Stress and cancer: The mechanisms of immune dysregulation and management

Abstract

Advances in the understanding of psychoneuroimmunology in the past decade have emphasized the notion that stress and cancer are interlinked closely. Durable chronic stress accelerated tumorigenesis and progression, which is unfavorable for clinical outcomes of cancer patients. Available evidence has provided unprecedented knowledge about the role and mechanisms of chronic stress in carcinogenesis, the most well-known one is dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). With abnormal activation of neuroendocrine system, stress-related hormones contribute to increased oncogenes expression, exacerbated chronic inflammation and impaired immunologic function. In addition, accumulating studies have demonstrated that diverse stress interventions including pharmacological approaches, physical exercises and psychological relaxation have been administered to assist in mental disorders reduction and life quality improvement in cancer patients. In this review, we systematically summarize the connection and mechanisms in the stress-immune-cancer axis identified by animal and clinical studies, as well as conclude the effectiveness and deficiencies of existing stress management strategies.

Keywords: chronic stress; hypothalamic-pituitary-adrenal axis; immunity; stress management; tumor microenvironment.

Figure 1

The neuroendocrine mechanisms of chronic stress. Chronic stress triggers activation of the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system, leading to the secretion of catecholamine (mainly epinephrine and norepinephrine) and glucocorticoid. These stress-related hormones promote most hallmarks of cancer through binding to receptors on diverse cells, especially immune cells. NK, natural killer; DC, dendritic cell; Th, helper T; TAM, tumor-associated macrophage; MDSC, myeloid-derived suppressor cell; Treg, regulatory T cell.

Figure 2

Effects of chronic stress on tumor immune microenvironment. The stressed tumor immune microenvironment is characterized with activated inflammation responses, impaired protective immunity and increased proportion of immunosuppressive cells. Chronic stress promotes the release of various pro-inflammatory and pro-tumor growth factors to accelerate tumor progression. IFN, interferon; TGF, transforming growth factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor; COX-2, cyclooxygenase-2; MMP, matrix metalloproteinase; NKCC, natural killer cell cytotoxicity; DC, dendritic cell; CTL, cytotoxic lymphocyte; Th, helper T cell; TAM, tumor-associated macrophage; MDSC, myeloid-derived suppressor cell; Treg, regulatory T cell.