Psychological aspect of cancer: From stressor to cancer progression

Abstract

Substantial evidence indicates that psychological stress can influence the incidence and progression of cancers, and adequate psychotherapies are beneficial to cancer patients. Recently, the mechanisms responsible for the effects of psychological stress on cancer cells have been extensively investigated at the systemic, biochemical and molecular levels. Accumulating data indicate that the effects of psychological stress on cancer cells are mainly mediated by key stress-related mediators and their corresponding receptors in multi-fold pathways: chronic stressors act on the paraventricular nucleus and the suprachiasmatic nuclei. The effects are then transmitted through the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, amplified by the unchecked release of stress-related mediators and altered behaviors. These mediators act as immunosuppressors or mitogens in the tumor microenvironment. The converging effects of psychological stress on cancer cells finally signal through receptors of the stress mediators and cytokines to activate the intracellular pro-proliferative and pro-migratory signaling pathways, and reset the molecular clock in tumor cells. Understanding these action mechanisms of psychological stress in promoting the growth and invasion of cancer cells is crucial for devising effective interventions.

Figure 1.

A schematic representation of the mechanism involved from stress to cancer progression. Chronic stressors act on the paraventricular nucleus (PVN) and suprachiasmatic nuclei (SCN). The effects are then transmitted through the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis by checked release of stress-related mediators. Failure in suppressing the generation of stress-related mediators and disruption of the central circadian rhythms due to repeated stress response result in dysfunction of the endocrine, metabolic and immune systems, which consequently promote the progression of cancer. AVP, arginine vasopressin; ANS, autonomic nervous system (modified from refs. and 11).

Figure 2.

The deleterious effects of psychological stress on the immune system. Chronic-flattened elevations of glucocorticoids (GCs) and catecholamine activate the transcription of cytokine genes in immune cells, resulting in a shift of immune response from Th1 to Th2. This impairs both humoral and cellular immune functions against tumor cells. IL, interleukin; IFN, interferon (modified from refs. and 14).

Figure 3.

Known mechanisms of stress hormones in modulating the growth and metastatic potency of cancer cells. The mitogenic effect of stress hormones is mediated primarily through β-adrenergic receptors (ARs), especially β2-AR. β2-AR then signals either through ‘G protein switching’ or the G protein-independent mechanism to activate AC/cAMP/PKA, Rho/Rac, Ras/Raf/MEK/ERK and PI3K/AKT signal pathways in cancer cells. GFs, growth factors; TFs, transcription factors (modified from refs. , and 19).

Figure 4.

Glucocorticoids (GCs) work in synergy with stress hormones to support cancer cell survival. Through binding to GC response elements (GREs) and interfering with other transcription factors, GCs up-regulate c-Myc, Bcl-xL, cIAP2, SGK and β2-adrenergic receptors (ARs) in tumor cells to promote the growth and survival of cancer cells. TFs, transcription factors (drawn by reviewing refs. –35).

Figure 5.

Mechanisms of disruption of circadian rhythms in promoting the progression of cancer: chronic stressor interferes with central circadian rhythms in both input and output pathways, leading to a dysfunction of neuroendocrine, metabolism and immunity. The increased stress-related mediators and cytokines in the tumor microenvironment induce immunosuppression, influence metabolic pathways and the circadian clock gene expression in tumor cells and reduce the sensitivity of tumor cells to treatments (modified from ref. 12).