordgren, S., & Delbro, D. S. (2008). Functional expression of mu-opioid receptors in the human colon cancer cell line, HT-29, and their localization in human colon. Digestive Diseases and Sciences, 53(2), 461–466.

    PubMed  CAS  Google Scholar 

  5. Maneckjee, R., & Minna, J. D. (1990). Opioid and nicotine receptors affect growth regulation of human lung cancer cell lines. Proceedings of the National Academy of Sciences of the United States of America, 87(9), 3294–3298.

    PubMed  CAS  Google Scholar 

  6. Hatzoglou, A., Bakogeorgou, E., & Castanas, E. (1996). The antiproliferative effect of opioid receptor agonists on the T47D human breast cancer cell line, is partially mediated through opioid receptors. European Journal of Pharmacology, 296(2), 199–207.

    PubMed  CAS  Google Scholar 

  7. Kampa, M., Bakogeorgou, E., Hatzoglou, A., Damianaki, A., Martin, P. M., & Castanas, E. (1997). Opioid alkaloids and casomorphin peptides decrease the proliferation of prostatic cancer cell lines (LNCaP, PC3 and DU145) through a partial interaction with opioid receptors. European Journal of Pharmacology, 335(2–3), 255–265.

    PubMed  CAS  Google Scholar 

  8. Fichna, J., Krajewska, U., Rozalski, M., Mirowski, M., & Janecka, A. (2005). Characterization of the [125I]endomorphin-2 binding sites in the MCF7 breast cancer cell line. Peptides, 26(2), 295–299.

    PubMed  CAS  Google Scholar 

  9. Yin, D., Woodruff, M., Zhang, Y., Whaley, S., Miao, J., Ferslew, K., et al. (2006). Morphine promotes Jurkat cell apoptosis through pro-apoptotic FADD/P53 and anti-apoptotic PI3K/Akt/NF-kappaB pathways. Journal of Neuroimmunology, 174(1–2), 101–107.

    PubMed  CAS  Google Scholar 

  10. Zhao, M., Zhou, G., Zhang, Y., Chen, T., Sun, X., Stuart, C., et al. (2009). Beta-arrestin2 inhibits opioid-induced breast cancer cell death through Akt and caspase-8 pathways. Neoplasma, 56(2), 108–113.

    PubMed  CAS  Google Scholar 

  11. Lin, X., Wang, Y. J., Li, Q., Hou, Y. Y., Hong, M. H., Cao, Y. L., et al. (2009). Chronic high-dose morphine treatment promotes SH-SY5Y cell apoptosis via c-Jun N-terminal kinase-mediated activation of mitochondria-dependent pathway. The FEBS Journal, 276(7), 2022–2036.

    PubMed  CAS  Google Scholar 

  12. Zagon, I. S., & McLaughlin, P. J. (2003). Opioids and the apoptotic pathway in human cancer cells. Neuropeptides, 37(2), 79–88.

    PubMed  CAS  Google Scholar 

  13. Cadet, P., Rasmussen, M., Zhu, W., Tonnesen, E., Mantione, K. J., & Stefano, G. B. (2004). Endogenous morphinergic signaling and tumor growth. Frontier in Bioscience, 9, 3176–3186.

    CAS  Google Scholar 

  14. Tegeder, I., Grosch, S., Schmidtko, A., Haussler, A., Schmidt, H., Niederberger, E., et al. (2003). G protein-independent G1 cell cycle block and apoptosis with morphine in adenocarcinoma cells: Involvement of p53 phosphorylation. Cancer Research, 63(8), 1846–1852.

    PubMed  CAS  Google Scholar 

  15. Hatzoglou, A., Ouafik, L., Bakogeorgou, E., Thermos, K., & Castanas, E. (1995). Morphine cross-reacts with somatostatin receptor SSTR2 in the T47D human breast cancer cell line and decreases cell growth. Cancer Research, 55(23), 5632–5636.

    PubMed  CAS  Google Scholar 

  16. Maneckjee, R., Biswas, R., & Vonderhaar, B. K. (1990). Binding of opioids to human MCF-7 breast cancer cells and their effects on growth. Cancer Research, 50(8), 2234–2238.

    PubMed  CAS  Google Scholar 

  17. Panagiotou, S., Bakogeorgou, E., Papakonstanti, E., Hatzoglou, A., Wallet, F., Dussert, C., et al. (1999). Opioid agonists modify breast cancer cell proliferation by blocking cells to the G2/M phase of the cycle: Involvement of cytoskeletal elements. Journal of Cellular Biochemistry, 73(2), 204–211.

    PubMed  CAS  Google Scholar 

  18. Sueoka, E., Sueoka, N., Kai, Y., Okabe, S., Suganuma, M., Kanematsu, K., et al. (1998). Anticancer activity of morphine and its synthetic derivative, KT-90, mediated through apoptosis and inhibition of NF-kappaB activation. Biochemical and Biophysical Research Communications, 252(3), 566–570.

    PubMed  CAS  Google Scholar 

  19. Sueoka, N., Sueoka, E., Okabe, S., & Fujiki, H. (1996). Anti-cancer effects of morphine through inhibition of tumour necrosis factor-alpha release and mRNA expression. Carcinogenesis, 17(11), 2337–2341.

    PubMed  CAS  Google Scholar 

  20. Iglesias, M., Segura, M. F., Comella, J. X., & Olmos, G. (2003). [mu]-Opioid receptor activation prevents apoptosis following serum withdrawal in differentiated SH-SY5Y cells and cortical neurons via phosphatidylinositol 3-kinase. Neuropharmacology, 44(4), 482–492.

    PubMed  CAS  Google Scholar 

  21. Lin, X., Li, Q., Wang, Y. J., Ju, Y. W., Chi, Z. Q., Wang, M. W., et al. (2007). Morphine inhibits doxorubicin-induced reactive oxygen species generation and nuclear factor κB transcriptional activation in neuroblastoma SH-SY5Y cells. The Biochemical Journal, 406(2), 215–221.

    PubMed  CAS  Google Scholar 

  22. Sergeeva, M. G., Grishina, Z. V., & Varfolomeyev, S. D. (1993). Morphine effect on proliferation of normal and tumor cells of immune origin. Immunology Letters, 36(2), 215–218.

    PubMed  CAS  Google Scholar 

  23. Debruyne, D. J., Mareel, M. M., & Bracke, M. E. (2010). Opioids affect focal contact-mediated cell-substrate adhesion. European Journal of Cancer Prevention, 19(3), 227–238.

    PubMed  CAS  Google Scholar 

  24. Harimaya, Y., Koizumi, K., Andoh, T., Nojima, H., Kuraishi, Y., & Saiki, I. (2002). Potential ability of morphine to inhibit the adhesion, invasion and metastasis of metastatic colon 26-L5 carcinoma cells. Cancer Letters, 187(1–2), 121–127.

    PubMed  CAS  Google Scholar 

  25. Horvath, R. J., & DeLeo, J. A. (2009). Morphine enhances microglial migration through modulation of P2X4 receptor signaling. The Journal of Neuroscience, 29(4), 998–1005.

    PubMed  CAS  Google Scholar 

  26. Zagon, I. S., Rahn, K. A., & McLaughlin, P. J. (2007). Opioids and migration, chemotaxis, invasion, and adhesion of human cancer cells. Neuropeptides, 41(6), 441–452.

    PubMed  CAS  Google Scholar 

  27. Gach, K., Szemraj, J., Wyrebska, A., & Janecka, A. (2011). The influence of opioids on matrix metalloproteinase-2 and -9 secretion and mRNA levels in MCF-7 breast cancer cell line. Molecular Biology Reports (in press).

  28. Gach, K., Szemraj, J., Fichna, J., Piestrzeniewicz, M., Delbro, D. S., & Janecka, A. (2009). The influence of opioids on urokinase plasminogen activator on protein and mRNA level in MCF-7 breast cancer cell line. Chemical Biology & Drug Design, 74(4), 390–396.

    CAS  Google Scholar 

  29. Dunn, G. P., Old, L. J., & Schreiber, R. D. (2004). The immunobiology of cancer immunosurveillance and immunoediting. Immunity, 21(2), 137–148.

    PubMed  CAS  Google Scholar 

  30. Grivennikov, S. I., Greten, F. R., & Karin, M. (2010). Immunity, inflammation, and cancer. Cell, 140(6), 883–899.

    PubMed  CAS  Google Scholar 

  31. Bindea, G., Mlecnik, B., Fridman, W. H., Pages, F., & Galon, J. (2010). Natural immunity to cancer in humans. Current Opinion in Immunology, 22(2), 215–222.

    PubMed  CAS  Google Scholar 

  32. McCarthy, L., Wetzel, M., Sliker, J. K., Eisenstein, T. K., & Rogers, T. J. (2001). Opioids, opioid receptors, and the immune response. Drug and Alcohol Dependence, 62(2), 111–123.

    PubMed  CAS  Google Scholar 

  33. Vallejo, R., de Leon-Casasola, O., & Benyamin, R. (2004). Opioid therapy and immunosuppression: A review. American Journal of Therapeutics, 11(5), 354–365.

    PubMed  Google Scholar 

  34. Roy, S., Wang, J., Kelschenbach, J., Koodie, L., & Martin, J. (2006). Modulation of immune function by morphine: Implications for susceptibility to infection. Journal of Neuroimmune Pharmacology, 1(1), 77–89.

    PubMed  Google Scholar 

  35. Sacerdote, P., Bianchi, M., Gaspani, L., Manfredi, B., Maucione, A., Terno, G., et al. (2000). The effects of tramadol and morphine on immune responses and pain after surgery in cancer patients. Anesthesia and Analgesia, 90(6), 1411–1414.

    PubMed  CAS  Google Scholar 

  36. Sacerdote, P. (2008). Opioid-induced immunosuppression. Current Opinion in Supportive and Palliative Care, 2(1), 14–18.

    PubMed  Google Scholar 

  37. Beilin, B., Shavit, Y., Hart, J., Mordashov, B., Cohn, S., Notti, I., et al. (1996). Effects of anesthesia based on large versus small doses of fentanyl on natural killer cell cytotoxicity in the perioperative period. Anesthesia and Analgesia, 82(3), 492–497.

    PubMed  CAS  Google Scholar 

  38. Shavit, Y., Ben-Eliyahu, S., Zeidel, A., & Beilin, B. (2004). Effects of fentanyl on natural killer cell activity and on resistance to tumor metastasis in rats. Dose and timing study. Neuroimmunomodulation, 11(4), 255–260.

    PubMed  CAS  Google Scholar 

  39. Franchi, S., Panerai, A. E., & Sacerdote, P. (2007). Buprenorphine ameliorates the effect of surgery on hypothalamus–pituitary–adrenal axis, natural killer cell activity and metastatic colonization in rats in comparison with morphine or fentanyl treatment. Brain, Behavior, and Immunity, 21(6), 767–774.

    PubMed  CAS  Google Scholar 

  40. Rahim, R. T., Meissler, J. J., Jr., Cowan, A., Rogers, T. J., Geller, E. B., Gaughan, J., et al. (2001). Administration of mu-, kappa- or delta2-receptor agonists via osmotic minipumps suppresses murine splenic antibody responses. International Immunopharmacology, 1(11), 2001–2009.

    PubMed  CAS  Google Scholar 

  41. Stefano, G. B., Burrill, J. D., Labur, S., Blake, J., & Cadet, P. (2005). Regulation of various genes in human leukocytes acutely exposed to morphine: Expression microarray analysis. Medical Science Monitor, 11(5), MS35–MS42.

    PubMed  CAS  Google Scholar 

  42. Eisenstein, T. K., & Hilburger, M. E. (1998). Opioid modulation of immune responses: Effects on phagocyte and lymphoid cell populations. Journal of Neuroimmunology, 83(1–2), 36–44.

    PubMed  CAS  Google Scholar 

  43. Mathews, P. M., Froelich, C. J., Sibbitt, W. L., & Bankhurst, A. D. (1983). Enhancement of natural cytotoxicity by beta-endorphin. Journal of Immunology, 130(4), 1658–1662.

    CAS  Google Scholar 

  44. Wei, G., Moss, J., & Yuan, C. S. (2003). Opioid-induced immunosuppression: Is it centrally mediated or peripherally mediated? Biochemical Pharmacology, 65(11), 1761–1766.

    PubMed  CAS  Google Scholar 

  45. Hall, D. M., Suo, J. L., & Weber, R. J. (1998). Opioid mediated effects on the immune system: Sympathetic nervous system involvement. Journal of Neuroimmunology, 83(1–2), 29–35.

    PubMed  CAS  Google Scholar 

  46. Liang-Suo, J., Gomez-Flores, R., & Weber, R. J. (2002). Immunosuppression induced by central action of morphine is not blocked by mifepristone (RU 486). Life Sciences, 71(22), 2595–2602.

    PubMed  Google Scholar 

  47. Wang, J., Charboneau, R., Balasubramanian, S., Barke, R. A., Loh, H. H., & Roy, S. (2002). The immunosuppressive effects of chronic morphine treatment are partially dependent on corticosterone and mediated by the mu-opioid receptor. Journal of Leukocyte Biology, 71(5), 782–790.

    PubMed  CAS  Google Scholar 

  48. Pruett, S. B., Han, Y. C., & Fuchs, B. A. (1992). Morphine suppresses primary humoral immune responses by a predominantly indirect mechanism. The Journal of Pharmacology and Experimental Therapeutics, 262(3), 923–928.

    PubMed  CAS  Google Scholar 

  49. Rahim, R. T., Meissler, J. J., Jr., Adler, M. W., & Eisenstein, T. K. (2005). Splenic macrophages and B cells mediate immunosuppression following abrupt withdrawal from morphine. Journal of Leukocyte Biology, 78(6), 1185–1191.

    PubMed  CAS  Google Scholar 

  50. Gaveriaux-Ruff, C., Matthes, H. W., Peluso, J., & Kieffer, B. L. (1998). Abolition of morphine-immunosuppression in mice lacking the mu-opioid receptor gene. Proceedings of the National Academy of Sciences of the United States of America, 95(11), 6326–6330.

    PubMed  CAS  Google Scholar 

  51. Rahim, R. T., Meissler, J. J., Zhang, L., Adler, M. W., Rogers, T. J., & Eisenstein, T. K. (2003). Withdrawal from morphine in mice suppresses splenic macrophage function, cytokine production, and costimulatory molecules. Journal of Neuroimmunology, 144(1–2), 16–27.

    PubMed  CAS  Google Scholar 

  52. Colacchio, T. A., Yeager, M. P., & Hildebrandt, L. W. (1994). Perioperative immunomodulation in cancer surgery. American Journal of Surgery, 167(1), 174–179.

    PubMed  CAS  Google Scholar 

  53. Benish, M., Bartal, I., Goldfarb, Y., Levi, B., Avraham, R., Raz, A., et al. (2008). Perioperative use of beta-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis. Annals of Surgical Oncology, 15(7), 2042–2052.

    PubMed  Google Scholar 

  54. Glasner, A., Avraham, R., Rosenne, E., Benish, M., Zmora, O., Shemer, S., et al. (2010). Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a beta-adrenergic antagonist and a cyclooxygenase-2 inhibitor. Journal of Immunology, 184(5), 2449–2457.

    CAS  Google Scholar 

  55. Hua, S., & Cabot, P. J. (2010). Mechanisms of peripheral immune-cell-mediated analgesia in inflammation: Clinical and therapeutic implications. Trends in Pharmacological Sciences, 31(9), 427–433.

    PubMed  CAS  Google Scholar 

  56. Cabot, P. J., Carter, L., Gaiddon, C., Zhang, Q., Schafer, M., Loeffler, J. P., et al. (1997). Immune cell-derived beta-endorphin. Production, release, and control of inflammatory pain in rats. Journal of Clinical Investigation, 100(1), 142–148.

    PubMed  CAS  Google Scholar 

  57. Finley, M. J., Happel, C. M., Kaminsky, D. E., & Rogers, T. J. (2008). Opioid and nociceptin receptors regulate cytokine and cytokine receptor expression. Cellular Immunology, 252(1–2), 146–154.

    PubMed  CAS  Google Scholar 

  58. Martin, J. L., Charboneau, R., Barke, R. A., & Roy, S. (2010). Chronic morphine treatment inhibits LPS-induced angiogenesis: Implications in wound healing. Cellular Immunology, 265(2), 139–145.

    PubMed  CAS  Google Scholar 

  59. Stefano, G. B., Hartman, A., Bilfinger, T. V., Magazine, H. I., Liu, Y., Casares, F., et al. (1995). Presence of the mu3 opiate receptor in endothelial cells. Coupling to nitric oxide production and vasodilation. Journal of Biological Chemistry, 270(51), 30290–30293.

    PubMed  CAS  Google Scholar 

  60. Gupta, K., Kshirsagar, S., Chang, L., Schwartz, R., Law, P. Y., Yee, D., et al. (2002). Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Research, 62(15), 4491–4498.

    PubMed  CAS  Google Scholar 

  61. Fimiani, C., Mattocks, D., Cavani, F., Salzet, M., Deutsch, D. G., Pryor, S., et al. (1999). Morphine and anandamide stimulate intracellular calcium transients in human arterial endothelial cells: Coupling to nitric oxide release. Cellular Signalling, 11(3), 189–193.

    PubMed  CAS  Google Scholar 

  62. Hsiao, P. N., Chang, M. C., Cheng, W. F., Chen, C. A., Lin, H. W., Hsieh, C. Y., et al. (2009). Morphine induces apoptosis of human endothelial cells through nitric oxide and reactive oxygen species pathways. Toxicology, 256(1–2), 83–91.

    PubMed  CAS  Google Scholar 

  63. Chen, C., Farooqui, M., & Gupta, K. (2006). Morphine stimulates vascular endothelial growth factor-like signaling in mouse retinal endothelial cells. Current Neurovascular Research, 3(3), 171–180.

    PubMed  CAS  Google Scholar 

  64. Singleton, P. A., Lingen, M. W., Fekete, M. J., Garcia, J. G. N., & Moss, J. (2006). Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: Role of receptor transactivation. Microvascular Research, 72(1–2), 3–11.

    PubMed  CAS  Google Scholar 

  65. Belcheva, M. M., Haas, P. D., Tan, Y., Heaton, V. M., & Coscia, C. J. (2002). The fibroblast growth factor receptor is at the site of convergence between mu-opioid receptor and growth factor signaling pathways in rat C6 glioma cells. The Journal of Pharmacology and Experimental Therapeutics, 303(3), 909–918.

    PubMed  CAS  Google Scholar 

  66. Ustun, F., Durmus-Altun, G., Altaner, S., Tuncbilek, N., Uzal, C., & Berkarda, S. (2011). Evaluation of morphine effect on tumour angiogenesis in mouse breast tumour model, EATC. Medical Oncology (in press).

  67. Poonawala, T., Levay-Young, B. K., Hebbel, R. P., & Gupta, K. (2005). Opioids heal ischemic wounds in the rat. Wound Repair and Regeneration, 13(2), 165–174.

    PubMed  Google Scholar 

  68. Singleton, P. A., Mambetsariev, N., Lennon, F. E., Mathew, B., Siegler, J. H., & Moreno-Vinasco, L. (2010). Methylnaltrexone potentiates the anti-angiogenic effects of mTOR inhibitors. J Angiogenes Res, 2(1), 5.

    PubMed  Google Scholar 

  69. Dai, X., Song, H. J., Cui, S. G., Wang, T., Liu, Q., & Wang, R. (2010). The stimulative effects of endogenous opioids on endothelial cell proliferation, migration and angiogenesis in vitro. European Journal of Pharmacology, 628(1–3), 42–50.

    PubMed  CAS  Google Scholar 

  70. Farooqui, M., Li, Y., Rogers, T., Poonawala, T., Griffin, R. J., Song, C. W., et al. (2007). COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia. British Journal of Cancer, 97(11), 1523–1531.

    PubMed  CAS  Google Scholar 

  71. Radisavljevic, Z., Avraham, H., & Avraham, S. (2000). Vascular endothelial growth factor up-regulates ICAM-1 expression via the phosphatidylinositol 3 OH-kinase/AKT/Nitric oxide pathway and modulates migration of brain microvascular endothelial cells. The Journal of Biological Chemistry, 275(27), 20770–20774.

    PubMed  CAS  Google Scholar 

  72. Kevil, C. G., Orr, A. W., Langston, W., Mickett, K., Murphy-Ullrich, J., Patel, R. P., et al. (2004). Intercellular adhesion molecule-1 (ICAM-1) regulates endothelial cell motility through a nitric oxide-dependent pathway. The Journal of Biological Chemistry, 279(18), 19230–19238.

    PubMed  CAS  Google Scholar 

  73. Wu, Y., Ip, J. E., Huang, J., Zhang, L., Matsushita, K., Liew, C. C., et al. (2006). Essential role of ICAM-1/CD18 in mediating EPC recruitment, angiogenesis, and repair to the infarcted myocardium. Circulation Research, 99(3), 315–322.

    PubMed  CAS  Google Scholar 

  74. Nair, M., Mahajan, S., & Reynolds, J. (2006). Opiates upregulate adhesion molecule expression in brain microvascular endothelial cells: Implications for altered blood brain barrier permeability. American Journal of Infectious Diseases, 2(2), 58–66.

    CAS  Google Scholar 

  75. Pasi, A., Qu, B. X., Steiner, R., Senn, H. J., Bar, W., & Messiha, F. S. (1991). Angiogenesis: Modulation with opioids. General Pharmacology, 22(6), 1077–1079.

    PubMed  CAS  Google Scholar 

  76. Blebea, J., Mazo, J. E., Kihara, T. K., Vu, J. H., McLaughlin, P. J., Atnip, R. G., et al. (2000). Opioid growth factor modulates angiogenesis. Journal of Vascular Surgery, 32(2), 364–373.

    PubMed  CAS  Google Scholar 

  77. Lam, C. F., Liu, Y. C., Tseng, F. L., Sung, Y. H., Huang, C. C., Jiang, M. J., et al. (2007). High-dose morphine impairs vascular endothelial function by increased production of superoxide anions. Anesthesiology, 106(3), 532–537.

    PubMed  CAS  Google Scholar 

  78. Lam, C. F., Chang, P. J., Huang, Y. S., Sung, Y. H., Huang, C. C., Lin, M. W., et al. (2008). Prolonged use of high-dose morphine impairs angiogenesis and mobilization of endothelial progenitor cells in mice. Anesthesia and Analgesia, 107(2), 686–692.

    PubMed  CAS  Google Scholar 

  79. Martin, J. L., Koodie, L., Krishnan, A. G., Charboneau, R., Barke, R. A., & Roy, S. (2010). Chronic morphine administration delays wound healing by inhibiting immune cell recruitment to the wound site. The American Journal of Pathology, 176(2), 786–799.

    PubMed  CAS  Google Scholar 

  80. Balasubramanian, S., Ramakrishnan, S., Charboneau, R., Wang, J., Barke, R. A., & Roy, S. (2001). Morphine sulfate inhibits hypoxia-induced vascular endothelial growth factor expression in endothelial cells and cardiac myocytes. Journal of Molecular and Cellular Cardiology, 33(12), 2179–2187.

    PubMed  CAS  Google Scholar 

  81. Roy, S., Balasubramanian, S., Wang, J., Chandrashekhar, Y., Charboneau, R., & Barke, R. (2003). Morphine inhibits VEGF expression in myocardial ischemia. Surgery, 134(2), 336–344.

    PubMed  CAS  Google Scholar 

  82. Koodie, L., Ramakrishnan, S., & Roy, S. (2010). Morphine suppresses tumor angiogenesis through a HIF-1alpha/p38MAPK pathway. The American Journal of Pathology, 177(2), 984–997.

    PubMed  CAS  Google Scholar 

  83. Faramarzi, N., Abbasi, A., Tavangar, S. M., Mazouchi, M., & Dehpour, A. R. (2009). Opioid receptor antagonist promotes angiogenesis in bile duct ligated rats. Journal of Gastroenterology and Hepatology, 24(7), 1226–1229.

    PubMed  CAS  Google Scholar 

  84. Beilin, B., Shavit, Y., Trabekin, E., Mordashev, B., Mayburd, E., Zeidel, A., et al. (2003). The effects of postoperative pain management on immune response to surgery. Anesthesia and Analgesia, 97(3), 822–827.

    PubMed  Google Scholar 

  85. Bar-Yosef, S., Melamed, R., Page, G. G., Shakhar, G., Shakhar, K., & Ben-Eliyahu, S. (2001). Attenuation of the tumor-promoting effect of surgery by spinal blockade in rats. Anesthesiology, 94(6), 1066–1073.

    PubMed  CAS  Google Scholar 

  86. Wada, H., Seki, S., Takahashi, T., Kawarabayashi, N., Higuchi, H., Habu, Y., et al. (2007). Combined spinal and general anesthesia attenuates liver metastasis by preserving TH1/TH2 cytokine balance. Anesthesiology, 106(3), 499–506.

    PubMed  CAS  Google Scholar 

  87. Exadaktylos, A. K., Buggy, D. J., Moriarty, D. C., Mascha, E., & Sessler, D. I. (2006). Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology, 105(4), 660–664.

    PubMed  Google Scholar 

  88. Biki, B., Mascha, E., Moriarty, D. C., Fitzpatrick, J. M., Sessler, D. I., & Buggy, D. J. (2008). Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: A retrospective analysis. Anesthesiology, 109(2), 180–187.

    PubMed  Google Scholar 

  89. Christopherson, R., James, K. E., Tableman, M., Marshall, P., & Johnson, F. E. (2008). Long-term survival after colon cancer surgery: A variation associated with choice of anesthesia. Anesthesia and Analgesia, 107(1), 325–332.

    PubMed  Google Scholar 

  90. Gottschalk, A., Ford, J. G., Regelin, C. C., You, J., Mascha, E. J., Sessler, D. I., et al. (2010). Association between epidural analgesia and cancer recurrence after colorectal cancer surgery. Anesthesiology, 113(1), 27–34.

    PubMed  Google Scholar 

  91. Tsui, B. C., Rashiq, S., Schopflocher, D., Murtha, A., Broemling, S., Pillay, J., et al. (2010). Epidural anesthesia and cancer recurrence rates after radical prostatectomy. Canadian Journal of Anaesthesia, 57(2), 107–112.

    PubMed  Google Scholar 

  92. Sessler, D. I., Ben-Eliyahu, S., Mascha, E. J., Parat, M. O., & Buggy, D. J. (2008). Can regional analgesia reduce the risk of recurrence after breast cancer? Methodology of a multicenter randomized trial. Contemp Clin Trials, 29(4), 517–526.

    PubMed  Google Scholar 

  93. O’Riain, S. C., Buggy, D. J., Kerin, M. J., Watson, R. W., & Moriarty, D. C. (2005). Inhibition of the stress response to breast cancer surgery by regional anesthesia and analgesia does not affect vascular endothelial growth factor and prostaglandin E2. Anesthesia and Analgesia, 100(1), 244–249.

    PubMed  Google Scholar 

  94. Looney, M., Doran, P., & Buggy, D. J. (2010). Effect of anesthetic technique on serum vascular endothelial growth factor C and transforming growth factor beta in women undergoing anesthesia and surgery for breast cancer. Anesthesiology, 113(5), 1118–1125.

    PubMed  CAS  Google Scholar 

  95. Deegan, C. A., Murray, D., Doran, P., Moriarty, D. C., Sessler, D. I., Mascha, E., et al. (2010). Anesthetic technique and the cytokine and matrix metalloproteinase response to primary breast cancer surgery. Regional Anesthesia and Pain Medicine, 35(6), 490–495.

    PubMed  Google Scholar 

  96. Deegan, C. A., Murray, D., Doran, P., Ecimovic, P., Moriarty, D. C., & Buggy, D. J. (2009). Effect of anaesthetic technique on oestrogen receptor-negative breast cancer cell function in vitro. British Journal of Anaesthesia, 103(5), 685–690.

    PubMed  CAS  Google Scholar 

  97. Singleton, P. A., & Moss, J. (2010). Effect of perioperative opioids on cancer recurrence: A hypothesis. Future Oncology, 6(8), 1237–1242.

    PubMed  CAS  Google Scholar 

  98. Ishikawa, M., Tanno, K., Kamo, A., Takayanagi, Y., & Sasaki, K. (1993). Enhancement of tumor growth by morphine and its possible mechanism in mice. Biological & Pharmaceutical Bulletin, 16(8), 762–766.

    CAS  Google Scholar 

  99. Maneckjee, R., & Minna, J. D. (1994). Opioids induce while nicotine suppresses apoptosis in human lung cancer cells. Cell Growth & Differentiation, 5(10), 1033–1040.

    CAS  Google Scholar 

  100. Kawase, M., Sakagami, H., Furuya, K., Kikuchi, H., Nishikawa, H., & Motohashi, N. (2002). Cell death-inducing activity of opiates in human oral tumor cell lines. Anticancer Research, 22(1A), 211–214.

    PubMed  CAS  Google Scholar 

  101. Yeager, M. P., & Colacchio, T. A. (1991). Effect of morphine on growth of metastatic colon cancer in vivo. Archives of Surgery, 126(4), 454–456.

    PubMed  CAS  Google Scholar 

  102. Page, G. G., Ben-Eliyahu, S., Yirmiya, R., & Liebeskind, J. C. (1993). Morphine attenuates surgery-induced enhancement of metastatic colonization in rats. Pain, 54(1), 21–28.

    PubMed  CAS  Google Scholar 

  103. Page, G. G., Ben-Eliyahu, S., & Liebeskind, J. C. (1994). The role of LGL/NK cells in surgery-induced promotion of metastasis and its attenuation by morphine. Brain, Behavior, and Immunity, 8(3), 241–250.

    PubMed  CAS  Google Scholar 

  104. Page, G. G., McDonald, J. S., & Ben-Eliyahu, S. (1998). Pre-operative versus postoperative administration of morphine: Impact on the neuroendocrine, behavioural, and metastatic-enhancing effects of surgery. British Journal of Anaesthesia, 81(2), 216–223.

    PubMed  CAS  Google Scholar 

  105. Fuggetta, M. P., Di, F. P., Falchetti, R., Cottarelli, A., Rossi, L., Tricarico, M., et al. (2005). Effect of morphine on cell-mediated immune responses of human lymphocytes against allogeneic malignant cells. Journal of Experimental & Clinical Cancer Research, 24(2), 255–263.

    CAS  Google Scholar 

  106. Sasamura, T., Nakamura, S., Iida, Y., Fujii, H., Murata, J., Saiki, I., et al. (2002). Morphine analgesia suppresses tumor growth and metastasis in a mouse model of cancer pain produced by orthotopic tumor inoculation. European Journal of Pharmacology, 441(3), 185–191.

    PubMed  CAS  Google Scholar 

  107. Dai, X., Cui, S. G., Wang, T., Liu, Q., Song, H. J., & Wang, R. (2008). Endogenous opioid peptides, endomorphin-1 and -2 and deltorphin I, stimulate angiogenesis in the CAM assay. European Journal of Pharmacology, 579(1–3), 269–275.

    PubMed  CAS  Google Scholar 

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Correspondence to Marie-Odile Parat.

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Afsharimani, B., Cabot, P. & Parat, MO. Morphine and tumor growth and metastasis. Cancer Metastasis Rev 30, 225–238 (2011). https://doi.org/10.1007/s10555-011-9285-0

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