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Stress and cancer: mechanisms, significance and future directions

Abstract

The notion that stress and cancer are interlinked has dominated lay discourse for decades. More recent animal studies indicate that stress can substantially facilitate cancer progression through modulating most hallmarks of cancer, and molecular and systemic mechanisms mediating these effects have been elucidated. However, available clinical evidence for such deleterious effects is inconsistent, as epidemiological and stress-reducing clinical interventions have yielded mixed effects on cancer mortality. In this Review, we describe and discuss specific mediating mechanisms identified by preclinical research, and parallel clinical findings. We explain the discrepancy between preclinical and clinical outcomes, through pointing to experimental strengths leveraged by animal studies and through discussing methodological and conceptual obstacles that prevent clinical studies from reflecting the impacts of stress. We suggest approaches to circumvent such obstacles, based on targeting critical phases of cancer progression that are more likely to be stress-sensitive; pharmacologically limiting adrenergic–inflammatory responses triggered by medical procedures; and focusing on more vulnerable populations, employing personalized pharmacological and psychosocial approaches. Recent clinical trials support our hypothesis that psychological and/or pharmacological inhibition of excess adrenergic and/or inflammatory stress signalling, especially alongside cancer treatments, could save lives.

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Fig. 1: Stress responses and reciprocal stress–cancer interactions.
Fig. 2: Effects of stress on the tumour and its microenvironment.

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Acknowledgements

The authors thank I. Ben-Ami Bartal for fruitful discussions and for critiques of the manuscript, and are grateful to the Emerson Collective, the Israel Cancer Research Fund and the Israel Science Foundation for their support.

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All authors researched data for the article, substantially contributed to discussion of content and wrote, reviewed and edited the manuscript before submission.

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Correspondence to Shamgar Ben-Eliyahu.

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Glossary

Sympathetic nervous system

(SNS). Part of the autonomic nervous system that is involuntarily activated by stressors (for example, a dangerous or stressful situation) and orchestrates the ‘fight or flight’ response through adrenergic innervation of the adrenal medulla and of various organs (for example, the heart) through systemic and local release of adrenaline and noradrenaline, respectively.

Hypothalamic–pituitary–adrenal (HPA) axis

A neuroendocrine system with negative feedback that increases systemic glucocorticoid (for example, cortisol) levels in various circumstances, including stressful conditions. Hypothalamic corticotropin-releasing hormone (CRH) elevates systemic release of adrenocorticotropic hormone (ACTH) from the anterior pituitary, which triggers the release of glucocorticoids from the adrenal cortex, which also trigger negative feedback through the pituitary and hypothalamic levels.

Damage-associated molecular patterns

Endogenous host-derived molecules that are released by damaged and dying cells. They are recognized by pattern recognition receptors on numerous cells, which lead to migration and activation of various immune cells and consequent innate and adaptive immune responses.

Catecholamines

A family of molecules that are characterized by a catechol and an amine group in their chemical structure, and function as neurotransmitters and hormones within the body. These include dopamine, noradrenaline and adrenaline, all of which are synthesized from the amino acid tyrosine.

Restraint stress

An experimental stress paradigm, where the animal is placed in a confined space (a tube-shaped apparatus perforated for air exchange) that prevents free movement but does not press or induce pain to the animal. Such restraint can last minutes to hours and can be repeated daily for several weeks as a chronic stress paradigm.

Sympathetic denervation

Refers to experimental methods for ablation of sympathetic nerves (also called sympathectomy), by either surgical cut of sympathetic nerve fibres or chemical ablation (for example, using 6-hydroxydopamine).

Prostaglandin receptors

A class of cell surface G-protein-coupled receptors that bind different prostaglandins and are expressed on various cell types, including immune cells; for example, prostaglandin E2 binds to the prostaglandin E2 receptor 1–4 subtypes.

T helper 1 cell

(TH1 cell). A CD4+ T cell that participates in the pro-inflammatory type 1 or cellular immune response against intracellular pathogens and malignant cells. Naive T cells are differentiated into the type 1 phenotype following exposure to interleukin-12 (IL-12), and are known for the secretion of interferon-γ (IFNγ), which is also involved in the effector functions of cytotoxic T cells.

T helper 2 cell

(TH2 cell). A CD4+ T cell that participates in type 2 or humoral immune response against extracellular pathogens (for example, helminths) and allergens. Naive T cells are differentiated into a type 2 phenotype following exposure to interleukin-4 (IL-4), and are known for the secretion of IL-4, IL-13 and IL-5, and promotion of the production of antibodies.

β-Blockers

A class of drugs with antagonistic activity towards β-adrenergic receptors (β-ARs). The drugs vary in specificity to the different β-ARs (β1-AR, β2-AR and β3-AR) and are classified as selective or non-selective to a certain receptor subtype.

Tilt–light stress

An experimental stress paradigm in which the home cage of rodents is placed in a lit room in a 45° tilted position, starting before the onset of the animals’ dark period, resulting in reduced available floor space and disruption of the dark–light cycle.

Swim stress

An experimental stress paradigm where a weight is attached to the tail of rodents (usually rats, up to 2.5% of total body weight), which are then placed in a room temperature water tank for few minutes, followed by a rest period. This swim–rest cycle is usually repeated several times.

Laparotomy

An experimental stress paradigm in which a midline abdominal incision is performed under anaesthesia, and often the small intestine is externalized and left hydrated in a soaked gauze pad for 30 min. The intestine is then internalized and the abdomen is sutured.

Social confrontation stress

An experimental stress paradigm where an intruder rodent (a non-cage-mate animal) is introduced into a home cage populated with several stable cage-mates. The intruder is usually attacked by the residents cage-mates and/or displays submissive behaviour.

Foot shock stress

An experimental stress paradigm that is executed in an apparatus containing an electrified grid floor, in which the animal is exposed to electric shocks of varying intensity and duration. The paradigm can be acute or chronic, and is also used for fear-conditioning.

Hazard ratio

The ratio of the probability of events in a treatment group to the probability of events in a control group.

Publication bias

The tendency to publish a study based on its results (positive rather than negative findings or significant rather than non-significant findings). Existence of this bias can be statistically assessed in meta-analyses by Egger’s linear regression test.

Cochrane

A non-profit organization (maintaining no conflict of interests), which, among other activities, publishes methodologies and guidelines to produce high-quality systematic reviews and meta-analyses.

CpG class C

(CpG-C). A synthetic oligodeoxynucleotide (ODN) that functions as a Toll-like receptor 9 (TLR9) agonist and induces a physiological host-dependent activation of the immune system.

Glucopyranosyl lipid-A stable emulsion

(GLA-SE). A synthetic agonist of Toll-like receptor 4 (TLR4). For administration, GLA is dissolved in an oil–water stable emulsion that serves as an adjuvant delivery system.

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Eckerling, A., Ricon-Becker, I., Sorski, L. et al. Stress and cancer: mechanisms, significance and future directions. Nat Rev Cancer (2021). https://doi.org/10.1038/s41568-021-00395-5

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