Riddle of the Sphinx: facts and evidence regarding the link between mental stress and tumor occurrence and development : Chinese Medical Journal

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Riddle of the Sphinx: facts and evidence regarding the link between mental stress and tumor occurrence and development

Wang, Ruilin; Yu, Sheng; Yu, Limeng; Wang, Qiming; Wu, Yufeng

Editor(s): Wei, Peifang

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Chinese Medical Journal ():10.1097/CM9.0000000000002129, December 30, 2022. | DOI: 10.1097/CM9.0000000000002129

To the Editor: The answer to the “Riddle of Sphinx” is “human”, whose image is both negative and positive. It is often used as a metaphor for complex, mysterious, and incomprehensible problems. With the deterioration of modern living environment and the aggravation of stress, the incidence of the tumor is on the rise. Excessive or prolonged stress can lead to acute or chronic organ dysfunction and metabolic disorders. Studies have shown that tumor patients are often under long-term adverse stress states. Chronic mental stress alters tumor cell survival, proliferation and metastasis by activating stress-related transcriptional regulators and signaling pathways in the body. With the demonstration of their important role in tumor development under stress, related pathways or cytokines could be antagonized or inhibited to change the trajectory of the tumor development. This article explores how chronic mental stress affects the presence of tumor cells by influencing the expression of brain-derived neurotrophic factor (BDNF), insulin-like growth factor 2/insulin-like growth factor 1 receptor (IGF2/IGF1R), C-reactive protein (CRP) and other possible pathways in cancer patients.

BDNF is a secretory protein in the neurotrophic protein family, which plays an important role in the occurrence and development of tumors under chronic mental stress state. Long-term stress can reduce the volume of gray matter in the hippocampus and other marginal brain regions and downregulate the expression of BDNF in different regions of the central nervous system, thereby reducing the expression level of BDNF and its receptor tyrosine kinase receptor 2.[1] The Bdnf gene has nine selective promoters, of which promoter I (pI) and promoter IV (pIV) are highly sensitive to neuronal activity. The transcription factor binding sites in pI and pIV of the Bdnf gene have a variety of calcium response elements, which are necessary for membrane depolarization-driven L voltage-gated calcium channel (L-VGCC)-dependent induction of Bdnf expression. Myocyte enhancer factor 2 (MEF2) protein is a family of transcription factors that regulates transcriptional programs associated with cell proliferation, differentiation, survival and apoptosis. The different outcomes of BDNF expression depend on the MEF2 subtypes involved, for example, MEF2C promotes BDNF-related synaptic enhancement and up regulates BDNF expression. Adenosine triphosphate (ATP) binding cassette (ABC) efflux transport proteins belong to the largest transporter superfamily. ATP-binding cassette efflux transporter G2 (ABCG2) is one of the most important ABC efflux transport proteins and functions by actively expelling substances from cells to protect normal tissues from the intrusion of heterogeneous substances. ABCG2 is widely expressed in various tissues and participates in the distribution of multiple endogenous substances and drugs. This protein is also widely considered a transporter involved in multidrug resistance. The decrease in BDNF levels under stress state leads to the upregulation of ABCG2 expression and enhanced drug resistance, which cause accelerated growth and metastasis of tumor cells. ABCG2 upregulation may be one of the mechanisms by which BDNF induces tumor resistance. Therefore, the decrease of BDNF level under chronic mental stress will promote the disease progression and the formation of drug resistance in tumor patients. However, the level of the BDNF in the body is dynamic, and all substances in the body have a range or critical value, so the effect of the BDNF on patients with different tumors may vary and need to be further studied.

The insulin-like growth factor (IGF) system consists of the peptide ligands IGF1, IGF2 and insulin and the receptors IGF1R, IGF2R, insulin receptor and IGF-binding proteins and plays a key role in regulating cell proliferation, differentiation, apoptosis, and so on. Among them, overexpression of IGF2 in tumor cells usually leads to excessive proliferation of cells, which is significantly related to clinical indicators of disease progression, drug resistance and survival time. Stress is usually caused by social, physical and mental stressors that induce the release of stress-related neurotransmitters and hormones by activating the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis, such as norepinephrine (NE). NE induces L-VGCC phosphorylation via the ß-adrenergic receptor- protein kinase A pathway, which triggers calcium mobilization and promotes IGF2 secretion. The biological function of IGF2 is mainly realized by combining with IGF1R. IGF1R regulates cell proliferation, inhibits apoptosis and promotes invasion by activating downstream phosphatidyl inositol 3-kinase/ protein kinase B (AKT)/mammalian target of rapamycin (mTOR) and RAS/ extracellular regulated protein kinases pathways.[2] AKT downstream effectors modulate cell proliferation, survival, and angiogenesis and also play a key role in apoptosis, in which mTOR complex 1 is a major effector at the downstream of AKT. The role of AKT in invasion and metastasis further demonstrates the importance of IGF2 in the cancer-related IGF signaling pathways. Stress-activated IGF2/IGF1R axis can promote the proliferation and migration of tumor cells, and improve tumor invasiveness and chemoresistance, thus shortening the survival time of tumor patients and reducing their quality of life. Due to the upregulation of IGF2 expression in tumor cells, IGF2/ IGF1R has become an interesting target in cancer therapy. Blocking the IGF2/IGF1R pathway by blocking receptor-ligand interactions or limiting kinase activation can inhibit the proliferation and growth of tumor cells and make them sensitive to programmed cell death, so as to inhibit tumor occurrence and development, restore drug sensitivity and improve the prognosis of patients. Therefore, how to block the IGF2/IGF1R axis will become the important concerns to inhibit tumor cell growth and migration and restore drug sensitivity. The IGF2/IGF1R signaling pathway will be an important target to prevent tumorigenesis and metastasis.

CRP is an acute phase reactant and biomarker produced by the liver in response to a variety of proinflammatory cytokines, especially interleukin (IL)-6 and is a common marker of inflammatory diseases. Tumors are mostly caused by inflammatory stimulation, and the tumor microenvironment is also composed of inflammatory cells, so inflammation is an important player in cancer occurrence and progression and promotes tumor cell formation, proliferation and metastasis. Stress activates the HPA axis and the SNS, resulting in increased stress hormone (mainly catecholamines and cortisol) release. Stress hormones directly or indirectly activate the immune system, thus increasing the expression of IL-6, IL-1β, tumor necrosis factor-a and other proinflammatory cytokines. Elevation of the expression levels of stress-related proinflammatory cytokines stimulates increased production and release of CRP in the liver. Proinflamma-tory cytokines can also induce the production of more proinflammatory cytokines by activating the p38 mitogen-activated protein kinase pathway. Extensive evidence indicates that elevated CRP levels are related to increased tumor incidence, tumor metastasis and shortened total survival time and can thus serve as a prognostic marker in tumor patients.[3] Chronic mental stress promotes tumor proliferation and metastasis through CRP and proinflam-matory cytokines, so reducing the levels of CRP and proinflammatory cytokines in the body is a feasible strategy to delay the occurrence and development of tumor, especially for patients with increased inflammatory activity before treatment. IL-1 and IL-6 antagonists inhibit HPA signaling pathways, which may prolong survival time and improve prognosis in tumor patients. Antidepressants have also been shown to reduce the production of proinflammatory cytokines, improving depressive symptoms while reducing inflammatory activity. Consequently, further studies on the inhibitors of CRP and proinflammatory cytokines to inhibit the release of CRP and proinflammatory cytokines are conducive to delaying tumor occurrence, proliferation and metastasis, which can significantly improve the prognosis of tumor patients.

There are three different subtypes of nitric oxide synthases (NOSs): endothelial-type nitric oxide synthase, neuronaltype nitric oxide synthase and inducible nitric oxide synthase (iNOS). iNOS overexpression promotes angio-genesis and accelerates tumor cell invasion and progression, which is related to the low survival of tumor patients. The HPA axis activated by chronic mental stress causes an increase in stress hormone levels, including cortisol, and then cortisol activates iNOS-mediated signal transduction pathways, resulting in an increase in nitric oxide (NO) levels. NO is a potentially destructive reactive nitrogen species (RNS) that can produce peroxynitrite and nitrogen trioxide through superoxide reactions and cause DNA damage. The increase of iNOS level induced by stress can therefore increase the production of RNS in tumor cells and interfere with the DNA repair process to induce DNA damage, thus promoting tumor occurrence and development.[4] High levels of NO induce growth, invasion and metastasis of tumor cells and angiogenesis, while low levels of NO are associated with cytotoxicity, which can induce apoptosis and antitumor effects. In addition, prolonged exposure to high concentrations of NO also leads to increased oxidative stress and DNA damage. The biphasic effect of NO depends on the positioning, expression, and activity of the NOS subtype, the concentration of NO, and the duration of NO exposure. NO's extensive physiological functions, complex mechanisms and concentration dependence pose great challenges to researchers. Overall, iNOS overexpression and the subsequent increase in NO have broad implications in malignancies. Therefore, iNOS is a potential target for eliminating the harmful effects of mental stress on tumorigenesis and development. NOS inhibitors are a novel topic of research and may be used to weaken the DNA damage and reduce the tumorigenic effects produced by RNS.

Twist protein is a highly conserved family of alkaline helix-loop-helix transcription factors, including Twist1 and Twist2, which are the major regulators of embryonic development and are significantly activated in tumors, thus driving tumor invasion and metastasis. Twist down-regulates the level of E-cadherin and induces the activation of epithelial–mesenchymal transition (EMT) pathway to improve the invasion and metastasis ability of tumor cells. The downregulation of E-cadherin leads to reduced intercellular adhesion, which is conducive to the invasion and metastasis of tumor cells. EMT converts epithelial cells into mesenchymal cells that promote tumor cell metastasis through severe destruction of cell-cell connectivity and extensive restructuring of the actin cytoskeleton. Thus, the overexpression of Twist is associated with the proliferation, differentiation, invasion and metastasis of tumor cells. Stress activates the HPA axis and SNS, causing an increase in stress hormone levels in circulation, including cortisol. This increase in stress hormone release upregu-lates the expression of Twist, which changes the tumor microenvironment by lowering E-cadherin levels to induce EMT pathway activation and promote angiogenesis and tumor cell metastasis. This evidence suggests that E-cadherin can serve as one of the potential targets of Twist. However, the relationship between Twist and E-cadherin has not been completely confirmed in clinical studies and needs to be verified by subsequent studies.

In addition to the above pathways, stress can also affect the development of tumor through other factors, for example, stress-induced phosphoprotein 1 (STIP1), also known as the heat shock protein 70 (Hsp70)/Hsp90-organizing protein. Stress causes high expression of STIP1, which promotes tumor metastasis and disease progression through activation of the focal adhesion kinase/AKT/matrix metalloproteinase (MMP) signaling pathway. Therefore, the upregulation of STIP1 is carcinogenic and enhances the viability and invasion of tumor cells. In addition, a subgroup of MMPs, namely, MMP-2 and MMP-9, are considered important for inflammation and tumor metastasis. Stress can increase sympathetic activity to increase the levels of circulating catecholamines, which are positively associated with the tissue expression of MMPs that promote invasion. Furthermore, serotonin is a neuromodulator with neuro-transmitter and neuroendocrine functions that contributes to the occurrence of tumors. Chronic stress causes elevated serotonin levels that promote both tumor bone metastasis through the runt-related transcription factor 2/parathyroid hormone-related protein/receptor activator for nuclear factor-kB ligand pathway and the Warburg effect through activation of serotonin receptor 2B, providing bioenergy and meeting anabolic needs for cell survival and proliferation. Chronic mental stress has more or less influence on the occurrence and development of tumor through the above pathways, which can provide new ideas for tumor targeted therapy.

In conclusion, with the deepening of tumor research, targeted drugs have become an important part of antitumor therapy. Stress participates in the development of tumors by activating multiple signaling pathways and cytokines. These studies of the stress-related pathways reviewed in this paper provide us with important clues. Chronic mental stress can not only promote tumorigene-sis and development by downregulating the level of BDNF and increasing the production of IGF2/IGF1R and CRP, but also promote tumorigenesis and development by other ways such as iNOS and Twist [Supplementary Figure 1, https://links.lww.com/CM9/B32]. Blocking or inhibiting these signal pathways have important therapeutic significance, which can prolong the survival time of cancer patients and improve the prognosis. However, these mechanisms need to be further studied and confirmed to provide potential strategies for follow-up targeted therapy research. Successful management of stress can improve abnormal activation of the neuroendocrine and immune systems, potentially affecting tumor development and progression. Therefore, inhibitors of stress-related pathways and cytokines can be used as potential targeted anticancer drugs, and the application of targeted drugs helps to reduce the impact of stress on cancer patients, and then reduce tumor metastasis and recurrence.

Conflicts of interest

None.

References

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