Cancer is a major public health problem and is the major cause of death worldwide. Eighteen million new cancer cases and 9 million deaths occurred worldwide in 2018 (1). The occurrence of tumors involves a multifactor and multistep process (2). Most tumors are caused by an interaction of environmental and genetic factors (3). Environmental factors mainly include biological, physical and chemical factors. Humans are exposed to these carcinogenic factors through a variety of lifestyle or occupational exposures. Moreover, in most cases, humans are not simply exposed to a single carcinogenic agent, but often to a complex mix of carcinogens through a variety of lifestyles (4). Genetic factors determine an individual’s susceptibility (5). There are at least three mechanisms by which certain individuals are susceptible to tumors. Offspring acquire mutated genes through inheritance. Genetic mutations make carriers more sensitive to environmental factors, accelerating the occurrence and accumulation of cancer events. The genetically acquired mutant genes are beneficial to the cloning and selection of tumor cells and the growth of tumor cells (6). So far, more and more evidences have shown that social stress or chronic stress promotes the occurrence and development of tumor by affecting the neuro-endocrine-immune system (7, 8).

Stress is an organism’s response to external stimuli, including physiological and psychological stimuli (9), which exert effects on the molecular, cellular, organ, and psychological levels (10). Depending on how long the stimulation lasts, stress can be divided into acute stress and chronic stress (11). Generally, acute stress is beneficial to the body, while chronic stress is harmful to the body at the psychological and physiological levels (12). Numerous clinical and in vitro studies have shown that chronic stress affects the initiation, progression and metastasis of various cancers through changes in the neuroendocrine system and immune system. Social stress is a potential factor for higher mortality from breast cancer in women (13). Social stress is associated with increased lung cancer morbidity and mortality. The present study confirmed that social stress can stimulate the growth of non-small cell lung cancer (NSCLC) in vivo, and that gamma-aminobutyric acid (GABA) inhibits this effect (14).

Chronic stress can cause changes in the neuroendocrine immune system. Disruption of neurotransmitters, stress hormones and immune cells alters the microenvironment to adapt to the occurrence and development of tumors. Recently, our research team have shown that chronic stress induces invasion and metastasis of epithelial ovarian cancer through the NE/AKT/β-catenin/SLUG axis (15) ( Table 1 ). In addition, chronic stress promotes breast cancer metastasis by activating the STAT3 signal pathway through Mir-337-3p (8). Chronic stress promotes lung metastasis of circulating breast cancer cells by activating β -adrenergic signal and remodeling the premetastatic niche (16)( Tables 1 , 2 ). Chronic stress induces the release of norepinephrine, which promotes oral cancer progression through β₂-adrenergic receptors (27). Isoprorenol promotes tumor angiogenesis by activating the PlexinA1/VEGFR2-JAK2-STAT3 signal transduction pathway within human umbilical vein endothelial cells (HUVECs), which may be a candidate target for the development of an anti-tumor angiogenesis strategy (28).

The two main neuroendocrine systems activated by chronic stress are the hypothalamic-pituitary adrenal (HPA) axis and sympathetic nervous system (SNS). The HPA axis contains three endocrine glands (the hypothalamus, pituitary, and adrenal glands). In response to chronic stress, the hypothalamus releases corticotropin-releasing hormone (CRH), which triggers the anterior pituitary gland to secrete adrenocorticotropic hormone (ACTH) (Antoni, M. H. 2006). ACTH stimulates the adrenal gland to release stress hormones, including epinephrine (E), norepinephrine (NE), and cortisol. The SNS is one of the two main parts of the autonomic nervous system, which can promote the release of catecholamines (dopamine (DA), E, and NE) by stimulating the adrenal medulla or through neurons (12).

Chronic stress also plays an important role in immune dysfunction that affects tumor behavior (29, 30). Chronic stress selectively inhibits Th1 - and CTL-mediated cellular immunity and interferon production, which impairing immune surveillance (7). The long-term decline in immune surveillance increases the risk of cancer invasion and metastasis and reduces the effectiveness of antitumor therapy. In addition, chronic stress causes DNA damage that decreases natural killer cells and dendritic cells, thus promoting lymphatic metastasis and hematogenous metastasis. Studies have reported that sympathetic fibres innervate lymphoid organs and tissues, including the thymus, spleen, lymph nodes, and bone marrow, indicating the presence of functional interactions between neurons and the immune system (31, 32). In addition, the lymphatic system is an interconnected system of vessels, spaces, and nodes in the body which circulates lymph, which is a major source of chemokines and provides a pathway for tumor cells to escape through the body (33). Thus, the interactions of neuroendocrine system and immune system may play an important role on the occurrence and development of tumors caused by chronic stress.

An increasing number of studies indicate that adrenergic signaling plays a fundamental role in chronic stress-induced tumor growth. Adrenergic receptor inhibitors take effect through blocking adrenergic signal. Propranolol, a non-selective β antagonist, inhibits the proliferation of gastric cancer cells by reducing the number of CD3+CD8+ T cells and reducing bone marrow-derived inhibitory cells (MDSC)-based immunosuppression (20) ( Tables 2 , 3 ). 6-Hydroxydopamine hydrobromide (6-OHDA) blocks adrenergic signaling through ablating sympathetic nerve function, thus inhibiting stress-induced lung metastasis (16). γ-aminobutyric acid (GABA) is a kind of inhibitory neurotransmitter, which inhibits the development of transplanted tumors by down-regulating the COX-2 protein and P-5-Lox (14). In addition, the resistance to radiotherapy and chemotherapy are often the failure of treatment and affect the patient life. It has been reported that adrenergic inhibitors combined with radiotherapy/chemotherapy can effectively reverse drug resistance and radiotherapy resistance, and improve the prognosis of cancer patients (34). This could be a potentially meaningful therapeutic strategy.

Here, we systematically review the role of chronic stress-mediated neuroendocrine and immune responses in the remodeling of tumor microenvironment that promotes tumorigenesis and tumor development. In addition, the inhibitory effect of adrenergic antagonists on chronic stress-related tumor development and the effect of adrenergic antagonists on chemoradiotherapy resistance will be fully discussed.

Pessimistic attitudes may be associated with decreased cytotoxicity of natural killer cells and cytotoxicity/suppressor T cells, causing squamous intraepithelial lesions and contributing to the development of cervical cancer (75). Vaccine failure in stressed mice was associated with reduced production of the effector CD8+ T cell interferons and a significant reduction in cytotoxic T lymphocyte (CTL)-mediated killing. An analysis of dendritic cell phenotypes showed that migratory and lymphoid dendritic cells were not fully mature after antigen uptake (76). Chronic stress induced a significant increase in the expression of Foxp3 and granzyme B, while social isolation significantly reduced the numbers of CD3+ and CD8+ T cells and activated CD69+ and CD3+ T cells (55) ( Table 1 ). Adrenergic signaling triggered by chronic stress participates in immunosuppression of the tumor microenvironment by promoting the proliferation and activation of bone marrow-derived inhibitory cells (MDSCs) (20). Chronic stress triggers the release of stress hormones that suppress the cancer cell killing ability of granulocytes (77). Chronic stress induces the release of prostaglandins by macrophages, which in turn increases tumor cell production of VEGF, leading to vascular remodeling and lymph node metastasis (33). Chronic stress exerts a significant effect on T cell function and the production of the Th1/Th2 cell mediator H₄R (78). Chronic stress induces Th1/Th2 imbalance in the immune system of mice and significantly promotes the progression of colon cancer (79). In chronically stressed mice, mitogen-induced T cell proliferation is reduced, the number of CD4+ T lymphocytes is reduced, and tumor necrosis factor (TNF) and interferon production are reduced, promoting tumor proliferation and progression via inhibition of T cell-mediated immunity (80). Thyroid hormones are important neuroendocrine regulators of tumor evolution that most likely modulate T cell-mediated immunity caused by chronic stress (80). Chronic stress may promote the progression of GC by increasing the NE-induced secretion of IL-6 in human gastric epithelial cells (81). Chronic stress reduces lymphocyte counts through TLR2-mediated PI3K signaling in a β-arrestin2-dependent manner (82). Chronic stress increases the susceptibility of a mouse model to UV light-induced squamous cell carcinoma by suppressing type 1 cytokines and protective T cells and increasing regulatory/suppressor T cell numbers (19) ( Table 1 ).

Chronic stress results in dysfunctions of SNS and HPA axis. The long-term activation of SNS and HPA axes makes the immune system expose to a higher levels of stress hormones, thus disrupting the physiological internal environment (83). Activation of HPA leads to increased glucocorticoid release and activation of glucocorticoid receptor (GR). Glucocorticoids can induce DC apoptosis and inhibit DC activation and migration (84).When SNS is activated, catecholamines (epinephrine and norepinephrine) are released, which can bind to α and β adrenergic receptor receptors on immune cells (85). Catecholamines can promote macrophages to secrete pro-inflammatory factors such as IL-1β and TNF-α, intensifying the pro-tumor properties of macrophages (86). Chronic stress may stimulate the immunosuppressive activity of MDSCs and promote tumor progression (87). Activation of β₂ receptors in TH1 cells inhibits IFN-γ production, which in turn inhibits IFN-γ -dependent B cells from producing IgG2a, thereby reducing the body’s immune capacity (88). In breast cancer, chronic stress rebuilds lymphatic networks in and around tumors through signals from the sympathetic nervous system, providing pathways for tumor cells to escape. This process is associated with macrophage COX2 inflammatory signaling and tumor-cell derived VEGFC (89). Psychological stress may induce high expression of the P53, NF-κB and p65 proteins and further promote ovarian cancer growth (90). Stress exposure decreases the TGF-β content in CD63⁺ exosomes to inhibit tumor growth. Several studies have attempted to address key mechanisms of organism reactions to stress (91). Human body is a unified organism, neuroendocrine and immunity are two very important parts of human body. Their dysfunctions provide physiological and pathological basis for the occurrence and development of tumors, and also provide ideas for the treatment of tumors.

Recent studies have shown that psychological and social factors can promote the development of tumors through epigenetic mechanisms (92). Epigenetic changes the expression of genes without altering the DNA sequence, including DNA methylation, histone modification, chromatin reprogramming, and non-coding RNA change (93–95). Stress hormone exposure affects the epigenetic regulation of oncogenes and tumor suppressor genes. Studies have shown that miRNA-145 is associated with chemotherapy tolerance of cervical cancer cells, and cortisol can down-regulate the expression of miRNA -145 in HPV-positive cervical cancer cells (96). Mothers with depression or anxiety had significantly increased methylation of the NR3C1 and 11β-HSD-2 genes in their placentas, which protect the fetus from maternal overexposure to stress hormones (97). Socially isolated mice had reduced expression of DNA methyltransferase (DNMT)3b and methyl CpG binding protein 2, both known epigenetic regulators (98). In a study of female ductal carcinoma in situ, high stress was associated with less histone acetylation in lymphocytes, which may influence susceptibility to tumor metastasis (99). Chronic stress induces upregulation of lysine-specific demethylase 5(KDM5A), which plays an important role in hypoxia-induced chromatin reprogramming, thereby promoting tumor progression (100). Progress has been made in the treatment of tumors, but acquired drug resistance remains an important challenge. Studies suggest that long-term exposure to stress may lead to the development of acquired resistance through epigenetic inheritance (101).

Chronic stress causes systemic changes in the human body, eventually leading to changes in the neuroendocrine system and immune system. Chronic stress can activate the hypothalamic-pituitary adrenal axis and the sympathetic nervous system, cause the release of endocrine hormones and promote the occurrence and development of tumors. Activated α and β receptors can promote cell cycle progression and inhibit cell apoptosis through downstream signaling pathways. Some studies have shown that β-blockers can reduce the effects of chronic stress-induced tumorigenesis and tumor progression. Chronic stress also promotes the development of tumors by causing immune disorders in the body, which decrease the numbers of CD4+ and CD8+ cells around tumors and reduce tumor necrosis factor, interferon and macrophage levels. Attention has been given to the crosstalk between the neuroendocrine and immune systems induced by chronic stress. Chronic stress causes the release of glucocorticoids, which can promote the progression of liver cancer by upregulating PD-1 and inhibiting the activity of NK cells. β-Adrenergic signaling promotes tumor invasion and metastasis by altering the microenvironment of circulating tumor cells, inducing dormant tumor cells to enter the cell cycle, increasing the output of monocytes in the premetastatic stage and the infiltration of macrophages into the lung. In addition, adrenergic receptor blockers may improve tumor resistance to chemoradiotherapy. In order to explore its application potential, more experimental studies are necessary.

In conclusion, chronic stress can activate the hypothalamic-pituitary adrenal axis and the sympathetic nervous system, causing the release of endocrine hormones that mediate intracellular signaling pathways that promote the occurrence and development of tumors. However, the mechanism underlying the role of the neuroendocrine immune interactions induced by chronic stress in tumor pathogenesis and metastasis needs further study. In today’s society, people are under increasing chronic stress, and the adverse effect of chronic stress on tumor growth cannot be ignored. The development of antitumor drugs targeting chronic stress related tumorigenesis and chemoradiotherapy resistance might be a new strategy of cancer therapy.

DML, HQH was involved in data acquisition, analysis and manuscript drafting. DML and MJ revised the manuscript. All authors contributed to the article and approved the submitted version.

This study was funded by the National Key Research and Developmental Program of China (2018YFC1004800 and 2018YFC1004802), the Shanghai Municipal Council for Science and Technology (18410721200 and 20JC1412100), and the National Natural Science Foundation of China (81971334).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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