Sympathetic nervous system regulation of the tumour microenvironment

Journal name:
Nature Reviews Cancer
Year published:
Published online


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


  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.


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  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

Competing interests statement

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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