Interplay between stress and cancer-A focus on inflammation

Abstract

Stress is an integral part of life. While acute responses to stress are generally regarded as beneficial in dealing with immediate threats, chronic exposure to threatening stimuli exerts deleterious effects and can be either a contributing or an aggravating factor for many chronic diseases including cancer. Chronic psychological stress has been identified as a significant factor contributing to the development and progression of cancer, but the mechanisms that link chronic stress to cancer remain incompletely understood. Psychological stressors initiate multiple physiological responses that result in the activation of the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic nervous system, and the subsequent changes in immune function. Chronic stress exposure disrupts the homeostatic communication between the neuroendocrine and immune systems, shifting immune signaling toward a proinflammatory state. Stress-induced chronic low-grade inflammation and a decline in immune surveillance are both implicated in cancer development and progression. Conversely, tumor-induced inflammatory cytokines, apart from driving a tumor-supportive inflammatory microenvironment, can also exert their biological actions distantly via circulation and therefore adversely affect the stress response. In this minireview, we summarize the current findings on the relationship between stress and cancer, focusing on the role of inflammation in stress-induced neuroendocrine-immune crosstalk. We also discuss the underlying mechanisms and their potential for cancer treatment and prevention.

Keywords: cancer; chronic stress; inflammation; microenvironment; proinflammatory cytokines.

FIGURE 1

Bidirectional relationship between chronic stress and cancer. Chronic stress persistently activates hypothalamus-pituitary-adrenal (HPA) axis and sympathetic-adreno-medullar (SAM) system. Stress hormones can promote tumorigenesis, suport cancer growth and/or progression, and regulate tumor microinvironment. Both, chronic stress and tumor, induce production of proinflammatory cytokines, which may cause neuroinflammation and thereby altering stress responses. Anti-cancer therapy may also contribute to a persistant proinflammatory state.

FIGURE 2

Chronic inflammation at the crossroads between chronic stress and cancer. Chronic stress, via catecholamine release, induces monocyte recruitment from bone marrow (BM) and spleen to the brain. Monocyte trafficking is induced via upregulated macrophage migration inhibitory factor (MIF) and C–C ligand 2—(CCL2)/C–C chemokine receptor 2 (CCR2) pathway. An increased expression of cell adhesion molecules in the cerebral endothelium facilitates the adherence and extravasation of peripherally derived monocytes, through blood brain barrier (BBB). Chronic stress activates microglia by altering the cerebral microenvironment through the production of proinflammatory cytokines and reactive oxygen species (ROS). Increase in ROS production triggers NF-κB-mediated NOD-like receptor protein 3 (NLRP3) inflammasome activation and subsequent proinflammatory cytokine secretion. Activation of this pathway in hippocampal microglia mediate chronic stress-induced neuroinflammation. Neuroinflammation may cause alterations in locus coeruleus (LC)-norepinephrine function resulting in overeactivity to subsequent stressors. Chronic inflammation contributes to tumor growth, angiogenesis and metastasis. Cancers with high expression levels of proinflammatory cytokines exhibit multiple drug resistance. Tumor-induced ROS and proinflammatory cytokine release further activates proinflammatory/oncogenic signaling pathways, creating the positive feedback loops.