The influence of bio-behavioural factors on tumour biology: pathways and mechanisms

Abstract

Epidemiological studies indicate that stress, chronic depression and lack of social support might serve as risk factors for cancer development and progression. Recent cellular and molecular studies have identified biological processes that could potentially mediate such effects. This review integrates clinical, cellular and molecular studies to provide a mechanistic understanding of the interface between biological and behavioural influences in cancer, and identifies novel behavioural or pharmacological interventions that might help improve cancer outcomes.

Figure 1. Important components of the central and peripheral stress systems

Stressful experiences activate components of the limbic system, which includes the hypothalamus, the hippocampus, the amygdala, and other nearby areas. In response to neurosensory signals, the hypothalamus secretes corticotrophin-releasing factor (CRF) and arginine vasopressin (AVP), both of which activate the pituitary to produce hormones such as adrenocorticotropic hormone (ACTH). Circulating ACTH stimulates the production of glucocorticoids from the adrenal cortex. The sympathetic nervous system originates from the brainstem, and the pre-ganglionic neurons terminate in the ganglia near the spinal column. From these ganglia, post-ganglionic fibres run to the effector organs. The main neurotransmitter of the pre-ganglionic sympathetic fibres is acetylcholine and the typical neurotransmitter released by the post-ganglionic neurons is noradrenaline. The adrenal medulla contains chromaffin cells, which release mainly adrenaline.

Figure 2. Effects of stress-associated factors on the tumour microenvironment

The responses to stressors involve central nervous system (CNS) perceptions of threat and subsequent activation of the autonomic nervous system (ANS) and the hypothalamic–pituitary–adrenal (HPA) axis. Catecholamines, glucocorticoids and other stress hormones are subsequently released from the adrenal gland, brain and sympathetic nerve terminals and can modulate the activity of multiple components of the tumour microenvironment. Effects include the promotion of tumour-cell growth, migration and invasive capacity, and stimulation of angiogenesis by inducing production of pro-angiogenic cytokines. Stress hormones can also activate oncogenic viruses and alter several aspects of immune function, including antibody production, cytokine production profiles and cell trafficking (see REF. for a comprehensive review of immune effects). Collectively, these downstream effects create a permissive environment for tumour initiation, growth and progression. CRF, corticotrophin-releasing factor; IL-6, interleukin-6; MMP, matrix metalloproteinase; VEGF, vascular endothelial growth factor.

Figure 3. Integrated model of bio-behavioural influences on cancer pathogenesis through neuroendocrine pathways

In this model, bio-behavioural factors such as life stress, psychological processes and health behaviours (blue panel) influence tumour-related processes (green panel) through the neuroendocrine regulation of hormones, including adrenaline, noradrenaline and glucocorticoids (red panel). Central control of peripheral endocrine function also allows social, environmental and behavioural processes to interact with biological risk factors such as genetic background, carcinogens and viral infections to systemically modulate malignant potential (red panel). Direct pathways of influence include effects of catecholamines and glucocorticoids on tumour-cell expression of genes that control cell proliferation, invasion, angiogenesis, metastasis and immune evasion (green panel). Stress-responsive neuroendocrine mediators can also influence malignant potential indirectly through their effects on oncogenic viruses and the cellular immune system (red panel). These pleiotropic hormonal influences induce a mutually reinforcing system of cellular signals that collectively support the initiation and progression of malignant cell growth (green panel). Furthermore, neuroendocrine deregulation can influence the response to conventional therapies such as surgery, chemotherapy and immunotherapy (green panel). In addition to explaining bio-behavioural risk factors for cancer, this model suggests novel targets for pharmacological or behavioural intervention. CTL, cytotoxic T lymphocytes; IL, interleukin; MRD, minimal residual disease; NKC, natural killer cell; TGFβ, transforming growth factor-β; TNFα, tumour-necrosis factor-α; TSH, thyroid-stimulating hormone.