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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LeShan, L. Psychological states as factors in the development of malignant disease: a critical review. J. Natl Cancer Inst. 22, 1–18 (1959).
Mravec, B., Tibensky, M. & Horvathova, L. Stress and cancer. Part I: mechanisms mediating the effect of stressors on cancer. J. Neuroimmunol. 346, 577311 (2020). This review describes mechanisms by which stress affects specific hallmarks of cancer, emphasizing how stress is an integral part of cancer biology.
Cole, S. W. & Sood, A. K. Molecular pathways: β-adrenergic signaling in cancer. Clin. Cancer Res. 18, 1201–1206 (2012).
Eng, J. W.-L. et al. A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response. Cancer Immunol. Immunother. 63, 1115–1128 (2014).
Armaiz-Pena, G. N., Cole, S. W., Lutgendorf, S. K. & Sood, A. K. Neuroendocrine influences on cancer progression. Brain Behav. Immun. 30, S19–S25 (2013).
Cole, S. W., Nagaraja, A. S., Lutgendorf, S. K., Green, P. A. & Sood, A. K. Sympathetic nervous system regulation of the tumour microenvironment. Nat. Rev. Cancer 15, 563 (2015). This review describes the contribution of adrenergic signalling to cancer progression, focusing on the tumour microenvironment.
Armaiz-Pena, G. N., Colon-Echevarria, C. B. & Lamboy-Caraballo, R. Neuroendocrine regulation of tumor-associated immune cells. Front. Oncol. 9, 1077 (2019). This review examines the effects of sympathetic and/or glucocorticoid signalling on various tumour-associated immune cells.
Antoni, M. H. & Dhabhar, F. S. The impact of psychosocial stress and stress management on immune responses in patients with cancer. Cancer 125, 1417–1431 (2019). This review discusses both preclinical and clinical studies and summarizes the effects of stress and stress management on immune indices in cancer, suggesting potential optimal strategies for stress management in patients with cancer.
Neeman, E. & Ben-Eliyahu, S. Surgery and stress promote cancer metastasis: new outlooks on perioperative mediating mechanisms and immune involvement. Brain Behav. Immun. 30, S32–S40 (2013).
Cui, B. et al. Cancer and stress: NextGen strategies. Brain Behav. Immun. 93, 368–383 (2020).
Lutgendorf, S. K. & Andersen, B. L. Biobehavioral approaches to cancer progression and survival: mechanisms and interventions. Am. Psychol. 70, 186–197 (2015).
Mravec, B., Tibensky, M. & Horvathova, L. Stress and cancer. Part II: therapeutic implications for oncology. J. Neuroimmunol. 346, 577312 (2020).
Moreno-Smith, M., Lutgendorf, S. K. & Sood, A. K. Impact of stress on cancer metastasis. Future Oncol. 6, 1863–1881 (2010).
Selye, H. The Stress of Life (McGraw-Hill, 1956).
Cacioppo, J. T., Cacioppo, S., Capitanio, J. P. & Cole, S. W. The neuroendocrinology of social isolation. Annu. Rev. Psychol. 66, 733–767 (2015).
Bortolato, B. et al. Depression in cancer: the many biobehavioral pathways driving tumor progression. Cancer Treat. Rev. 52, 58–70 (2017).
Liu, R. T. & Alloy, L. B. Stress generation in depression: a systematic review of the empirical literature and recommendations for future study. Clin. Psychol. Rev. 30, 582–593 (2010).
Wang, Q., Timberlake, M. A. II, Prall, K. & Dwivedi, Y. The recent progress in animal models of depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 77, 99–109 (2017).
Sapolsky, R. M. Stress and the brain: individual variability and the inverted-U. Nat. Neurosci. 18, 1344 (2015).
McEwen, B. S. Neurobiological and systemic effects of chronic stress. Chronic Stress 1, 2470547017692328 (2017).
McEwen, B. S. & Stellar, E. Stress and the individual: mechanisms leading to disease. Arch. Intern. Med. 153, 2093–2101 (1993).
McEwen, B. S. & Gianaros, P. J. Central role of the brain in stress and adaptation: links to socioeconomic status, health, and disease. Ann. NY Acad. Sci. 1186, 190 (2010).
Lazarus, R. S. & Folkman, S. Stress, Appraisal, and Coping (Springer, 1984).
Holmes, T. H. & Rahe, R. H. The social readjustment rating scale. J. Psychosom. Res. 11, 213–218 (1967).
McEwen, B. S., Gray, J. D. & Nasca, C. Recognizing resilience: learning from the effects of stress on the brain. Neurobiol. Stress. 1, 1–11 (2015).
Fava, G. A. et al. Clinical characterization of allostatic overload. Psychoneuroendocrinology 108, 94–101 (2019).
Kiecolt-Glaser, J. K., Renna, M. E., Shrout, M. R. & Madison, A. A. Stress reactivity: what pushes us higher, faster, and longer — and why it matters. Curr. Dir. Psychol.Sci. 29, 492–498 (2020).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Fouad, Y. A. & Aanei, C. Revisiting the hallmarks of cancer. Am. J. Cancer Res. 7, 1016 (2017).
Manjili, M. H. Tumor dormancy and relapse: from a natural byproduct of evolution to a disease state. Cancer Res. 77, 2564–2569 (2017).
Bergers, G. & Benjamin, L. E. Tumorigenesis and the angiogenic switch. Nat. Rev. Cancer 3, 401–410 (2003).
Patidar, A. et al. DAMP–TLR–cytokine axis dictates the fate of tumor. Cytokine 104, 114–123 (2018).
Melamed, R. et al. Marginating pulmonary-NK activity and resistance to experimental tumor metastasis: suppression by surgery and the prophylactic use of a β-adrenergic antagonist and a prostaglandin synthesis inhibitor. Brain Behav. Immun. 19, 114–126 (2005).
Melamed, R. et al. The marginating-pulmonary immune compartment in rats: characteristics of continuous inflammation and activated NK cells. J. Immunother. 33, 16–29 (2010).
Sorski, L. et al. Prevention of liver metastases through perioperative acute CpG-C immune stimulation. Cancer Immunol. Immunother. 69, 2021–2031 (2020).
Strilic, B. & Offermanns, S. Intravascular survival and extravasation of tumor cells. Cancer Cell 32, 282–293 (2017).
Shaashua, L. et al. Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome. BMC Biol. 18, 1–13 (2020).
Gonzalez, H., Hagerling, C. & Werb, Z. Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev. 32, 1267–1284 (2018).
Rosenne, E. et al. Inducing a mode of NK-resistance to suppression by stress and surgery: a potential approach based on low dose of poly I-C to reduce postoperative cancer metastasis. Brain Behav. Immun. 21, 395–408 (2007).
Ben-Eliyahu, S., Shakhar, G., Page, G. G., Stefanski, V. & Shakhar, K. Suppression of NK cell activity and of resistance to metastasis by stress: a role for adrenal catecholamines and β-adrenoceptors. Neuroimmunomodulation 8, 154–164 (2000).
Sloan, E. K. et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 70, 7042–7052 (2010). This preclinical study in a breast cancer model reports that whereas chronic stress does not promote primary tumour growth, it promotes its metastatic dissemination, demonstrating specific interactions between stress and unique stages in cancer progression.
Du, P. et al. Chronic stress promotes EMT-mediated metastasis through activation of STAT3 signaling pathway by miR-337-3p in breast cancer. Cell Death Dis. 11, 1–13 (2020).
Madden, K. S., Szpunar, M. J. & Brown, E. B. Early impact of social isolation and breast tumor progression in mice. Brain Behav. Immun. 30, S135–S141 (2013).
Volden, P. A. & Conzen, S. D. The influence of glucocorticoid signaling on tumor progression. Brain Behav. Immun. 30, S26–S31 (2013).
Flint, M. S., Baum, A., Chambers, W. H. & Jenkins, F. J. Induction of DNA damage, alteration of DNA repair and transcriptional activation by stress hormones. Psychoneuroendocrinology 32, 470–479 (2007).
Hara, M. R. et al. A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1. Nature 477, 349–353 (2011).
Hara, M. R., Sachs, B. D., Caron, M. G. & Lefkowitz, R. J. Pharmacological blockade of a β2AR–β-arrestin-1 signaling cascade prevents the accumulation of DNA damage in a behavioral stress model. Cell Cycle 12, 219–224 (2013).
Feng, Z. et al. Chronic restraint stress attenuates p53 function and promotes tumorigenesis. Proc. Natl Acad. Sci. USA 109, 7013–7018 (2012).
Gidron, Y., Russ, K., Tissarchondou, H. & Warner, J. The relation between psychological factors and DNA-damage: a critical review. Biol. Psychol. 72, 291–304 (2006).
Lamboy-Caraballo, R. et al. Norepinephrine-induced DNA damage in ovarian cancer cells. Int. J. Mol. Sci. 21, 2250 (2020).
Flaherty, R. L. et al. Glucocorticoids induce production of reactive oxygen species/reactive nitrogen species and DNA damage through an iNOS mediated pathway in breast cancer. Breast Cancer Res. 19, 1–13 (2017).
Reeder, A. et al. Stress hormones reduce the efficacy of paclitaxel in triple negative breast cancer through induction of DNA damage. Br. J. Cancer 112, 1461–1470 (2015).
Plummer, M. et al. Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Glob. Health 4, e609–e616 (2016).
de Martel, C., Georges, D., Bray, F., Ferlay, J. & Clifford, G. M. Global burden of cancer attributable to infections in 2018: a worldwide incidence analysis. Lancet Glob. Health 8, e180–e190 (2020).
Antoni, M. H. et al. The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat. Rev. Cancer 6, 240–248 (2006).
Irwin, M. R. & Cole, S. W. Reciprocal regulation of the neural and innate immune systems. Nat. Rev. Immunol. 11, 625–632 (2011).
Collado-Hidalgo, A., Sung, C. & Cole, S. Adrenergic inhibition of innate anti-viral response: PKA blockade of type I interferon gene transcription mediates catecholamine support for HIV-1 replication. Brain Behav. Immun. 20, 552–563 (2006).
Cacioppo, J. T. et al. Autonomic and glucocorticoid associations with the steady-state expression of latent Epstein–Barr virus. Hormones Behav. 42, 32–41 (2002).
Glaser, R. et al. The differential impact of training stress and final examination stress on herpesvirus latency at the United States Military Academy at West Point. Brain Behav. Immun. 13, 240–251 (1999).
Fang, C. Y. et al. Perceived stress is associated with impaired T-cell response to HPV16 in women with cervical dysplasia. Ann. Behav. Med. 35, 87–96 (2008).
Fang, F. et al. Risk of infection-related cancers after the loss of a child: a follow-up study in Sweden. Cancer Res. 71, 116–122 (2011).
Saul, A. N. et al. Chronic stress and susceptibility to skin cancer. J. Natl Cancer Inst. 97, 1760–1767 (2005).
Sumis, A. et al. Social isolation induces autophagy in the mouse mammary gland: link to increased mammary cancer risk. Endocr. Relat. Cancer 23, 839–856 (2016).
Kokolus, K. M. et al. Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature. Proc. Natl Acad. Sci. USA 110, 20176–20181 (2013).
Renz, B. W. et al. β2 adrenergic-neurotrophin feedforward loop promotes pancreatic cancer. Cancer Cell 33, 75–90.e7 (2018). This research demonstrates the reciprocal relations between the malignant tissue and its direct sympathetic innervation in preclinical pancreatic cancer models.
Magnon, C. et al. Autonomic nerve development contributes to prostate cancer progression. Science 341, 1236361 (2013).
Hermes, G. L. et al. Social isolation dysregulates endocrine and behavioral stress while increasing malignant burden of spontaneous mammary tumors. Proc. Natl Acad. Sci. USA 106, 22393–22398 (2009).
Hasen, N. S., O’Leary, K. A., Auger, A. P. & Schuler, L. A. Social isolation reduces mammary development, tumor incidence, and expression of epigenetic regulators in wild-type and p53-heterozygotic mice. Cancer Prev. Res. 3, 620–629 (2010).
Nguyen, K. D. et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480, 104–108 (2011).
Flierl, M. A. et al. Phagocyte-derived catecholamines enhance acute inflammatory injury. Nature 449, 721–725 (2007).
Wong, H. P. S. et al. Nicotine promotes cell proliferation via α7-nicotinic acetylcholine receptor and catecholamine-synthesizing enzymes-mediated pathway in human colon adenocarcinoma HT-29 cells. Toxicol. Appl. Pharmacol. 221, 261–267 (2007).
Shi, M. et al. The β2-adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells. Breast Cancer Res. Treat. 125, 351–362 (2011).
Amaro, F. et al. β-Adrenoceptor activation in breast MCF-10A cells induces a pattern of catecholamine production similar to that of tumorigenic MCF-7 cells. Int. J. Mol. Sci. 21, 7968 (2020).
Zhang, X. et al. Chronic stress promotes gastric cancer progression and metastasis: an essential role for ADRB2. Cell Death Dis. 10, 1–15 (2019).
Zhi, X. et al. Adrenergic modulation of AMPK-dependent autophagy by chronic stress enhances cell proliferation and survival in gastric cancer. Int. J. Oncol. 54, 1625–1638 (2019).
Wong, H. P. et al. Effects of adrenaline in human colon adenocarcinoma HT-29 cells. Life Sci. 88, 1108–1112 (2011).
Sood, A. K. et al. Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis. J. Clin. Invest. 120, 1515–1523 (2010).
Liu, H. et al. Activation of adrenergic receptor β2 promotes tumor progression and epithelial mesenchymal transition in tongue squamous cell carcinoma. Int. J. Mol. Med. 41, 147–154 (2018).
Nagaraja, A. S. et al. Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis. Oncogene 35, 2390–2397 (2016).
Kim-Fuchs, C. et al. Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for β-adrenergic signaling in the pancreatic microenvironment. Brain Behav. Immun. 40, 40–47 (2014).
Moretti, S. et al. β-Adrenoceptors are upregulated in human melanoma and their activation releases pro-tumorigenic cytokines and metalloproteases in melanoma cell lines. Lab. Invest. 93, 279–290 (2013).
Pu, J. et al. Adrenaline promotes epithelial-to-mesenchymal transition via HuR–TGFβ regulatory axis in pancreatic cancer cells and the implication in cancer prognosis. Biochem. Biophys. Res. Commun. 493, 1273–1279 (2017).
Liu, J. et al. A novel β2-AR/YB-1/β-catenin axis mediates chronic stress-associated metastasis in hepatocellular carcinoma. Oncogenesis 9, 1–14 (2020).
Bucsek, M. J. et al. β-Adrenergic signaling in mice housed at standard temperatures suppresses an effector phenotype in CD8+ T cells and undermines checkpoint inhibitor therapy. Cancer Res. 77, 5639–5651 (2017).
Chen, H. et al. Chronic psychological stress promotes lung metastatic colonization of circulating breast cancer cells by decorating a pre-metastatic niche through activating β-adrenergic signaling. J. Pathol. 244, 49–60 (2018).
Lamkin, D. M. et al. Chronic stress enhances progression of acute lymphoblastic leukemia via β-adrenergic signaling. Brain Behav. Immun. 26, 635–641 (2012).
Thaker, P. H. et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat. Med. 12, 939–944 (2006). This is the first preclinical study to demonstrate the effects of chronic stress on tumour angiogenesis, which also identifies the mediating adrenergic signalling pathway.
Chang, A. et al. β2-Adrenoceptors on tumor cells play a critical role in stress-enhanced metastasis in a mouse model of breast cancer. Brain Behav. Immun. 57, 106–115 (2016).
Zahalka, A. H. & Frenette, P. S. Nerves in cancer. Nat. Rev. Cancer 20, 143–157 (2020).
Qin, J.-f et al. Adrenergic receptor β2 activation by stress promotes breast cancer progression through macrophages M2 polarization in tumor microenvironment. BMB Rep. 48, 295 (2015).
Lutgendorf, S. K. et al. Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients. Brain Behav. Immun. 25, 250–255 (2011).
Yang, H. et al. Stress–glucocorticoid–TSC22D3 axis compromises therapy-induced antitumor immunity. Nat. Med. 25, 1428–1441 (2019). This preclinical study conducted in several cancer models identifies a novel stress-induced mechanism, mediated though glucocorticoid signalling in dendritic cells, that can compromise chemotherapy-induced and immunotherapy-induced antitumour immunity.
Obradović, M. M. et al. Glucocorticoids promote breast cancer metastasis. Nature 567, 540–544 (2019). This preclinical study uses several models of breast cancer to demonstrate that the activation of GR in breast cancer cells, through ROR1 kinase signalling, leads to increased metastasis and resistance to chemotherapy, thus emphasizing that GR signalling, either by endogenous (stress-induced) or exogenous sources of glucocorticoids, can worsen cancer progression.
Pan, D., Kocherginsky, M. & Conzen, S. D. Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen receptor-negative breast cancer. Cancer Res. 71, 6360–6370 (2011).
Madden, K. S., Szpunar, M. J. & Brown, E. B. β-Adrenergic receptors (β-AR) regulate VEGF and IL-6 production by divergent pathways in high β-AR-expressing breast cancer cell lines. Breast Cancer Res. Treat. 130, 747–758 (2011).
Lutgendorf, S. K. et al. Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines. Clin. Cancer Res. 9, 4514–4521 (2003).
Yang, E. V. et al. Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav. Immun. 23, 267–275 (2009).
Chen, H. et al. Adrenergic signaling promotes angiogenesis through endothelial cell–tumor cell crosstalk. Endocr. Relat. Cancer 21, 783–795 (2014).
Shan, T. et al. β2-AR–HIF-1α: a novel regulatory axis for stress-induced pancreatic tumor growth and angiogenesis. Curr. Mol. Med. 13, 1023–1034 (2013).
Xu, P. et al. Surgical trauma contributes to progression of colon cancer by downregulating CXCL4 and recruiting MDSCs. Exp. Cell Res. 370, 692–698 (2018).
Budiu, R. A. et al. Restraint and social isolation stressors differentially regulate adaptive immunity and tumor angiogenesis in a breast cancer mouse model. Cancer Clin. Oncol. 6, 12 (2017).
Hulsurkar, M. et al. β-Adrenergic signaling promotes tumor angiogenesis and prostate cancer progression through HDAC2-mediated suppression of thrombospondin-1. Oncogene 36, 1525–1536 (2017).
Lutgendorf, S. K. et al. Vascular endothelial growth factor and social support in patients with ovarian carcinoma. Cancer 95, 808–815 (2002).
Lutgendorf, S. K. et al. Biobehavioral influences on matrix metalloproteinase expression in ovarian carcinoma. Clin. Cancer Res. 14, 6839–6846 (2008).
Costanzo, E. S. et al. Psychosocial factors and interleukin-6 among women with advanced ovarian cancer. Cancer 104, 305–313 (2005).
Lutgendorf, S. K. et al. Interleukin-6, cortisol, and depressive symptoms in ovarian cancer patients. J. Clin. Oncol. 26, 4820–4827 (2008).
Stacker, S. A. et al. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat. Rev. Cancer 14, 159–172 (2014).
Le, C. P. et al. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nat. Commun. 7, 10634 (2016). This preclinical study demonstrates the effects of chronic stress on lymphatic modulation and metastasis, and identifies the underlying adrenergic mechanisms.
Bower, J. E. et al. Prometastatic molecular profiles in breast tumors from socially isolated women. JNCI Cancer Spectr. 2, pky029 (2018).
Qiao, G., Chen, M., Bucsek, M. J., Repasky, E. A. & Hylander, B. L. Adrenergic signaling: a targetable checkpoint limiting development of the antitumor immune response. Front. Immunol. 9, 164 (2018).
Hirata, T. & Narumiya, S. (2012). in Advances in Immunology (ed. Alt, F. W.) 143–174 (Elvesier, 2012)
Shakhar, G. & Ben-Eliyahu, S. In vivo β-adrenergic stimulation suppresses natural killer activity and compromises resistance to tumor metastasis in rats. J. Immunol. 160, 3251–3258 (1998).
Inbar, S. et al. Do stress responses promote leukemia progression? An animal study suggesting a role for epinephrine and prostaglandin-E2 through reduced NK activity. PLoS ONE 6, e19246 (2011).
Rosenne, E. et al. In vivo suppression of NK cell cytotoxicity by stress and surgery: glucocorticoids have a minor role compared to catecholamines and prostaglandins. Brain Behav. Immun. 37, 207–219 (2014).
Lutgendorf, S. K. et al. Social support, psychological distress, and natural killer cell activity in ovarian cancer. J. Clin. Oncol. 23, 7105–7113 (2005).
Hou, N. et al. A novel chronic stress-induced shift in the TH1 to TH2 response promotes colon cancer growth. Biochem. Biophys. Res. Commun. 439, 471–476 (2013).
Lutgendorf, S. K. et al. Depressed and anxious mood and T-cell cytokine expressing populations in ovarian cancer patients. Brain Behav. Immun. 22, 890–900 (2008).
Mohammadpour, H. et al. β2 adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells. J. Clin. Invest. 129, 5537–5552 (2019).
Mundy-Bosse, B. L., Thornton, L. M., Yang, H.-C., Andersen, B. L. & Carson, W. E. Psychological stress is associated with altered levels of myeloid-derived suppressor cells in breast cancer patients. Cell. Immunol. 270, 80–87 (2011).
Armaiz-Pena, G. N. et al. Adrenergic regulation of monocyte chemotactic protein 1 leads to enhanced macrophage recruitment and ovarian carcinoma growth. Oncotarget 6, 4266–4273 (2015).
Lamkin, D. M. et al. β-Adrenergic-stimulated macrophages: comprehensive localization in the M1–M2 spectrum. Brain Behav. Immun. 57, 338–346 (2016).
Campbell, J. P. et al. Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice. PLoS Biol. 10, e1001363 (2012).
Simpson, C. D., Anyiwe, K. & Schimmer, A. D. Anoikis resistance and tumor metastasis. Cancer Lett. 272, 177–185 (2008).
Lutgendorf, S. K. et al. Epithelial–mesenchymal transition polarization in ovarian carcinomas from patients with high social isolation. Cancer 126, 4407–4413 (2020).
Benish, M. et al. Perioperative use of β-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis. Ann. Surg. Oncol. 15, 2042–2052 (2008).
Kaira, K. et al. Prognostic impact of β2 adrenergic receptor expression in surgically resected pulmonary pleomorphic carcinoma. Anticancer. Res. 39, 395–403 (2019).
Choy, C. et al. Inhibition of β2-adrenergic receptor reduces triple-negative breast cancer brain metastases: the potential benefit of perioperative β-blockade. Oncol. Rep. 35, 3135–3142 (2016).
Al-Niaimi, A. et al. The impact of perioperative β blocker use on patient outcomes after primary cytoreductive surgery in high-grade epithelial ovarian carcinoma. Gynecol. Oncol. 143, 521–525 (2016).
Barron, T. I., Connolly, R. M., Sharp, L., Bennett, K. & Visvanathan, K. β blockers and breast cancer mortality: a population-based study. J. Clin. Oncol. 29, 2635–2644 (2011).
Lemeshow, S. et al. β-Blockers and survival among Danish patients with malignant melanoma: a population-based cohort study. Cancer Epidemiol. Biomarkers Prev. 20, 2273–2279 (2011).
Cata, J. P. et al. Perioperative β-blocker use and survival in lung cancer patients. J. Clin. Anesth. 26, 106–117 (2014).
Heitz, F. et al. Intake of selective β blockers has no impact on survival in patients with epithelial ovarian cancer. Gynecol. Oncol. 144, 181–186 (2017).
Matzner, P. et al. Deleterious synergistic effects of distress and surgery on cancer metastasis: abolishment through an integrated perioperative immune-stimulating stress-inflammatory-reducing intervention. Brain Behav. Immun. 80, 170–178 (2019).
Stefanski, V. & Ben-Eliyahu, S. Social confrontation and tumor metastasis in rats: defeat and β-adrenergic mechanisms. Physiol. Behav. 60, 277–282 (1996).
Dhabhar, F. S. et al. Short-term stress enhances cellular immunity and increases early resistance to squamous cell carcinoma. Brain Behav. Immun. 24, 127–137 (2010).
Benaroya-Milshtein, N., Hollander, N., Apter, A., Yaniv, I. & Pick, C. G. Stress conditioning in mice: alterations in immunity and tumor growth. Stress 14, 301–311 (2011).
Williams, J. B. et al. A model of gene–environment interaction reveals altered mammary gland gene expression and increased tumor growth following social isolation. Cancer Prev. Res. 2, 850–861 (2009).
Dawes, R. P. et al. Chronic stress exposure suppresses mammary tumor growth and reduces circulating exosome TGF-β content via β-adrenergic receptor signaling in MMTV-PyMT mice. Breast Cancer 14, 1178223420931511 (2020).
Huo, J. et al. Bone marrow-derived mesenchymal stem cells promoted cutaneous wound healing by regulating keratinocyte migration via β2-adrenergic receptor signaling. Mol. Pharmaceutics 15, 2513–2527 (2018).
Ren, H. et al. Inhibition of α1-adrenoceptor reduces TGF-β1-induced epithelial-to-mesenchymal transition and attenuates UUO-induced renal fibrosis in mice. FASEB J. 34, 14892–14904 (2020).
Panina-Bordignon, P. et al. β2-agonists prevent TH1 development by selective inhibition of interleukin 12. J. Clin. Invest. 100, 1513–1519 (1997).
Ağaç, D., Estrada, L. D., Maples, R., Hooper, L. V. & Farrar, J. D. The β2-adrenergic receptor controls inflammation by driving rapid IL-10 secretion. Brain Behav. Immun. 74, 176–185 (2018).
Kavelaars, A., Van De Pol, M., Zijlstra, J. & Heijnen, C. J. β2-Adrenergic activation enhances interleukin-8 production by human monocytes. J. Neuroimmunol. 77, 211–216 (1997).
Steinle, J. J., Cappocia, F. C. Jr & Jiang, Y. β-Adrenergic receptor regulation of growth factor protein levels in human choroidal endothelial cells. Growth Factors 26, 325–330 (2008).
Asano, A., Morimatsu, M., Nikami, H., Yoshida, T. & Saito, M. Adrenergic activation of vascular endothelial growth factor mRNA expression in rat brown adipose tissue: implication in cold-induced angiogenesis. Biochem. J. 328, 179–183 (1997).
Chida, Y., Hamer, M., Wardle, J. & Steptoe, A. Do stress-related psychosocial factors contribute to cancer incidence and survival? Nat. Clin. Pract. Oncol. 5, 466–475 (2008). This paper is the most comprehensive meta-analysis assessing the contribution of psychosocial stress to cancer incidence, survival and mortality in several human malignancies.
Coyne, J. C., Ranchor, A. V. & Palmer, S. C. Meta-analysis of stress-related factors in cancer. Nat. Rev. Clin. Oncol. 7, 1–2 (2010).
Mravec, B. & Tibensky, M. Increased cancer incidence in “cold” countries: an (un)sympathetic connection? J. Therm. Biol. 89, 102538 (2020).
Keinan-Boker, L., Vin-Raviv, N., Liphshitz, I., Linn, S. & Barchana, M. Cancer incidence in Israeli Jewish survivors of World War II. J. Natl Cancer Inst. 101, 1489–1500 (2009).
Huang, T. et al. Depression and risk of epithelial ovarian cancer: results from two large prospective cohort studies. Gynecol. Oncol. 139, 481–486 (2015).
Schoemaker, M. J. et al. Psychological stress, adverse life events and breast cancer incidence: a cohort investigation in 106,000 women in the United Kingdom. Breast Cancer Res. 18, 72 (2016).
Trudel-Fitzgerald, C. et al. The association of work characteristics with ovarian cancer risk and mortality. Psychosom. Med. 79, 1059 (2017).
Liang, J.-A. et al. The analysis of depression and subsequent cancer risk in Taiwan. Cancer Epidemiol. Prev. Biomarkers 20, 473–475 (2011).
Heikkilä, K. et al. Work stress and risk of cancer: meta-analysis of 5700 incident cancer events in 116 000 European men and women. BMJ 346, f165 (2013).
Yang, T. et al. Work stress and the risk of cancer: a meta-analysis of observational studies. Int. J. Cancer 144, 2390–2400 (2019).
Perego, M. et al. Reactivation of dormant tumor cells by modified lipids derived from stress-activated neutrophils. Sci. Transl Med. 12, eabb5817 (2020). This preclinical study identifies a distinct mechanism by which tumour-associated neutrophils respond to stress-induced adrenergic activation, and lead to reactivation of dormant tumour cells. This study highlights β-blockade as a potential strategy to prevent stress-induced cancer relapse.
Krall, J. A. et al. The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy. Sci. Transl Med. 10, eaan3464 (2018).
Decker, A. M. et al. Sympathetic signaling reactivates quiescent disseminated prostate cancer cells in the bone marrow. Mol. Cancer Res. 15, 1644–1655 (2017).
Gil, F., Costa, G., Hilker, I. & Benito, L. First anxiety, afterwards depression: psychological distress in cancer patients at diagnosis and after medical treatment. Stress. Health 28, 362–367 (2012).
Carlson, L. et al. High levels of untreated distress and fatigue in cancer patients. Br. J. Cancer 90, 2297–2304 (2004).
Wang, X. et al. Prognostic value of depression and anxiety on breast cancer recurrence and mortality: a systematic review and meta-analysis of 282,203 patients. Mol. Psychiatry 25, 3186–3197 (2020).
Pinquart, M. & Duberstein, P. Depression and cancer mortality: a meta-analysis. Psychol. Med. 40, 1797 (2010).
Pinquart, M. & Duberstein, P. R. Associations of social networks with cancer mortality: a meta-analysis. Crit. Rev. Oncol. Hematol. 75, 122–137 (2010).
Cohen, L. et al. Depressive symptoms and cortisol rhythmicity predict survival in patients with renal cell carcinoma: role of inflammatory signaling. PLoS ONE 7, e42324 (2012).
Lutgendorf, S. K. et al. Social influences on clinical outcomes of patients with ovarian cancer. J. Clin. Oncol. 30, 2885 (2012).
Chou, A. F., Stewart, S. L., Wild, R. C. & Bloom, J. R. Social support and survival in young women with breast carcinoma. Psychooncology 21, 125–133 (2012).
Kroenke, C. H. et al. Prediagnosis social support, social integration, living status, and colorectal cancer mortality in postmenopausal women from the women’s health initiative. Cancer 126, 1766–1775 (2020).
Fagundes, C. P. et al. Basal cell carcinoma: stressful life events and the tumor environment. Arch. Gen. Psychiatry 69, 618–626 (2012).
Armer, J. S. et al. Life stress as a risk factor for sustained anxiety and cortisol dysregulation during the first year of survivorship in ovarian cancer. Cancer 124, 3401–3408 (2018).
Mirosevic, S. et al. “Not just another meta-analysis”: sources of heterogeneity in psychosocial treatment effect on cancer survival. Cancer Med. 8, 363–373 (2019). This meta-analysis assesses the effects of psychosocial stress management on cancer survival, discusses limitations of meta-analytic methods and identifies subpopulations that may better benefit from stress-management approaches.
Fu, W. W. et al. The impact of psychosocial intervention on survival in cancer: a meta-analysis. Ann. Palliat. Med. 5, 93–106 (2016).
Xia, Y. et al. Psychosocial and behavioral interventions and cancer patient survival again: hints of an adjusted meta-analysis. Integr. Cancer Therapies 13, 301–309 (2014).
Oh, P., Shin, S., Ahn, H. S. & Kim, H. Meta-analysis of psychosocial interventions on survival time in patients with cancer. Psychol. Health 31, 396–419 (2016).
Andersen, B. L. et al. Psychological, behavioral, and immune changes after a psychological intervention: a clinical trial. J. Clin. Oncol. 22, 3570 (2004).
Fawzy, F. I. et al. A structured psychiatric intervention for cancer patients. I. Changes over time in methods of coping and affective disturbance. Arch. Gen. Psychiatry 47, 720–725 (1990).
Antoni, M. H. et al. Cognitive-behavioral stress management reverses anxiety-related leukocyte transcriptional dynamics. Biol. Psychiatry 71, 366–372 (2012).
Fawzy, F. I. & Fawzy, N. W. Malignant melanoma: effects of a brief, structured psychiatric intervention on survival and recurrence at 10-year follow-up. Arch. Gen. Psychiatry 60, 100–103 (2003).
Stefanek, M. E., Palmer, S. C., Thombs, B. D. & Coyne, J. C. Finding what is not there: unwarranted claims of an effect of psychosocial intervention on recurrence and survival. Cancer 115, 5612–5616 (2009).
Coyne, J. C. & Tennen, H. Positive psychology in cancer care: bad science, exaggerated claims, and unproven medicine. Ann. Behav. Med. 39, 16–26 (2010).
Coyne, J. C., Stefanek, M. & Palmer, S. C. Psychotherapy and survival in cancer: the conflict between hope and evidence. Psychol. Bull. 133, 367 (2007).
Kraemer, H. C., Kuchler, T. & Spiegel, D. Use and misuse of the consolidated standards of reporting trials (CONSORT) guidelines to assess research findings: comment on Coyne, Stefanek, and Palmer (2007). Psychol. Bull. 135, 173–178 (2009).
Spiegel, D., Bloom, J. R., Kraemer, H. C. & Gottheil, E. Effect of psychosocial treatment on survival of patients with metastatic breast cancer. Lancet 2, 888–891 (1989).
Spiegel, D. et al. Effects of supportive-expressive group therapy on survival of patients with metastatic breast cancer: a randomized prospective trial. Cancer 110, 1130–1138 (2007).
Goodwin, P. J. et al. The effect of group psychosocial support on survival in metastatic breast cancer. N. Engl. J. Med. 345, 1719–1726 (2001).
Boesen, E. H. et al. Survival after a psychoeducational intervention for patients with cutaneous malignant melanoma: a replication study. J. Clin. Oncol. 25, 5698–5703 (2007).
Ben-Eliyahu, S. Tumor excision as a metastatic russian roulette: perioperative interventions to improve long-term survival of cancer patients. Trends Cancer 6, 951–959 (2020).
Burton, M. V. et al. A randomized controlled trial of preoperative psychological preparation for mastectomy. Psychooncology 4, 1–19 (1995).
Kuchler, T., Bestmann, B., Rappat, S., Henne-Bruns, D. & Wood-Dauphinee, S. Impact of psychotherapeutic support for patients with gastrointestinal cancer undergoing surgery: 10-year survival results of a randomized trial. J. Clin. Oncol. 25, 2702–2708 (2007).
Zhang, X.-D. et al. Perioperative comprehensive supportive care interventions for Chinese patients with esophageal carcinoma: a prospective study. Asian Pac. J. Cancer Prev. 14, 7359–7366 (2013).
Shaashua, L. et al. Perioperative COX-2 and β-adrenergic blockade improves metastatic biomarkers in breast cancer patients in a phase-II randomized trial. Clin. Cancer Res. 23, 4651–4661 (2017). This study is the first clinical trial in patients with cancer to assess perioperative safety and efficacy of the combined use of propranolol and etodolac on biomarkers related to breast cancer progression.
Benjamin, B. et al. Effect of β blocker combined with COX-2 inhibitor on colonic anastomosis in rats. Int. J. Colorectal Dis. 25, 1459–1464 (2010).
Hazut, O. et al. The effect of β-adrenergic blockade and COX-2 inhibition on healing of colon, muscle, and skin in rats undergoing colonic anastomosis. Int. J. Clin. Pharmacol. Ther. 49, 545–554 (2011).
Hiller, J. G. et al. Preoperative β-blockade with propranolol reduces biomarkers of metastasis in breast cancer: a phase II randomized trial. Clin. Cancer Res. 26, 1803–1811 (2020).
Jang, H. I., Lim, S. H., Lee, Y. Y., Kim, T. J. & Choi, C. H. Perioperative administration of propranolol to women undergoing ovarian cancer surgery: a pilot study. Obstet. Gynecol. Sci. 60, 170–177 (2017).
Knight, J. M. et al. Propranolol inhibits molecular risk markers in HCT recipients: a phase 2 randomized controlled biomarker trial. Blood Adv. 4, 467–476 (2020).
Gandhi, S. et al. Phase I clinical trial of combination propranolol and pembrolizumab in locally advanced and metastatic melanoma: safety, tolerability, and preliminary evidence of antitumor activity. Clin. Cancer Res. 27, 87–95 (2021).
Ricon, I., Hanalis-Miller, T., Haldar, R., Jacoby, R. & Ben-Eliyahu, S. Perioperative biobehavioral interventions to prevent cancer recurrence through combined inhibition of β-adrenergic and cyclooxygenase 2 signaling. Cancer 125, 45–56 (2019).
Horowitz, M., Neeman, E., Sharon, E. & Ben-Eliyahu, S. Exploiting the critical perioperative period to improve long-term cancer outcomes. Nat. Rev. Clin. Oncol. 12, 213–226 (2015). This review summarizes important aspects within the perioperative period that make this time frame critical in affecting long-term cancer outcomes, and suggests potential clinical perioperative interventions to reduce metastatic disease.
Hiller, J. G., Perry, N. J., Poulogiannis, G., Riedel, B. & Sloan, E. K. Perioperative events influence cancer recurrence risk after surgery. Nat. Rev. Clin. Oncol. 15, 205–218 (2018). This review highlights perioperative events as critical in affecting cancer outcomes and suggests how to reduce perioperative risks.
Sorski, L. et al. Reducing liver metastases of colon cancer in the context of extensive and minor surgeries through β-adrenoceptors blockade and COX2 inhibition. Brain Behav. Immun. 58, 91–98 (2016).
Glasner, A. et al. Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a β-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J. Immunol. 184, 2449–2457 (2010). This preclinical study demonstrates the synergistic beneficial effects of perioperative blockade of adrenergic and prostaglandin signalling on immunity and postoperative survival in two models of spontaneous metastasis.
Haldar, R. et al. Perioperative inhibition of β-adrenergic and COX2 signaling in a clinical trial in breast cancer patients improves tumor Ki-67 expression, serum cytokine levels, and PBMCs transcriptome. Brain Behav. Immun. 73, 294–309 (2018).
Haldar, R. et al. Perioperative COX2 and β-adrenergic blockade improves biomarkers of tumor metastasis, immunity, and inflammation in colorectal cancer: a randomized controlled trial. Cancer 126, 3991–4001 (2020). This clinical trial demonstrates safety, feasibility and efficacy of perioperative combined treatment with propranolol and etodolac to improve cancer biomarkers and, potentially, survival outcomes in patients with CRC.
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03838029 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03919461 (2019).
Busby, J., Mills, K., Zhang, S.-D., Liberante, F. G. & Cardwell, C. R. Selective serotonin reuptake inhibitor use and breast cancer survival: a population-based cohort study. Breast Cancer Res. 20, 4 (2018).
Boursi, B., Lurie, I., Haynes, K., Mamtani, R. & Yang, Y.-X. Chronic therapy with selective serotonin reuptake inhibitors and survival in newly diagnosed cancer patients. Eur. J. Cancer Care 27, e12666 (2018).
Zingone, A. et al. Relationship between anti-depressant use and lung cancer survival. Cancer Treat. Res. Commun. 10, 33–39 (2017).
Stockler, M. R. et al. Effect of sertraline on symptoms and survival in patients with advanced cancer, but without major depression: a placebo-controlled double-blind randomised trial. Lancet Oncol. 8, 603–612 (2007).
Sternbach, H. Are antidepressants carcinogenic? A review of preclinical and clinical studies. J. Clin. Psychiatry 64, 1153–1162 (2003).
Grygier, B. et al. Inhibitory effect of antidepressants on B16F10 melanoma tumor growth. Pharmacol. Rep. 65, 672–681 (2013).
Kubera, M. et al. Stimulatory effect of antidepressant drug pretreatment on progression of B16F10 melanoma in high-active male and female C57BL/6J mice. J. Neuroimmunol. 240–241, 34–44 (2011).
Andersen, B. L., Shapiro, C. L., Farrar, W. B., Crespin, T. & Wells-DiGregorio, S. Psychological responses to cancer recurrence: a controlled prospective study. Cancer 104, 1540–1547 (2005).
Linden, W., Vodermaier, A., MacKenzie, R. & Greig, D. Anxiety and depression after cancer diagnosis: prevalence rates by cancer type, gender, and age. J. Affect. Disord. 141, 343–351 (2012).
Mitchell, A. J., Ferguson, D. W., Gill, J., Paul, J. & Symonds, P. Depression and anxiety in long-term cancer survivors compared with spouses and healthy controls: a systematic review and meta-analysis. Lancet Oncol. 14, 721–732 (2013).
Watts, S., Prescott, P., Mason, J., McLeod, N. & Lewith, G. Depression and anxiety in ovarian cancer: a systematic review and meta-analysis of prevalence rates. BMJ Open 5, e007618 (2015).
Sephton, S. E. et al. Depression, cortisol, and suppressed cell-mediated immunity in metastatic breast cancer. Brain Behav. Immun. 23, 1148–1155 (2009).
Andersen, B. L. et al. Stress and immune responses after surgical treatment for regional breast cancer. J. Natl Cancer Inst. 90, 30–36 (1998).
Blomberg, B. B. et al. Psychosocial adaptation and cellular immunity in breast cancer patients in the weeks after surgery: an exploratory study. J. Psychosom. Res. 67, 369–376 (2009).
Schrepf, A. et al. Cortisol and inflammatory processes in ovarian cancer patients following primary treatment: relationships with depression, fatigue, and disability. Brain Behav. Immun. 30, S126–S134 (2013).
Pyter, L. M., Pineros, V., Galang, J. A., McClintock, M. K. & Prendergast, B. J. Peripheral tumors induce depressive-like behaviors and cytokine production and alter hypothalamic–pituitary–adrenal axis regulation. Proc. Natl Acad. Sci. USA 106, 9069–9074 (2009).
Bower, J. E. & Lamkin, D. M. Inflammation and cancer-related fatigue: mechanisms, contributing factors, and treatment implications. Brain Behav. Immun. 30, S48–S57 (2013).
Bower, J. E. et al. Inflammation and behavioral symptoms after breast cancer treatment: do fatigue, depression, and sleep disturbance share a common underlying mechanism? J. Clin. Oncol. 29, 3517 (2011).
Norden, D. M. et al. Tumor growth increases neuroinflammation, fatigue and depressive-like behavior prior to alterations in muscle function. Brain Behav. Immun. 43, 76–85 (2015).
Vardy, J. L. et al. Cognitive function in patients with colorectal cancer who do and do not receive chemotherapy: a prospective, longitudinal, controlled study. J. Clin. Oncol. 33, 4085 (2015).
Hutchinson, A. D., Hosking, J. R., Kichenadasse, G., Mattiske, J. K. & Wilson, C. Objective and subjective cognitive impairment following chemotherapy for cancer: a systematic review. Cancer Treat. Rev. 38, 926–934 (2012).
Chrousos, G. P. The hypothalamic–pituitary–adrenal axis and immune-mediated inflammation. N. Engl. J. Med. 332, 1351–1363 (1995).
Ben-Shaanan, T. L. et al. Modulation of anti-tumor immunity by the brain’s reward system. Nat. Commun. 9, 2723 (2018).
Matzner, P. et al. Harnessing cancer immunotherapy during the unexploited immediate perioperative period. Nat. Rev. Clin. Oncol. 17, 313–326 (2020).
Goldfarb, Y. et al. Improving postoperative immune status and resistance to cancer metastasis: a combined perioperative approach of immunostimulation and prevention of excessive surgical stress responses. Ann. Surg. 253, 798–810 (2011).
Levi, B. et al. Stress impairs the efficacy of immune stimulation by CpG-C: potential neuroendocrine mediating mechanisms and significance to tumor metastasis and the perioperative period. Brain Behav. Immun. 56, 209–220 (2016).
Shaashua, L. et al. Plasma IL-12 levels are suppressed in vivo by stress and surgery through endogenous release of glucocorticoids and prostaglandins but not catecholamines or opioids. Psychoneuroendocrinology 42, 11–23 (2014).
Sommershof, A., Scheuermann, L., Koerner, J. & Groettrup, M. Chronic stress suppresses anti-tumor T CD8+ responses and tumor regression following cancer immunotherapy in a mouse model of melanoma. Brain Behav. Immun. 65, 140–149 (2017).
Nissen, M. D., Sloan, E. K. & Mattarollo, S. R. β-adrenergic signaling impairs antitumor CD8+ T-cell responses to B-cell lymphoma immunotherapy. Cancer Immunol. Res. 6, 98–109 (2018).
Kang, Y. et al. Adrenergic stimulation of DUSP1 impairs chemotherapy response in ovarian cancer. Clin. Cancer Res. 22, 1713–1724 (2016).
Deng, G.-H. et al. Exogenous norepinephrine attenuates the efficacy of sunitinib in a mouse cancer model. J. Exp. Clin. Cancer Res. 33, 21 (2014).
Liu, J. et al. The effect of chronic stress on anti-angiogenesis of sunitinib in colorectal cancer models. Psychoneuroendocrinology 52, 130–142 (2015).
Hassan, S. et al. β2-Adrenoreceptor signaling increases therapy resistance in prostate cancer by upregulating MCL1. Mol. Cancer Res. 18, 1839–1848 (2020).
Eng, J. W.-L. et al. Housing temperature-induced stress drives therapeutic resistance in murine tumour models through β2-adrenergic receptor activation. Nat. Commun. 6, 6426 (2015). This preclinical study in pancreatic cancer models demonstrates that the ambient housing temperature of laboratory mice can cause chronic adrenergic stress, which in turn can lead to resistance to cytotoxic therapies, but this effect can be reversed by blockade of β-adrenergic signalling. This study supports the potential beneficial effects of β-blockade in the context of cancer therapy.
Chen, M. et al. Adrenergic stress constrains the development of anti-tumor immunity and abscopal responses following local radiation. Nat. Commun. 11, 1821 (2020).
Shi, M. et al. Catecholamine-induced β2-adrenergic receptor activation mediates desensitization of gastric cancer cells to trastuzumab by upregulating MUC4 expression. J. Immunol. 190, 5600–5608 (2013).
Liu, D. et al. β2-AR signaling controls trastuzumab resistance-dependent pathway. Oncogene 35, 47–58 (2016).
Zhang, C. et al. Clinical and mechanistic aspects of glucocorticoid-induced chemotherapy resistance in the majority of solid tumors. Cancer Biol. Ther. 6, 278–287 (2007).
Arora, V. K. et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 155, 1309–1322 (2013).
Skor, M. N. et al. Glucocorticoid receptor antagonism as a novel therapy for triple-negative breast cancer. Clin. Cancer Res. 19, 6163–6172 (2013).
Zhang, C. et al. Corticosteroids induce chemotherapy resistance in the majority of tumour cells from bone, brain, breast, cervix, melanoma and neuroblastoma. Int. J. Oncol. 29, 1295–1301 (2006). This comprehensive screen identifies glucocorticoid-induced chemotherapy resistance in numerous human carcinoma cell lines.
Fiala, O. et al. Incidental use of β-blockers is associated with outcome of metastatic colorectal cancer patients treated with bevacizumab-based therapy: a single-institution retrospective analysis of 514 patients. Cancers 11, 1856 (2019).
Chaudhary, K. R. et al. Effects of β-adrenergic antagonists on chemoradiation therapy for locally advanced non-small cell lung cancer. J. Clin. Med. 8, 575 (2019).
Wang, H. et al. Improved survival outcomes with the incidental use of β-blockers among patients with non-small-cell lung cancer treated with definitive radiation therapy. Ann. Oncol. 24, 1312–1319 (2013).
Kokolus, K. M. et al. β blocker use correlates with better overall survival in metastatic melanoma patients and improves the efficacy of immunotherapies in mice. Oncoimmunology 7, e1405205 (2018).
Navari, R. M. & Aapro, M. Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N. Engl. J. Med. 374, 1356–1367 (2016).
Pufall, M. A. in Glucocorticoid Signaling (eds Wang, J. C. & Harris, C.) 315–333 (Springer, 2015).
Boutros, C. et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat. Rev. Clin. Oncol. 13, 473–486 (2016).
Arbour, K. C. et al. Deleterious effect of baseline steroids on efficacy of PD-(L)1 blockade in patients with NSCLC. J. Clin. Oncol. 36, 2872–2878 (2018). This retrospective study in patients with non-small-cell lung cancer reports an association between the use of high-dose corticosteroids, reduced efficacy of immune checkpoint inhibitor therapy and poorer clinical outcome, emphasizing the importance of reassessing the prevalent use of synthetic glucocorticoids in patients with cancer.
Scott, S. C. & Pennell, N. A. Early use of systemic corticosteroids in patients with advanced NSCLC treated with nivolumab. J. Thorac. Oncol. 13, 1771–1775 (2018).
Fucà, G. et al. Modulation of peripheral blood immune cells by early use of steroids and its association with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors. ESMO Open 4, e000457 (2019).
Kissane, D. W. et al. Effect of cognitive-existential group therapy on survival in early-stage breast cancer. J. Clin. Oncol. 22, 4255–4260 (2004).
Andersen, B. L. et al. Psychologic intervention improves survival for breast cancer patients: a randomized clinical trial. Cancer 113, 3450–3458 (2008).
Boesen, E. H. et al. Psychosocial group intervention for patients with primary breast cancer: a randomised trial. Eur. J. Cancer 47, 1363–1372 (2011).
Stagl, J. M. et al. A randomized controlled trial of cognitive-behavioral stress management in breast cancer: survival and recurrence at 11-year follow-up. Breast Cancer Res. Treat. 154, 319–328 (2015).
Cunningham, A. et al. A randomized controlled trial of the effects of group psychological therapy on survival in women with metastatic breast cancer. Psychooncology 7, 508–517 (1998).
Edelman, S., Lemon, J., Bell, D. R. & Kidman, A. D. Effects of group CBT on the survival time of patients with metastatic breast cancer. Psychooncology 8, 474–481 (1999).
Kissane, D. W. et al. Supportive-expressive group therapy for women with metastatic breast cancer: survival and psychosocial outcome from a randomized controlled trial. Psychooncology 16, 277–286 (2007).
Andersen, B. L. et al. Biobehavioral, immune, and health benefits following recurrence for psychological intervention participants. Clin. Cancer Res. 16, 3270–3278 (2010).
Linn, M. W., Linn, B. S. & Harris, R. Effects of counseling for late stage cancer patients. Cancer 49, 1048–1055 (1982).
Ilnyckyj, A., Farber, J., Cheang, M. & Weinerman, B. A randomized controlled trial of psychotherapeutic intervention in cancer patients. Ann. R. Coll. Physicians Surg. Can. 27, 93–96 (1994).
Ratcliffe, M. A., Dawson, A. A. & Walker, L. G. Eysenck personality inventory L-scores in patients with Hodgkin’s disease and non-Hodgkin’s lymphoma. Psychooncology 4, 39–45 (1995).
Ross, L. et al. No effect on survival of home psychosocial intervention in a randomized study of Danish colorectal cancer patients. Psychooncology 18, 875–885 (2009).
Temel, J. S. et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N. Engl. J. Med. 363, 733–742 (2010).
Guo, Z. et al. The benefits of psychosocial interventions for cancer patients undergoing radiotherapy. Health Qual. Life Outcomes 11, 121 (2013).
Dhabhar, F. S. Effects of stress on immune function: the good, the bad, and the beautiful. Immunol. Res. 58, 193–210 (2014).
Viswanathan, K. & Dhabhar, F. S. Stress-induced enhancement of leukocyte trafficking into sites of surgery or immune activation. Proc. Natl Acad. Sci. USA 102, 5808–5813 (2005).
Neeman, E. et al. Stress and skin leukocyte trafficking as a dual-stage process. Brain Behav. Immun. 26, 267–276 (2012).
Russell, G. & Lightman, S. The human stress response. Nat. Rev. Endocrinol. 15, 525–534 (2019).
Cruz-Topete, D. & Cidlowski, J. A. One hormone, two actions: anti-and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation 22, 20–32 (2015).
Shaashua, L. et al. In vivo suppression of plasma IL-12 levels by acute and chronic stress paradigms: potential mediating mechanisms and sex differences. Brain Behav. Immun. 26, 996–1005 (2012).
Baum, A., O’Keeffe, M. K. & Davidson, L. M. Acute stressors and chronic response: the case of traumatic stress 1. J. Appl. Soc. Psychol. 20, 1643–1654 (1990).
Hawley, J. A., Hargreaves, M., Joyner, M. J. & Zierath, J. R. Integrative biology of exercise. Cell 159, 738–749 (2014).
Neufer, P. D. et al. Understanding the cellular and molecular mechanisms of physical activity-induced health benefits. Cell Metab. 22, 4–11 (2015).
Brownley, K. A. et al. Sympathoadrenergic mechanisms in reduced hemodynamic stress responses after exercise. Med. Sci. Sports Exerc. 35, 978–986 (2003).
Traustadóttir, T., Bosch, P. R. & Matt, K. S. The HPA axis response to stress in women: effects of aging and fitness. Psychoneuroendocrinology 30, 392–402 (2005).
Petersen, A. M. W. & Pedersen, B. K. The anti-inflammatory effect of exercise. J. Appl. Physiol. 98, 1154–1162 (2005).
Speck, R. M., Courneya, K. S., Mâsse, L. C., Duval, S. & Schmitz, K. H. An update of controlled physical activity trials in cancer survivors: a systematic review and meta-analysis. J. Cancer Surviv. 4, 87–100 (2010).
Rogers, L. Q. et al. Effects of a multicomponent physical activity behavior change intervention on fatigue, anxiety, and depressive symptomatology in breast cancer survivors: randomized trial. Psychooncology 26, 1901–1906 (2017).
Mehnert, A. et al. Effects of a physical exercise rehabilitation group program on anxiety, depression, body image, and health-related quality of life among breast cancer patients. Oncol. Res. Treat. 34, 248–253 (2011).
Dimeo, F. C., Stieglitz, R. D., Novelli-Fischer, U., Fetscher, S. & Keul, J. Effects of physical activity on the fatigue and psychologic status of cancer patients during chemotherapy. Cancer 85, 2273–2277 (1999).
McNeely, M. L. et al. Effects of exercise on breast cancer patients and survivors: a systematic review and meta-analysis. CMAJ 175, 34–41 (2006).
Kruijsen-Jaarsma, M., Révész, D., Bierings, M. B., Buffart, L. M. & Takken, T. Effects of exercise on immune function in patients with cancer: a systematic review. Exerc. Immunol. Rev. 19, 120–143 (2013).
Davies, N., Batehup, L. & Thomas, R. The role of diet and physical activity in breast, colorectal, and prostate cancer survivorship: a review of the literature. Br. J. Cancer 105, S52–S73 (2011).
Stout, N. L., Baima, J., Swisher, A. K., Winters-Stone, K. M. & Welsh, J. A systematic review of exercise systematic reviews in the cancer literature (2005–2017). PMR 9, S347–S384 (2017).
Hanns, P., Paczulla, A. M., Medinger, M., Konantz, M. & Lengerke, C. Stress and catecholamines modulate the bone marrow microenvironment to promote tumorigenesis. Cell Stress. 3, 221 (2019).
Dethlefsen, C. et al. Exercise-induced catecholamines activate the hippo tumor suppressor pathway to reduce risks of breast cancer development. Cancer Res. 77, 4894–4904 (2017).
Pedersen, L. et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metab. 23, 554–562 (2016).
Song, Y. et al. Enriching the housing environment for mice enhances their NK cell antitumor immunity via sympathetic nerve-dependent regulation of NKG2D and CCR5. Cancer Res. 77, 1611–1622 (2017).
Graff, R. M. et al. β2-Adrenergic receptor signaling mediates the preferential mobilization of differentiated subsets of CD8+ T-cells, NK-cells and non-classical monocytes in response to acute exercise in humans. Brain Behav. Immun. 74, 143–153 (2018).
Devalon, M. et al. DOPA in plasma increases during acute exercise and after exercise training. J. Lab. Clin. Med. 114, 321–327 (1989).
Yamaguchi, K., Takagi, Y., Aoki, S., Futamura, M. & Saji, S. Significant detection of circulating cancer cells in the blood by reverse transcriptase-polymerase chain reaction during colorectal cancer resection. Ann. Surg. 232, 58–65 (2000).
Hashimoto, M. et al. Significant increase in circulating tumour cells in pulmonary venous blood during surgical manipulation in patients with primary lung cancer. Interact. Cardiovasc. Thorac. Surg. 18, 775–783 (2014).
O’Reilly, M. S. et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285 (1997).
O’Reilly, M. S. et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79, 315–328 (1994).
Abramovitch, R., Marikovsky, M., Meir, G. & Neeman, M. Stimulation of tumour growth by wound-derived growth factors. Br. J. Cancer 79, 1392–1398 (1999).
Pascual, M. et al. Randomized clinical trial comparing inflammatory and angiogenic response after open versus laparoscopic curative resection for colonic cancer. Br. J. Surg. 98, 50–59 (2011).
Garssen, B., Boomsma, M. F. & Beelen, R. H. Psychological factors in immunomodulation induced by cancer surgery: a review. Biol. Psychol. 85, 1–13 (2010).
Cata, J. P. et al. Intraoperative use of dexmedetomidine is associated with decreased overall survival after lung cancer surgery. J. Anaesthesiol. Clin. Pharmacol. 33, 317 (2017).
Lavon, H. et al. Dexmedetomidine promotes metastasis in rodent models of breast, lung, and colon cancers. Br. J. Anaesth. 120, 188–196 (2018).
Del Mastro, L. et al. Impact of two different dose-intensity chemotherapy regimens on psychological distress in early breast cancer patients. Eur. J. Cancer 38, 359–366 (2002).
Vyas, D., Laput, G. & Vyas, A. K. Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis. Onco. Targets Ther. 7, 1015 (2014).
Shaked, Y. Balancing efficacy of and host immune responses to cancer therapy: the yin and yang effects. Nat. Rev. Clin. Oncol. 13, 611 (2016).
Antoni, M. H. et al. How stress management improves quality of life after treatment for breast cancer. J. Consul. Clin. Psychol. 74, 1143 (2006).
Andersen, B. L. et al. Distress reduction from a psychological intervention contributes to improved health for cancer patients. Brain Behav. Immun. 21, 953–961 (2007).
Riba, M. B. et al. Distress management, version 3.2019, NCCN clinical practice guidelines in oncology. J. Natl Compr. Cancer Netw. 17, 1229–1249 (2019).
Buffart, L. M. et al. Physical and psychosocial benefits of yoga in cancer patients and survivors, a systematic review and meta-analysis of randomized controlled trials. BMC Cancer 12, 1–21 (2012).
Bower, J. E. et al. Yoga reduces inflammatory signaling in fatigued breast cancer survivors: a randomized controlled trial. Psychoneuroendocrinology 43, 20–29 (2014).
Witek-Janusek, L. et al. Effect of mindfulness based stress reduction on immune function, quality of life and coping in women newly diagnosed with early stage breast cancer. Brain Behav. Immun. 22, 969–981 (2008).
Bower, J. E. et al. Mindfulness meditation for younger breast cancer survivors: a randomized controlled trial. Cancer 121, 1231–1240 (2015).
Antoni, M. H. Stress Management Intervention for Women with Breast Cancer (American Psychological Association, 2003).
Antoni, M. H. et al. Cognitive behavioral stress management effects on psychosocial and physiological adaptation in women undergoing treatment for breast cancer. Brain Behav. Immun. 23, 580–591 (2009).
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.
The authors declare no competing interests.
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Nature Reviews Cancer thanks E. Repasky, who co-reviewed with H. Mohammadpour, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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- 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.
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.
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.
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.
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