Chronic Stress Promotes Cancer Development

Abstract

Stress is an inevitable part of life. Chronic stress on account of reasons like adversity, depression, anxiety, or loneliness/social isolation can endanger human health. Recent studies have shown that chronic stress can induce tumorigenesis and promote cancer development. This review describes the latest progress of research on the molecular mechanisms by which chronic stress promotes cancer development. Primarily, chronic stress activates the classic neuroendocrine system [the hypothalamic-pituitary-adrenal (HPA) axis] and the sympathetic nervous system (SNS) and leads to a decline and dysfunction of the prefrontal cortex and the hippocampus under stress. Stress hormones produced during the activation of both the HPA axis and the SNS can promote tumorigenesis and cancer development through a variety of mechanisms. Chronic stress can also cause corresponding changes in the body's immune function and inflammatory response, which is significant because a long-term inflammatory response and the decline of the body's immune surveillance capabilities are implicated in tumorigenesis. Stress management is essential for both healthy people and cancer patients. Whether drugs that limit the signaling pathways downstream of the HPA axis or the SNS can suppress chronic stress-induced cancers or prolong patient survival deserves further study.

Keywords: cancer; catecholamines; corticosteroids; hormone; hypothalamic-pituitary-adrenal axis; immunity; inflammation; stress.

Figure 1

The neuroendocrine mechanisms of chronic stress. Chronic stress produces stress hormones during the activation of the neuroendocrine system (hypothalamus-pituitary-adrenal axis) and the sympathetic nervous system, which can promote tumor development and regulate the tumor microenvironment.

Figure 2

Signaling pathways activated by catecholamines. Stress-induced catecholamines activate the cAMP-PKA signaling pathway through β2 adrenergic receptors, thereby causing a series of downstream reactions. Src phosphorylation, DNA damage, p53 degradation, upregulation of VEGF and MMPs, and enhanced stem-like traits are key factors of tumorigenesis.

Figure 3

Effects of stress hormones on the immune system. Stress hormones stimulate pro-tumorigenic immune cells to produce IL-6, IL-10, and other cytokines, and activate the COX-2/PGE2 pathway to produce VEGF, which together affect the tumor microenvironment to suppress tumor immunity. The decrease in IL-12 and the increase in IL-10 lead to selective Th1 inhibition, thereby suppressing the CTL-mediated cellular immunity and interferon production.