Sympathetic nervous system regulation of the tumour microenvironment

Journal name:
Nature Reviews Cancer
Volume:
15,
Pages:
563–572
Year published:
DOI:
doi:10.1038/nrc3978
Published online

Abstract

The peripheral autonomic nervous system (ANS) is known to regulate gene expression in primary tumours and their surrounding microenvironment. Activation of the sympathetic division of the ANS in particular modulates gene expression programmes that promote metastasis of solid tumours by stimulating macrophage infiltration, inflammation, angiogenesis, epithelial–mesenchymal transition and tumour invasion, and by inhibiting cellular immune responses and programmed cell death. Haematological cancers are modulated by sympathetic nervous system (SNS) regulation of stem cell biology and haematopoietic differentiation programmes. In addition to identifying a molecular basis for physiologic stress effects on cancer, these findings have also identified new pharmacological strategies to inhibit cancer progression in vivo.

At a glance

Figures

  1. Sympathetic nervous system regulation of the tumour microenvironment.
    Figure 1: Sympathetic nervous system regulation of the tumour microenvironment.

    Sympathetic nervous system (SNS) activation can regulate gene expression and cellular function in the tumour microenvironment through various pathways. Direct SNS effects on tumour biology are mediated by catecholamine neuroeffector molecules (adrenaline and noradrenaline) that are released into the tumour microenvironment to engage adrenergic receptors that are expressed on many types of tumour cells and their surrounding stromal elements, such as tumour-associated macrophages and vascular endothelial cells. Adrenaline is released from the adrenal gland and circulates to the tumour microevironment through the vasculature, whereas noradrenaline is released from sympathetic nerve fibres within the tumour microenvironment, which generally associate with the vasculature and can sometimes radiate dendritic fibres into the tumour parenchyma. Indirect effects on tumour biology are mediated by release of catecholamine neuroeffector molecules into distal tissue sites that regulate systemic biological processes that subsequently impinge on tumour biology, such as regulation of immune cell development (for example, myelopoiesis in the bone marrow and spleen, and lymphocyte differentiation in secondary lymphoid organs such as the spleen and lymph nodes) and trafficking (for example, monocyte and macrophage recruitment by chemokines such as C-C motif ligand 2 (CCL2) and growth factors such as colony-stimulation factor 1 (CSF1)), or regulation of systemic metabolic and hormonal regulators of tumour growth (for example, glucose mobilization from the liver and circulating adipokines from white adipose tissue). These multiple regulatory pathways allow the SNS to exert highly pleiotropic effects on tumour progression and metastasis of many solid epithelial tumours (for example, breast, prostate, ovary, lung and pancreas tumours) as well as haematological malignancies by innervation of lymphoid organs such as the bone marrow, spleen and lymph nodes. MDSC, myeloid-derived suppressor cell; NK cell, natural killer cell.

  2. Molecular mechanisms for sympathetic nervous system regulation of tumour progression.
    Figure 2: Molecular mechanisms for sympathetic nervous system regulation of tumour progression.

    Sympathetic nervous system (SNS) signalling through α-adrenergic and β-adrenergic receptor systems can regulate a wide variety of molecular processes involved in tumour progression and metastasis, including DNA damage repair, signalling by cellular and viral oncogenes, expression of pro-inflammatory mediators (such as cytokines, chemokines and prostaglandins) by tumour cells and immune cells, recruitment and pro-metastatic transcriptional programming of macrophages, angiogenesis and lymphangiogenesis, epithelial–mesenchymal transition (EMT), tumour cell motility and invasive capacity, resistance to apoptosis and chemotherapy-mediated cell death, and inhibition of cytokines and cytotoxic function in adaptive immune responses. SNS activation also exerts immunoregulatory effects through innervation of the bone marrow haematopoietic niche to promote stem cell mobilization and development of myeloid lineage immune cells (monocytes and macrophages, and myeloid-derived suppressor cells), through innervation of the spleen to influence extramedullary myelopoiesis of monocytes, macrophages and myeloid-derived suppressor cells, and through innervation of other primary and secondary lymphoid organs to inhibit cellular immune responses and promote humoral immune responses. SNS activation additionally regulates a wide variety of systemic metabolic and hormonal processes that can affect tumour progression, including mobilization of glucose and fatty acids from the liver, and adipokines and pro-inflammatory cytokines from white adipose tissue. Many of these molecular effects have been found to be regulated by β-adrenergic receptors, which regulate cellular and viral gene expression via activation of multiple intracellular signal transduction pathways including cyclic AMP-mediated activation of protein kinase A (PKA), which subsequently phosphorylates transcription factors such as cAMP response element-binding protein (CREB); cAMP-mediated activation of the guanine exchange protein activated by adenylyl cyclase (EPAC); and β-arrestin-mediated activation of MAP kinase signalling pathways. β-adrenergic-induction of multiple intracellular signalling pathways further amplifies the impact of the multiple parallel extracellular signalling pathways (Fig. 1) to generate a highly pleiotropic network of molecular effects that generally stimulate tumour progression and metastasis. TH, T helper.

References

  1. Weiner, H. Perturbing the Organism: The Biology of Stressful Experience (Univ. of Chicago Press, 1992).
  2. Sapolsky, R. M. Why Zebras Don't Get Ulcers: A Guide To Stress, Stress-Related Diseases, And Coping (Freeman, 1994).
  3. Sherwood, L. Human Physiology: From Cells to Systems (Cengage Learning, 2015).
  4. Katayama, Y. et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124, 407421 (2006).
  5. Sloan, E. K. et al. Social stress enhances sympathetic innervation of primate lymph nodes: mechanisms and implications for viral pathogenesis. J. Neurosci. 27, 88578865 (2007).
  6. Lutgendorf, S. K. et al. Depression, social support, and β-adrenergic transcription control in human ovarian cancer. Brain Behav. Immun. 23, 176183 (2009).
  7. Powell, N. D. et al. Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis. Proc. Natl Acad. Sci. USA 110, 1657416579 (2013).
  8. Scheiermann, C., Kunisaki, Y. & Frenette, P. S. Circadian control of the immune system. Nat. Rev. Immunol. 13, 190198 (2013).
  9. Cole, S. W. Social regulation of human gene expression: mechanisms and implications for public health. Am. J. Publ. Health 103 (Suppl. 1), S84S92 (2013).
  10. Cole, S. W. Human social genomics. PLoS Genet. 10, e1004601 (2014).
  11. Hanoun, M., Maryanovich, M., Arnal-Estape, A. & Frenette, P. S. Neural regulation of hematopoiesis, inflammation, and cancer. Neuron 86, 360373 (2015).
  12. Irwin, M. R. & Cole, S. W. Reciprocal regulation of the neural and innate immune systems. Nat. Rev. Immunol. 11, 625632 (2011).
  13. Antoni, M. H. et al. The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat. Rev. Cancer. 6, 240248 (2006).
  14. Cole, S. W. & Sood, A. K. Molecular pathways: β-adrenergic signaling in cancer. Clin. Cancer Res. 18, 12011206 (2012).
  15. Armaiz-Pena, G. N., Cole, S. W., Lutgendorf, S. K. & Sood, A. K. Neuroendocrine influences on cancer progression. Brain Behav. Immun. 30, S19S25 (2013).
  16. Cole, S. W. Nervous system regulation of the cancer genome. Brain Behav. Immun. 30 (Suppl.), S10S18 (2013).
  17. Powe, D. G. & Entschladen, F. Targeted therapies: using β-blockers to inhibit breast cancer progression. Nat. Rev. Clin. Oncol. 8, 511512 (2011).
  18. Richter, S. D. et al. Time kinetics of the endocrine response to acute psychological stress. J. Clin. Endocrinol. Metab. 81, 19561960 (1996).
  19. Schommer, N. C., Hellhammer, D. H. & Kirschbaum, C. Dissociation between reactivity of the hypothalamus–pituitary–adrenal axis and the sympathetic–adrenal–medullary system to repeated psychosocial stress. Psychosom. Med. 65, 450460 (2003).
  20. Wingenfeld, K., Whooley, M. A., Neylan, T. C., Otte, C. & Cohen, B. E. Effect of current and lifetime posttraumatic stress disorder on 24-h urinary catecholamines and cortisol: results from the Mind Your Heart Study. Psychoneuroendocrinology 52, 8391 (2015).
  21. Sloan, E. K., Capitanio, J. P., Tarara, R. P. & Cole, S. W. Social temperament and lymph node innervation. Brain Behav. Immun. 22, 717726 (2008).
  22. Schofl, C., Becker, C., Prank, K., von zur Muhlen, A. & Brabant, G. Twenty-four-hour rhythms of plasma catecholamines and their relation to cardiovascular parameters in healthy young men. Eur. J. Endocrinol. 137, 675683 (1997).
  23. Dimitrov, S. et al. Cortisol and epinephrine control opposing circadian rhythms in T cell subsets. Blood 113, 51345143 (2009).
  24. Eng, J. W. et al. Housing temperature-induced stress drives therapeutic resistance in murine tumour models through β2-adrenergic receptor activation. Nat. Commun. 6, 6426 (2015).
  25. Mendez-Ferrer, S., Lucas, D., Battista, M. & Frenette, P. S. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442447 (2008).
  26. Dutta, P. et al. Myocardial infarction accelerates atherosclerosis. Nature 487, 325329 (2012).
  27. Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754758 (2014).
  28. Nakai, A., Hayano, Y., Furuta, F., Noda, M. & Suzuki, K. Control of lymphocyte egress from lymph nodes through β2-adrenergic receptors. J. Exp. Med. 211, 25832598 (2014).
  29. Sloan, E. K., Capitanio, J. P. & Cole, S. W. Stress-induced remodeling of lymphoid innervation. Brain Behav. Immun. 22, 1521 (2008).
  30. Elenkov, I. J., Wilder, R. L., Chrousos, G. P. & Vizi, E. S. The sympathetic nerve — an integrative interface between two supersystems: the brain and the immune system. Pharmacol. Rev. 52, 595638 (2000).
  31. Kohm, A. P. & Sanders, V. M. Norepinephrine and β 2-adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo. Pharmacol. Rev. 53, 487525 (2001).
  32. Cole, S. et al. Computational identification of gene-social environment interaction at the human IL6 locus. Proc. Natl Acad. Sci. USA 107, 56815686 (2010).
  33. Hori, Y. et al. Naftopidil, a selective α1-adrenoceptor antagonist, suppresses human prostate tumor growth by altering interactions between tumor cells and stroma. Cancer Prev. Res. 4, 8796 (2011).
  34. Calvani, M. et al. Norepinephrine promotes tumor microenvironment reactivity through β3-adrenoreceptors during melanoma progression. Oncotarget 6, 46154632 (2015).
  35. Thaker, P. H. et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat. Med. 12, 939944 (2006).
  36. Dal Monte, M. et al. Functional involvement of β3-adrenergic receptors in melanoma growth and vascularization. J. Mol. Med. 91, 14071419 (2013).
  37. Sterling, P. in Allostasis, Homeostasis, and the Costs of Physiological Adaptation (ed. Schulkin, J.) 1764 (Cambridge Univ. Press, 2004).
  38. Chida, Y., Hamer, M., Wardle, J. & Steptoe, A. Do stress-related psychosocial factors contribute to cancer incidence and survival? Nat. Clin. Pract. Oncol. 5, 466475 (2008).
  39. Powe, D. G. et al. β-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget 1, 628638 (2010).
  40. Barron, T. I., Connolly, R. M., Sharp, L., Bennett, K. & Visvanathan, K. β blockers and breast cancer mortality: a population-based study. J. Clin. Oncol. 29, 26352644 (2011).
  41. Melhem-Bertrandt, A. et al. β-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J. Clin. Oncol. 29, 26452652 (2011).
  42. De Giorgi, V. et al. Treatment with β-blockers and reduced disease progression in patients with thick melanoma. Arch. Intern. Med. 171, 779781 (2011).
  43. Lemeshow, S. et al. β-blockers and survival among Danish patients with malignant melanoma: a population-based cohort study. Cancer Epidemiol. Biomarkers Prev. 20, 22732279 (2011).
  44. Aydiner, A., Ciftci, R., Karabulut, S. & Kilic, L. Does β-blocker therapy improve the survival of patients with metastatic non-small cell lung cancer? Asian Pac. J. Cancer Prev. 14, 61096114 (2013).
  45. Botteri, E. et al. Therapeutic effect of β-blockers in triple-negative breast cancer postmenopausal women. Breast Cancer Res. Treat. 140, 567575 (2013).
  46. De Giorgi, V. et al. Effect of β-blockers and other antihypertensive drugs on the risk of melanoma recurrence and death. Mayo Clin. Proc. 88, 11961203 (2013).
  47. Grytli, H. H., Fagerland, M. W., Fossa, S. D., Tasken, K. A. & Haheim, L. L. Use of β-blockers is associated with prostate cancer-specific survival in prostate cancer patients on androgen deprivation therapy. Prostate 73, 250260 (2013).
  48. Grytli, H. H., Fagerland, M. W., Fossa, S. D. & Tasken, K. A. Association between use of β-blockers and prostate cancer-specific survival: a cohort study of 3561 prostate cancer patients with high-risk or metastatic disease. Eur. Urol. 65, 635641 (2014).
  49. Sloan, E. K. et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 70, 70427052 (2010).
  50. Madden, K. S., Szpunar, M. J. & Brown, E. B. β-adrenergic receptors (β-AR) regulate VEGF and IL-6 production by divergent pathways in high β-AR-expressing breast cancer cell lines. Breast Cancer Res. Treat. 130, 747758 (2011).
  51. Palm, D. et al. The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by β-blockers. Int. J. Cancer. 118, 27442749 (2006).
  52. Hassan, S. et al. Behavioral stress accelerates prostate cancer development in mice. J. Clin. Invest. 123, 874886 (2013).
  53. Pasquier, E. et al. β-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma. Br. J. Cancer 108, 24852494 (2013).
  54. Wolter, J. K. et al. Anti-tumor activity of the β-adrenergic receptor antagonist propranolol in neuroblastoma. Oncotarget 5, 161172 (2014).
  55. Hasegawa, H. & Saiki, I. Psychosocial stress augments tumor development through β-adrenergic activation in mice. Jpn J. Cancer Res. 93, 729735 (2002).
  56. Goldfarb, Y. et al. Improving postoperative immune status and resistance to cancer metastasis: a combined perioperative approach of immunostimulation and prevention of excessive surgical stress responses. Ann. Surg. 253, 798810 (2011).
  57. Kim-Fuchs, C. et al. Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for β-adrenergic signaling in the pancreatic microenvironment. Brain Behav. Immun. 40, 4047 (2014).
  58. Lamkin, D. M. et al. Chronic stress enhances progression of acute lymphoblastic leukemia via β-adrenergic signaling. Brain Behav. Immun. 26, 635641 (2012).
  59. Inbar, S. 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 6, e19246 (2011).
  60. Hara, M. R. et al. A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1. Nature 477, 349353 (2011).
  61. Hara, M. R., Sachs, B. D., Caron, M. G. & Lefkowitz, R. J. Pharmacological blockade of a β2AR-β-arrestin-1 signaling cascade prevents the accumulation of DNA damage in a behavioral stress model. Cell Cycle 12, 219224 (2013).
  62. Reeder, A. et al. Stress hormones reduce the efficacy of paclitaxel in triple negative breast cancer through induction of DNA damage. Br. J. Cancer 112, 14611470 (2015).
  63. Armaiz-Pena, G. N. et al. Src activation by β-adrenoreceptors is a key switch for tumour metastasis. Nat. Commun. 4, 1403 (2013).
  64. Shi, M. et al. The β2-adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells. Breast Cancer Res. Treat. 125, 351362 (2011).
  65. Gu, L., Lau, S. K., Loera, S., Somlo, G. & Kane, S. E. Protein kinase A activation confers resistance to trastuzumab in human breast cancer cell lines. Clin. Cancer Res. 15, 71967206 (2009).
  66. Chang, M. et al. β-adrenoreceptors reactivate Kaposi's sarcoma-associated herpesvirus lytic replication via PKA-dependent control of viral RTA. J. Virol. 79, 1353813547 (2005).
  67. zur Hausen, H. Infections Causing Human Cancer, (Wiley-VCH, 2008).
  68. Nilsson, M. B. et al. Stress hormones regulate interleukin-6 expression by human ovarian carcinoma cells through a Src-dependent mechanism. J. Biol. Chem. 282, 2991929926 (2007).
  69. Shahzad, M. M. et al. Stress effects on FosB- and interleukin-8 (IL8)-driven ovarian cancer growth and metastasis. J. Biol. Chem. 285, 3546235470 (2010).
  70. Yang, R., Lin, Q., Gao, H. B. & Zhang, P. Stress-related hormone norepinephrine induces interleukin-6 expression in GES-1 cells. Braz. J. Med. Biol. Res. 47, 101109 (2014).
  71. Cakir, Y., Plummer, H. K., 3rd, Tithof, P. K. & Schuller, H. M. β-adrenergic and arachidonic acid-mediated growth regulation of human breast cancer cell lines. Int. J. Oncol. 21, 153157 (2002).
  72. Armaiz-Pena, G. N. et al. Adrenergic regulation of monocyte chemotactic protein 1 leads to enhanced macrophage recruitment and ovarian carcinoma growth. Oncotarget 6, 42664273 (2015).
  73. Collado-Hidalgo, A., Sung, C. & Cole, S. Adrenergic inhibition of innate anti-viral response: PKA blockade of type I interferon gene transcription mediates catecholamine support for HIV-1 replication. Brain Behav. Immun. 20, 552563 (2006).
  74. Cole, S. W., Korin, Y. D., Fahey, J. L. & Zack, J. A. Norepinephrine accelerates HIV replication via protein kinase A-dependent effects on cytokine production. J. Immunol. 161, 610616 (1998).
  75. Glasner, A. et al. Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a β-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J. Immunol. 184, 24492457 (2010).
  76. Lee, J. W. et al. Surgical stress promotes tumor growth in ovarian carcinoma. Clin. Cancer Res. 15, 26952702 (2009).
  77. Magnon, C. et al. Autonomic nerve development contributes to prostate cancer progression. Science 341, 1236361 (2013).
  78. Bruzzone, A. et al. α2-adrenoceptors enhance cell proliferation and mammary tumor growth acting through both the stroma and the tumor cells. Curr. Cancer Drug Targets 11, 763774 (2011).
  79. Flint, M. S. et al. Chronic exposure to stress hormones promotes transformation and tumorigenicity of 3T3 mouse fibroblasts. Stress 16, 114121 (2013).
  80. Cao, L. et al. Environmental and genetic activation of a brain–adipocyte BDNF/leptin axis causes cancer remission and inhibition. Cell 142, 5264 (2010).
  81. Cao, L. & During, M. J. What is the brain–cancer connection? Annu. Rev. Neurosci. 35, 331345 (2012).
  82. Hanoun, M. et al. Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell 15, 365375 (2014).
  83. Lang, K. et al. Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs. Int. J. Cancer 112, 231238 (2004).
  84. Drell, T. L. t. et al. Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells. Breast Cancer Res. Treat. 80, 6370 (2003).
  85. Landen, C. N. Jr et al. Neuroendocrine modulation of signal transducer and activator of transcription-3 in ovarian cancer. Cancer Res. 67, 1038910396 (2007).
  86. Sood, A. K. et al. Stress hormone-mediated invasion of ovarian cancer cells. Clin. Cancer Res. 12, 369375 (2006).
  87. Yang, E. V. et al. Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells. Cancer Res. 66, 1035710364 (2006).
  88. Chakroborty, D., Sarkar, C., Basu, B., Dasgupta, P. S. & Basu, S. Catecholamines regulate tumor angiogenesis. Cancer Res. 69, 37273730 (2009).
  89. Yang, E. V. et al. Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav. Immun. 23, 267275 (2009).
  90. Moretti, S. et al. β-adrenoceptors are upregulated in human melanoma and their activation releases pro-tumorigenic cytokines and metalloproteases in melanoma cell lines. Lab Invest. 93, 279290 (2013).
  91. Liu, J. et al. The effect of chronic stress on anti-angiogenesis of sunitinib in colorectal cancer models. Psychoneuroendocrinology 52, 130142 (2015).
  92. Sood, A. K. et al. Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis. J. Clin. Invest. 120, 15151523 (2010).
  93. Sastry, K. S. et al. Epinephrine protects cancer cells from apoptosis via activation of cAMP-dependent protein kinase and BAD phosphorylation. J. Biol. Chem. 282, 1409414100 (2007).
  94. Deng, G. H. et al. Exogenous norepinephrine attenuates the efficacy of sunitinib in a mouse cancer model. J. Exp. Clin. Cancer Res. 33, 21 (2014).
  95. Dar, A. et al. Rapid mobilization of hematopoietic progenitors by AMD3100 and catecholamines is mediated by CXCR4-dependent SDF-1 release from bone marrow stromal cells. Leukemia 25, 12861296 (2011).
  96. Lucas, D. et al. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nat. Med. 19, 695703 (2013).
  97. Lutgendorf, S. K. et al. Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients. Brain Behav. Immun. 25, 250255 (2011).
  98. Ayala, G. E. et al. Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin. Cancer Res. 14, 75937603 (2008).
  99. Voss, M. J. & Entschladen, F. Tumor interactions with soluble factors and the nervous system. Cell Commun. Signal 8, 21 (2010).
  100. Guo, K. et al. Interaction of the sympathetic nerve with pancreatic cancer cells promotes perineural invasion through the activation of STAT3 signaling. Mol. Cancer Ther. 12, 264273 (2013).
  101. Xu, Q. et al. Stromal-derived factor-1α/CXCL12–CXCR4 chemotactic pathway promotes perineural invasion in pancreatic cancer. Oncotarget 6, 47174732 (2015).
  102. Flierl, M. A. et al. Phagocyte-derived catecholamines enhance acute inflammatory injury. Nature. 449, 721725 (2007).
  103. Campbell, J. P. et al. Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice. PLoS Biol. 10, e1001363 (2012).
  104. Lu, H. et al. Impact of β-blockers on prostate cancer mortality: a meta-analysis of 16,825 patients. Onco Targets Ther. 8, 985990 (2015).
  105. Wang, H. M. et al. Improved survival outcomes with the incidental use of β-blockers among patients with non-small-cell lung cancer treated with definitive radiation therapy. Ann. Oncol. 24, 13121319 (2013).
  106. Diaz, E. S., Karlan, B. Y. & Li, A. J. Impact of β blockers on epithelial ovarian cancer survival. Gynecol. Oncol. 127, 375378 (2012).
  107. Watkins, J. L. et al. Clinical impact of selective and non-selective β-blockers on survival in ovarian cancer patients. Cancer (in the press).
  108. Schuller, H. M., Porter, B. & Riechert, A. β-adrenergic modulation of NNK-induced lung carcinogenesis in hamsters. J. Cancer Res. Clin. Oncol. 126, 624630 (2000).
  109. Pasquier, E. et al. Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment. Oncotarget 2, 797809 (2011).
  110. Lin, Q. et al. Effect of chronic restraint stress on human colorectal carcinoma growth in mice. PLoS ONE 8, e61435 (2013).
  111. Ganz, P. A. & Cole, S. W. Expanding our therapeutic options: β blockers for breast cancer? J. Clin. Oncol. 29, 26122616 (2011).
  112. Neeman, E., Zmora, O. & Ben-Eliyahu, S. A new approach to reducing postsurgical cancer recurrence: perioperative targeting of catecholamines and prostaglandins. Clin. Cancer Res. 18, 48954902 (2012).
  113. Horowitz, M., Neeman, E., Sharon, E. & Ben-Eliyahu, S. Exploiting the critical perioperative period to improve long-term cancer outcomes. Nat. Rev. Clin. Oncol. 12, 213226 (2015).
  114. Boucek, R. J. Jr., Kirsh, A. L., Majesky, M. W. & Perkins, J. A. Propranolol responsiveness in vascular tumors is not determined by qualitative differences in adrenergic receptors. Otolaryngol. Head Neck Surg. 149, 772776 (2013).
  115. Mendez-Ferrer, S., Battista, M. & Frenette, P. S. Cooperation of β2- and β3-adrenergic receptors in hematopoietic progenitor cell mobilization. Ann. NY Acad. Sci. 1192, 139144 (2010).
  116. Magnon, C., Lucas, D. & Frenette, P. S. Trafficking of stem cells. Methods Mol. Biol. 750, 324 (2011).
  117. Szpunar, M. J., Burke, K. A., Dawes, R. P., Brown, E. B. & Madden, K. S. The antidepressant desipramine and α2-adrenergic receptor activation promote breast tumor progression in association with altered collagen structure. Cancer Prev. Res. 6, 12621272 (2013).
  118. Lamkin, D. M. et al. α2-adrenergic blockade mimics the enhancing effect of chronic stress on breast cancer progression. Psychoneuroendocrinology 51, 262270 (2015).
  119. Friedman, G. D., Udaltsova, N. & Habel, L. A. Norepinephrine antagonists and cancer risk. Int. J. Cancer 128, 737738; author reply 739 (2011).
  120. Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 14231437 (2013).
  121. Shan, T. et al. β2-adrenoceptor blocker synergizes with gemcitabine to inhibit the proliferation of pancreatic cancer cells via apoptosis induction. Eur. J. Pharmacol. 665, 17 (2011).
  122. Obeid, E. I. & Conzen, S. D. The role of adrenergic signaling in breast cancer biology. Cancer Biomark. 13, 161169 (2013).
  123. Zhao, C. M. et al. Denervation suppresses gastric tumorigenesis. Sci. Transl Med. 6,250ra115 (2014).
  124. Rosas-Ballina, M. et al. Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proc. Natl Acad. Sci. USA 105, 1100811013 (2008).
  125. Villanueva, M. T. Therapeutics: gastric cancer gets a red carpet treatment. Nat. Rev. Cancer 14, 648649 (2014).

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Affiliations

  1. Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles (UCLA) Molecular Biology Institute, 11–934 Factor Building, UCLA School of Medicine, Los Angeles California 90095–1678, USA; and the Jonsson Comprehensive Cancer Center, UCLA, 8–684 Factor Building, Box 951781, Los Angeles, California 90095–1781, USA.

    • Steven W. Cole
  2. Department of Gynecologic Oncology; and the Department of Cancer Biology, University of Texas M. D. Anderson Comprehensive Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.

    • Archana S. Nagaraja
  3. Department of Psychology, E11 Seashore Hall, Department of Obstetrics and Gynecology, 200 Hawkins Drive; Department of Urology, 3 Roy Carver Pavilion, 200 Hawkins Drive; and the Holden Comprehensive Cancer Center, 200 Hawkins Drive, University of Iowa, Iowa City 52242–1407, USA.

    • Susan K. Lutgendorf
  4. Basic Biobehavioral and Psychological Sciences Branch, Behavioral Research Program, Division of Cancer Control and Population Sciences, United States National Cancer Institute, Building 9609 Room 3E133, 9609 Medical Center Drive, Rockville, Maryland 20850, USA.

    • Paige A. Green
  5. Department of Gynecologic Oncology; and the Department of Cancer Biology, University of Texas M. D. Anderson Comprehensive Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.

    • Anil K. Sood

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The authors declare no competing interests.

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Author details

  • Steven W. Cole

    Steven W. Cole is a professor of medicine in the Division of Hematology–Oncology at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA), USA. His research uses molecular genetics and computational bioinformatics to analyse the pathways by which social and environmental factors influence the activity of the human genome, as well as viral and tumour genomes. He pioneered the field of human social genomics, and serves as Director of the UCLA Social Genomics Core Laboratory. He is also a member of the Jonsson Comprehensive Cancer Center, the Norman Cousins Center, the UCLA AIDS Institute, and the UCLA Molecular Biology Institute.

  • Archana S. Nagaraja

    Archana S. Nagaraja is a doctoral student in the Department of Cancer Biology and Department of Gynecologic Oncology at the University of Texas at MD Anderson Cancer Center, Houston, Texas. She is supported by a Research Training Award from the Cancer Prevention and Research Institute of Texas. Her research studies the role of adrenergic signalling in modulating inflammation and metastasis in ovarian cancer.

  • Susan K. Lutgendorf

    Susan K. Lutgendorf is a professor in the Departments of Psychology, Obstetrics and Gynecology, and Urology and member of the Holden Comprehensive Cancer Center at the University of Iowa, USA. She directs US National Institute of General Medical Sciences (NIGMS)-funded training programme entitled 'Mechanisms of Health and Disease at the Behavioral–Biomedical Interface'. Her current work, funded by the US National Cancer Institute, Maryland, USA, examines how stress, depression and social support are linked to biological processes involved in tumour progression. Her work has been recognized by a New Investigator Award from the Psychoneuroimmunology Research Society, an American Psychological Association Award for Outstanding Contributions to Health Psychology.

  • Paige A. Green

    Paige A. Green is the Chief of at the Basic Biobehavioral and Psychological Sciences Branch in the Behavioral Research Program, of the Division of Cancer Control and Population Sciences at the US National Cancer Institute (NCI), Maryland, USA. She serves as the Chair for the NCI Network on Biobehavioural Pathways in Cancer, a research consortium that strives to accelerate the discovery, development, and clinical translation of cancer relevant molecular pathways and networks regulated by social, behavioural, and psychological factors through the central nervous system.

  • Anil K. Sood

    Anil K. Sood is the Professor and Vice Chairman for Translational Research in the Department of Gynecologic Oncology and has a joint appointment in the Department of Cancer Biology at the University of Texas M.D. Anderson Cancer Center, Houston, USA. He is also Co-Director of the Center for RNA Interference (RNAi) and Non-Coding RNA and Director of the Blanton-Davis Ovarian Cancer Research Programme. His main research interests include neuroendocrine effects on cancer metastasis, RNAi therapeutics, and development of new strategies for targeting the tumour microenvironment.

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