Psychoneuroimmunology of Cancer – Recent Findings and Perspectives

Authors: Mravec Boris 1,2;  Tibenský Miroslav 1;  Horváthová Ľubica 2
Authors‘ workplace: Fyziologický ústav LF UK v Bratislave 1;  Biomedicínske centrum, Ústav experimentálnej endokrinológie, Slovenská akadémia vied, Bratislava 2
Published in: Klin Onkol 2018; 31(5): 345-352
Category: Review
doi: 10.14735/amko2018345



Gallen observed that psychosocial factors influence tumor incidence. Findings of the last decades have enabled us to understand the mechanisms and pathways responsible for this influence. Ader, Solomon, Besedovsky, and other pioneers of psychoneuroimmunology demonstrated that the nervous system can regulate the activity of immune cells. Based on their findings, the mechanisms via which psychosocial stressors potentiate tumor growth indirectly through inhibition of anti-tumor immune cells have been reported. Human tumor innervation, the presence of β-adrenergic receptors on tumor cells, and the stimulating effect of noradrenaline on tumor growth and metastasis development have revealed that psychosocial stressors have a direct stimulatory effect on tumor growth, mainly via sympathetic nerves. In recent years, the possibility of modulating signal transduction between the nervous system, immune system, and tumor cells, with the intention of inhibiting tumor growth and metastasis, has been intensively investigated.


The aim of this review paper is to provide an overview of recent experimental and clinical findings from psychoneuroimmunological research, which reveal an increasingly complex link between stress and the onset and progression of tumor diseases and provide a basis for the introduction of new therapeutic approaches for the treatment of cancer patients.


Some approaches tested in psychoneuroimmunological studies reported that they had inhibitory effects on cancer growth and used already clinically-approved drugs and psychological procedures, which may facilitate their application in oncology in the near future.

Key words:

β-blockers – cancer – psychoneuroimmunology – stress

„Whatever happens in the mind of man, is always reflected in the diseases of his body.“
René Dubos

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted: 12. 7. 2018

Accepted: 5. 8. 2018


1. Sternberg EM. The balance within: the science connecting health and emotions. 1st ed. New York: W. H. Freeman 2001.

2. Kiecolt-Glaser JK, McGuire L, Robles TF et al. Emotions, morbidity, and mortality: new perspectives from psychoneuroimmunology. Annu Rev Psychol 2002; 53: 83–107. doi: 10.1146/annurev.psych.53.100901.135217.

3. Besedovsky HO, Rey AD. Physiology of psychoneuroimmunology: a personal view. Brain Behav Immun 2007; 21 (1): 34–44. doi: 10.1016/j.bbi.2006.09.008.

4. Kiecolt-Glaser JK, Robles TF, Heffner KL et al. Psycho-oncology and cancer: psychoneuroimmunology and cancer. Ann Oncol 2002; 13 (Suppl 4): 165–169.

5. Skrivanova K, Gregor J, Bendova M et al. Psychoneuroimmunology in context of comprehensive breast cancer treatment. Klin Onkol 2014; 27 (2): 103–107. doi: 10.14735/amko2014103.

6. Rosch PJ. Stress and cancer: Disorders of communication, control, and civilization. In: Cooper CL (ed). Handbook of stress, medicine and health. 1st ed. Boca Raton: CRC Press 1996: 27–60.

7. Selye H. A syndrome produced by diverse nocuous agents. Nature 1936; 138: 32.

8. Selye H. Stress, Cancer, and the Mind. In: Taché J et al (eds). Cancer, stress, and death sloan-kettering institute cancer series. 1st ed. Boston, MA: Springer 1978: 11–19.

9. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004; 21 (2): 137–148. doi: 10.1016/j.immuni.2004.07.017.

10. Solomon GF, Moss RH. Emotions, immunity, and disease; a speculative theoretical integration. Arch Gen Psychiatry 1964; 11: 657–674.

11. Ader R, Cohen N. Behaviorally conditioned immunosuppression. Psychosom Med 1975; 37 (4): 333–340.

12. Ader R. On the development of psychoneuroimmunology. Eur J Pharmacol 2000; 405 (1–3): 167–176.

13. Spiegel D, Bloom JR, Kraemer HC et al. Effect of psychosocial treatment on survival of patients with metastatic breast cancer. Lancet 1989; 2 (8668): 888–891.

14. Fawzy FI, Fawzy NW, Hyun CS et al. Malignant melanoma. Effects of an early structured psychiatric intervention, coping, and affective state on recurrence and survival 6 years later. Arch Gen Psychiatry 1993; 50 (9):  681–689.

15. Goodwin PJ, Leszcz M, Ennis M et al. The effect of group psychosocial support on survival in metastatic breast cancer. N Engl J Med 2001; 345 (24): 1719–1726. doi: 10.1056/NEJMoa011871.

16. Kissane DW, Grabsch B, Clarke DM et al. Supportive-expressive group therapy for women with metastatic breast cancer: survival and psychosocial outcome from a randomized controlled trial. Psychooncology 2007; 16 (4): 277–286. doi: 10.1002/pon.1185.

17. Spiegel D, Butler LD, Giese-Davis J et al. Effects of supportive-expressive group therapy on survival of patients with metastatic breast cancer: a randomized prospective trial. Cancer 2007; 110 (5): 1130–1138. doi: 10.1002/cncr.22890.

18. Andersen BL, Yang HC, Farrar WB et al. Psychologic intervention improves survival for breast cancer patients: a randomized clinical trial. Cancer 2008; 113 (12): 3450–3458. doi: 10.1002/cncr.23969.

19. Jassim GA, Whitford DL, Hickey A et al. Psychological interventions for women with non-metastatic breast cancer. Cochrane Database Syst Rev 2015; (5): CD008729. doi: 10.1002/14651858.CD008729.pub2.

20. Barrera I, Spiegel D. Review of psychotherapeutic interventions on depression in cancer patients and their impact on disease progression. Int Rev Psychiatry 2014; 26 (1): 31–43. doi: 10.3109/09540261.2013.864259.

21. Barron TI, Connolly RM, Sharp L et al. Beta blockers and breast cancer mortality: a population-based study. J Clin Oncol 2011; 29 (19): 2635–2644. doi: 10.1200/JCO.2010.33.5422.

22. Cardwell CR, Coleman HG, Murray LJ et al. Beta-blocker usage and prostate cancer survival: a nested case-control study in the UK Clinical Practice Research Datalink cohort. Cancer Epidemiol 2014; 38 (3): 279–285. doi: 10.1016/j.canep.2014.03.011.

23. Cardwell CR, Coleman HG, Murray LJ et al. Beta-blocker usage and breast cancer survival: a nested case-control study within a UK clinical practice research datalink cohort. Int J Epidemiol 2013; 42 (6): 1852–1861. doi: 10.1093/ije/dyt196.

24. Kim SA, Moon H, Roh JL et al. Postdiagnostic use of beta-blockers and other antihypertensive drugs and the risk of recurrence and mortality in head and neck cancer patients: an observational study of 10,414 person-years of follow-up. Clin Transl Oncol 2017; 19 (7): 826–833. doi: 10.1007/s12094-016-1608-8.

25. De Giorgi V, Grazzini M, Benemei S et al. Propranolol for off-label treatment of patients with melanoma: results from a cohort study. JAMA Oncol 2018; 4 (2): e172908. doi: 10.1001/jamaoncol.2017.2908.

26. 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 (2): 457–463. doi: 10.1007/s10549-011-1371-z.

27. Desautels M, Bhaumick B, Ram JI. Comparison of trophic effects of norepinephrine, insulin, and IGF-1 in mouse brown adipocytes. Am J Physiol 1996; 270 (6 Pt 2): R1287–R1295. doi: 10.1152/ajpregu.1996.270.6.R1287.

28. Zaglia T, Milan G, Franzoso M et al. Cardiac sympathetic neurons provide trophic signal to the heart via beta2-adrenoceptor-dependent regulation of proteolysis. Cardiovasc Res 2013; 97 (2): 240–250. doi: 10.1093/cvr/cvs320.

29. Giese-Davis J, Collie K, Rancourt KM et al. Decrease in depression symptoms is associated with longer survival in patients with metastatic breast cancer: a secondary analysis. J Clin Oncol 2011; 29 (4): 413–420. doi: 10.1200/JCO.2010.28.4455.

30. Plotsky PM, Owens MJ, Nemeroff CB. Psychoneuroendocrinology of depression. Hypothalamic-pituitary-adrenal axis. Psychiatr Clin North Am 1998; 21 (2): 293–307.

31. Armaiz-Pena GN, Cole SW, Lutgendorf SK et al. Neuroendocrine influences on cancer progression. Brain Behav Immun 2013; (Suppl 30): S19–S25. doi: 10.1016/j.bbi.2012.06.005.

32. Lu YJ, Geng ZJ, Sun XY et al. Isoprenaline induces epithelial-mesenchymal transition in gastric cancer cells. Mol Cell Biochem 2015; 408 (1–2): 1–13. doi: 10.1007/s11010-015-2477-0.

33. Shi M, Liu D, Duan H et al. Catecholamine up-regulates MMP-7 expression by activating AP-1 and STAT3 in gastric cancer. Mol Cancer 2010; 9: 269. doi: 10.1186/1476-4598-9-269.

34. Kim-Fuchs C, Le CP, Pimentel MA et al. Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment. Brain Behav Immun 2014; 40: 40–47. doi: 10.1016/j.bbi.2014.02.019.

35. Raju B, Hultstrom M, Haug SR et al. Sympathectomy suppresses tumor growth and alters gene-expression profiles in rat tongue cancer. Eur J Oral Sci 2009; 117 (4): 351–361. doi: 10.1111/j.1600-0722.2009.00646.x.

36. Grzanna R, Frondoza CG, Otten U. Sympathectomy inhibits growth of a murine plasmacytoma tumor. J Auton Nerv Syst 1985; 13 (2): 149–160.

37. Horvathova L, Padova A, Tillinger A et al. Sympathectomy reduces tumor weight and affects expression of tumor-related genes in melanoma tissue in the mouse. Stress 2016; 19 (5): 528–534. doi: 10.1080/10253890.2016.1213808.

38. Lackovicova L, Banovska L, Bundzikova J et al. Chemical sympathectomy suppresses fibrosarcoma development and improves survival of tumor-bearing rats. Neoplasma 2011; 58 (5): 424–429.

39. Schneiderman N, Ironson G, Siegel SD. Stress and health: psychological, behavioral, and biological determinants. Annu Rev Clin Psychol 2005; 1: 607–628. doi: 10.1146/annurev.clinpsy.1.102803.144141.

40. Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci 2009; 10 (6): 397–409. doi: 10.1038/nrn2647.

41. Thaker PH, Lutgendorf SK, Sood AK. The neuroendocrine impact of chronic stress on cancer. Cell Cycle 2007; 6 (4): 430–433. doi: 10.4161/cc.6.4.3829.

42. Armaiz-Pena GN, Lutgendorf SK, Cole SW et al. Neuroendocrine modulation of cancer progression. Brain Behav Immun 2009; 23 (1): 10–15. doi: 10.1016/j.bbi.2008.06.007.

43. Magnon C, Hall SJ, Lin J et al. Autonomic nerve development contributes to prostate cancer progression. Science 2013; 341 (6142): 1236361. doi: 10.1126/science.1236361.

44. Naugler WE, Sakurai T, Kim S et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent

IL-6 production. Science 2007; 317 (5834): 121– 124. doi: 10.1126/ science.1140485.

45. Huan HB, Wen XD, Chen XJ et al. Sympathetic nervous system promotes hepatocarcinogenesis by modulating inflammation through activation of alpha1-adrenergic receptors of Kupffer cells. Brain Behav Immun 2017; 59: 118–134. doi: 10.1016/j.bbi.2016.08.016.

46. Worlicek M, Knebel K, Linde HJ et al. Splanchnic sympathectomy prevents translocation and spreading of E coli but not S aureus in liver cirrhosis. Gut 2010; 59 (8): 1127–1134. doi: 10.1136/gut.2009.185413.

47. Hara MR, Kovacs JJ, Whalen EJ et al. A stress response pathway regulates DNA damage through beta2-adrenoreceptors and beta-arrestin-1. Nature 2011; 477 (7364): 349–353. doi: 10.1038/nature10368.

48. Chen H, Zhang W, Cheng X et al. β2-AR activation induces chemoresistance by modulating p53 acetylation through upregulating Sirt1 in cervical cancer cells. Cancer Sci 2017; 108 (7): 1310–1317. doi: 10.1111/cas.13275.

49. Feng Z, Liu L, Zhang C et al. Chronic restraint stress attenuates p53 function and promotes tumorigenesis. Proc Natl Acad Sci U S A 2012; 109 (18): 7013–7018. doi: 10.1073/pnas.1203930109.

50. Shi M, Du L, Liu D et al. Glucocorticoid regulation of a novel HPV-E6-p53-miR-145 pathway modulates invasion and therapy resistance of cervical cancer cells. J Pathol 2012; 228 (2): 148–157. doi: 10.1002/path.3997.

51. Jenkins FJ, Van Houten B, Bovbjerg DH. Effects on DNA damage and/or repair processes as biological mechanisms linking psychological stress to cancer risk. J Appl Biobehav Res 2014; 19 (1): 3–23. doi: 10.1111/jabr.12019.

52. Flint MS, Baum A, Chambers WH et al. Induction of DNA damage, alteration of DNA repair and transcriptional activation by stress hormones. Psychoneuroendocrinology 2007; 32 (5): 470–479. doi: 10.1016/j.psyneuen.2007.02.013.

53. Lang K, Drell TL, Niggemann B et al. Neurotransmitters regulate the migration and cytotoxicity in natural killer cells. Immunol Lett 2003; 90 (2–3): 165–172.

54. Inbar S, Neeman E, Avraham R et al. Do stress responses promote leukemia progression? An animal study suggesting a role for epinephrine and prostaglandin-E2 through reduced NK activity. PLoS One 2011; 6 (4): e19246. doi: 10.1371/journal.pone.0019 246.

55. Qiao G, Chen M, Bucsek MJ et al. Adrenergic Signaling: A targetable checkpoint limiting development of the antitumor immune response. Front Immunol 2018; 9: 164. doi: 10.3389/fimmu.2018.00164.

56. Antoni MH, Lutgendorf SK, Cole SW et al. The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat Rev Cancer 2006; 6 (3): 240–248. doi: 10.1038/nrc1820.

57. Thaker PH, Han LY, Kamat AA et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med 2006; 12 (8): 939–944. doi: 10.1038/nm1447.

58. Le CP, Nowell CJ, Kim-Fuchs C et al. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nat Commun 2016; 7: 10634. doi: 10.1038/ncomms10634.

59. Tilan J, Kitlinska J. Sympathetic neurotransmitters and tumor angiogenesis-link between stress and cancer progression. J Oncol 2010; 2010: 539706. doi: 10.1155/ 2010/ 539706.

60. Nagaraja AS, Dood RL, Armaiz-Pena G et al. Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens. JCI Insight 2017; 2 (16): 93076. doi: 10.1172/jci.insight.93076.

61. Lin KT, Wang LH. New dimension of glucocorticoids in cancer treatment. Steroids 2016; 111: 84–88. doi: 10.1016/j.steroids.2016.02.019.

62. Thaker PH, Sood AK. Neuroendocrine influences on cancer biology. Semin Cancer Biol 2008; 18 (3): 164–170. doi: 10.1016/j.semcancer.2007.12.005.

63. Spiegel D. Embodying the mind in psychooncology research. Adv Mind Body Med 1999; 15 (4): 267–273; discussion 275–281. doi: 10.1054/ambm.1999.0102.

64. Dhabhar FS. The short-term stress response – Moth-er nature‘s mechanism for enhancing protection and performance under conditions of threat, challenge, and opportunity. Front Neuroendocrinol 2018; 49: 175–192. doi: 10.1016/j.yfrne.2018.03.004.

65. Chochinov HM. Depression in cancer patients. Lancet Oncol 2001; 2 (8): 499–505. doi: 10.1016/S1470-2045 (01) 00456-9.

66. Grygier B, Kubera M, Wrona D et al. Stimulatory effect of desipramine on lung metastases of adenocarcinoma MADB 106 in stress highly-sensitive and stress non-reactive rats. Prog Neuropsychopharmacol Biol Psychiatry 2018; 80 (Pt C): 279–290. doi: 10.1016/j.pnpbp.2017.04.024.

67. Lang K, Drell TLt, Lindecke A et al. Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs. Int J Cancer 2004; 112 (2): 231–238. doi: 10.1002/ijc.20 410.

68. Breitbart W, Rosenfeld B, Pessin H et al. Meaning-centered group psychotherapy: an effective intervention for improving psychological well-being in patients with advanced cancer. J Clin Oncol 2015; 33 (7): 749–754. doi: 10.1200/JCO.2014.57.2198.

69. Gordon JS. Mind-body medicine and cancer. Hematol Oncol Clin North Am 2008; 22 (4): 683–708. doi: 10.1016/j.hoc.2008.04.010.

70. Goldfarb Y, Ben-Eliyahu S. Surgery as a risk factor for breast cancer recurrence and metastasis: mediating  mechanisms and clinical prophylactic approaches. Breast Dis 2006–2007; 26: 99–114.

71. Ben-Eliyahu S. The promotion of tumor metastasis by surgery and stress: immunological basis and implications for psychoneuroimmunology. Brain Behav Immun 2003; 17 (Suppl 1): S27–S36.

72. Benish M, Bartal I, Goldfarb Y et al. Perioperative use of beta-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis. Ann Surg Oncol 2008; 15 (7): 2042-2052. doi: 10.1245/s10434-008-9890-5.

73. Neeman E, Zmora O, Ben-Eliyahu S. A new approach to reducing postsurgical cancer recurrence: perioperative targeting of catecholamines and prostaglandins. Clin Cancer Res 2012; 18 (18): 4895–4902. doi: 10.1158/1078-0432.CCR-12-1087.

74. Horowitz M, Neeman E, Sharon E et al. Exploiting the critical perioperative period to improve long-term cancer outcomes. Nat Rev Clin Oncol 2015; 12 (4): 213–226. doi: 10.1038/nrclinonc.2014.224.

75. Grossarth-Maticek R, Eysenck HJ, Pfeifer A et al. The specific action of different personality risk factors on cancer of the breast, cervix, corpus uteri and other types of cancer: a prospective investigation. Personal Individ Differ 1997; 23 (6): 949–960. doi: 10.1016/S0191-8869 (97) 000 99-8.

76. Dunn GP, Bruce AT, Ikeda H et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002; 3 (11): 991–998. doi: 10.1038/ni1102-991.

77. Tilan J, Kitlinska J. Neuropeptide Y (NPY) in tumor growth and progression: Lessons learned from pediatric oncology. Neuropeptides 2016; 55: 55–66. doi: 10.1016/j.npep.2015.10.005.

Paediatric clinical oncology Surgery Clinical oncology

Article was published in

Clinical Oncology

Issue 5

2018 Issue 5

Most read in this issue

This topic is also in:

Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account