Sympathetic nervous system regulation of the tumour microenvironment

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.

Figure 1. SNS regulation of the tumour microenvironment

SNS activation can regulate gene expression and cellular function in the tumour microenvironment through a variety of pathways. Direct SNS effects on tumour biology are mediated by catecholamine neuroeffector molecules (epinephrine and norepinephrine) that are released into the tumor microenvironment to engage adrenergic receptors that are expressed on many types of tumor cells and their surrounding stromal elements such as tumor-associated macrophages and vascular endothelial cells. Epinephrine is released from the adrenal gland and circulates to the tumour microevironment through the vasculature, whereas norepinephrine is released from sympathetic nerve fibers within the tumour microenvironment, which generally associate with the vasculature and can sometimes radiate dendritic fibers into the tumor parenchyma. Indirect effects on tumor biology are mediated by release of catecholamine neuroeffector molecules into distal tissue sites that regulate systemic biological processes which subsequently impinge on tumour biology, such as regulation of immune cell development (e.g., myelopoiesis in the bone marrow and spleen, and lymphocyte differentiation in secondary lymphoid organs such as the spleen and lymph nodes) and trafficking (e.g., monocyte/macrophage recruitment via chemokines such as MCP-1/CCL2 and growth factors such as M-CSF/CSF1), or regulation of systemic metabolic and hormonal regulators of tumour growth (e.g., 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 tumors (e.g., breast, prostate, ovary, lung, pancreas) as well as hematologic malignancies via innervation of lymphoid organs such as the bone marrow, spleen, and lymph nodes.

Figure 2. Molecular mechanisms for SNS regulation of tumor progression

SNS signaling through α- and β-adrenergic receptor systems can regulate a wide variety of molecular processes involved in tumour progression and metastasis, including DNA damage repair, signaling by cellular and viral oncogenes, expression of pro-inflammatory mediators (cytokines, chemokines, prostaglandins) by tumour cells and immune cells, recruitment and pro-metastatic transcriptional programming of macrophages, angiogenesis and lymphangiogenesis, epithelial-mesenchymal transition, tumor 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 hematopoietic 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 extra-medullary 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 impact 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 (ADRB), which regulate cellular and viral gene expression via activation of multiple intracellular signal transduction pathways including cyclic-3′-5′-adenosine monophosphate (cAMP)-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 signaling pathways. β-adrenergic-induction of multiple intracellular signaling pathways further amplifies the impact of the multiple parallel extracellular signaling pathways (Figure 1) to generate a highly pleiotropic network of molecular effects that generally stimulate tumor progression and metastasis.