The perspective that cancer may be causally linked to stress has a long history. In 200 AD, Galen proposed that melancholic women were more susceptible to cancer than women who were sanguine. Rigorous examinations of related observations have lagged over the ensuing centuries. More recently, epidemiologic studies have shown that psychologic and social characteristics (e.g., chronic stress and negative life events, social isolation and support, socioeconomic burden, and emotional processes) might be associated with differential cancer incidence, progression, and mortality (Antoni et al., 2006; Lutgendorf et al., in press). The biologic mechanisms (e.g., signaling pathways) that may account for such observations are being discovered through the convergence of relevant molecular, cellular, and clinical data.
In this article, we review the clinical and experimental evidence regarding the effects of stress on tumor development, growth, and progression. Within this context, we define “stress” as an external event (“stressor”) or perception of such events that engender psychologic and physiologic changes (“stress responses”) designed to approach, avoid, or defend against the external event. “Stress” initiates a cascade of information-processing pathways in the central nervous system (CNS) and periphery, which activate the autonomic nervous system (ANS) or the hypothalamic-pituitary-adrenal (HPA) axis. Cognitive and emotional feedback from cortical and limbic areas of the brain modulate the activity of hypothalamic and brain stem structures directly controlling autonomic nervous system and hypothalamic-pituitary-adrenal activity. Hypothalamic-pituitary-adrenal responses are mediated by hypothalamic production of corticotrophin-releasing factor (CRF) and arginine vasopressin, which activate the secretion of pituitary hormones such as adrenocorti-cotrophic hormone (ACTH), enkephalins, and endorphins. ACTH induces downstream release of glucocorticoids such as cortisol from the adrenal cortex. Glucocorticoids control growth, metabolism, and immune function, and have a pivotal role in regulating basal function and stress reactivity across a wide variety of organ systems. Autonomic nervous system responses to stress are mediated primarily by activation of the sympathetic nervous system (SNS), and subsequent release of catecholamines (principally norepinephrine and epinephrine) from sympathetic neurons and the adrenal medulla. Individual differences in the perception and evaluation of external events (appraisal and coping processes) create variability in autonomic nervous system and hypothalamic-pituitary-adrenal activity levels. Stressors that have been associated with alterations in neuroendocrine dynamics include marital disruption, bereavement, depression, chronic sleep disruption, severe trauma, and post-traumatic stress disorder. For a review of central and periphery stress systems, see Chrousos and Gold (1992) and Charmandari et al. (2005).