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Review
. 2020 Sep 30:8:586757.
doi: 10.3389/fcell.2020.586757. eCollection 2020.

Systemic Regulation of Cancer Development by Neuro-Endocrine-Immune Signaling Network at Multiple Levels

Shu-Heng Jiang  1 , Xiao-Xin Zhang  1 , Li-Peng Hu  1 , Xu Wang  1 , Qing Li  1 , Xue-Li Zhang  1 , Jun Li  1 , Jian-Ren Gu  1 , Zhi-Gang Zhang  1
Affiliations
Review

Systemic Regulation of Cancer Development by Neuro-Endocrine-Immune Signaling Network at Multiple Levels

Shu-Heng Jiang et al. Front Cell Dev Biol. .

Abstract

The overarching view of current tumor therapies simplifies cancer to a cell-biology problem in which neoplasms are caused solely by malignant cells and the exploration of carcinogenesis and tumor progression largely focuses on somatic mutations and other genetic abnormalities of cancer cells. The limited therapeutic response indicates that cancer is driven not only by endogenous oncogenic factors and reciprocal interactions within the tumor microenvironment, but also by complex systemic processes. Homeostasis is the fundamental premise of health, and is maintained by systemic regulation of neuro-endocrine-immune axis. Cancer is also a systemic disease that manifested by dysfunction of the nervous, endocrine, and immune systems. Multiple axes of regulation exist in cancer, including central-, organ-, and microenvironment-level manipulation. At each specific regulatory level, the tridirectional communication among the nervous, endocrine, and immune factors transmit flexible signaling to induce proliferation, invasion, reprogrammed metabolism, therapeutic resistance, and other malignant phenotypes of cancer cells, resulting in the extremely poor prognosis of this lethal disease. Understanding this coordinated signaling network will enable the development of new approaches for cancer treatment via behavioral and pharmacological interventions.

Keywords: chronic stress; immune evasion; inter-organ communication; neurotransmitter; perineural invasion; systematic regulation.

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Figures

FIGURE 1
FIGURE 1
Effects of stress-associated factors on cancer pathogenesis. Stressful events result in activation of cortical and limbic structures of the central nervous system, which in turn activate the hypothalamic–pituitary–adrenal (HPA) axis and autonomic nervous system (ANS). In response to psychological stress, the paraventricular nucleus of the hypothalamus secretes corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP), both of which stimulate the anterior pituitary to release adrenocorticotrophic hormone (ACTH). Circulating ACTH activates the adrenal cortex to produce glucocorticoid hormone cortisol. ANS responses to stress are largely mediated by activation of the sympathetic nervous system (SNS) subsequent secretion of epinephrine (E) and norepinephrine (NE). Factors released from HPA and ANS axis have direct effects on cancer pathogenesis. Moreover, glucocorticoids, catecholamines, and other neuroendocrine factors can influence immune response to support tumor initiation, growth, metastasis, and therapy-resistance.
FIGURE 2
FIGURE 2
Neuro-endocrine-immune factors mediates tumor-organ communication. (A) In normal conditions, inter-organ communications are mediated primarily by neuro-endocrine-immune (NEI) factors. In cancers, the tumor microenvironment-derived endocrine hormones, immune factors (cytokines and chemokines) and metabolic byproducts (such as lactate) are secreted into the blood. These neuro-endocrine-immune factors can connect systemic metabolism and induce metabolic alterations in many human organs including the liver, the pancreas, adipose tissue, skeletal muscle and others as shown. Moreover, peripheral organs further facilitate tumorigenesis by potentially supplying metabolic fuel. (B) Adiponectin, leptin, and adiposin are secreted by adipose tissues. Then, they target the liver to increase hepatokine transcription, which ultimately promotes HCC progression. (C) Lung adenocarcinoma derived IL-6, TNFα, and lactate target the liver to induce pro-inflammatory response and alter the liver metabolism.
FIGURE 3
FIGURE 3
Neuro-endocrine-immune regulations in the tumor microenvironment. (A) In addition to cancer cells, the tumor microenvironment (TME) is infiltrated by many other cell types, including cancer-associated fibroblasts (CAFs), endothelial cells (ECs), and various immune cell subsets, such as macrophages, natural-killer cells, dendritic cells, and T cells. Notably, emerging evidence has revealed that infiltrated nerve is an important component of the TME. (B) Neurotransmitters (catecholamines and acetylcholine) released by nerve endings and endocrine-immune factors secreted by cancer cells and other cell components in the TME have a stimulatory impact on tumor growth, metastasis, angiogenesis, demoplasia, and inflammation in an autocrine or paracrine manner.
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