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Sympathetic nervous system regulation of the tumour microenvironment
Open accessAbstract
The peripheral autonomic nervous system (ANS) is known to regulate gene expression in primary tumours and their surrounding microenvironment. Activation of the sympathetic division of the ANS in particular modulates gene expression programmes that promote metastasis of solid tumours by stimulating macrophage infiltration, inflammation, angiogenesis, epithelial-mesenchymal transition and tumour invasion, and by inhibiting cellular immune responses and programmed cell death. Haematological cancers are modulated by sympathetic nervous system (SNS) regulation of stem cell biology and haematopoietic differentiation programmes. In addition to identifying a molecular basis for physiologic stress effects on cancer, these findings have also identified new pharmacological strategies to inhibit cancer progression in vivo.
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“…agonists on cancer malignancy, whereas its inhibition could contribute to the beneficial effects of β-blockers, as documented in mouse cancer models and human cancer epidemiologic studies (Chida et al., 2008; Powe and Entschladen, 2011; Cole and Sood, 2012; Cole et al., 2015; Tang et al., 2013).”
BackgroundInfluentialZimmaro, L., Sephton, S. E., Siwik, C. J., Phillips, K. M., Rebholz, W., Kraemer, H., Giese-Davis, J., Wilson, L. D., Bumpous, J., & Cash, E. D. (2018) · Cancer · doi:10.1002/cncr.31109 · Cited by 86
Wrobel, L. J., Bod, L., Lengagne, R., Kato, M., Prévost‐Blondel, A., & Gal, F. L. (2016) · Oncotarget · doi:10.18632/oncotarget.12833 · Cited by 82
Targeting tumor innervation: premises, promises, and challenges
Li, X., Peng, X., Yang, S., Wei, S., Fan, Q., Liu, J., Yang, L., & Li, H. (2022) · Cell Death Discovery · doi:10.1038/s41420-022-00930-9 · Cited by 85
“Both the central nervous system and the nervous cells in the TME can exert significant impacts on cancers [105].”
BackgroundNerve input to tumours: Pathophysiological consequences of a dynamic relationship
Hutchings, C., Phillips, J. A., & Djamgoz, M. B. A. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188411 · Cited by 79
The Behavioral Medicine Research Council: Its origins, mission, and methods.
Freedland, K. E. (2019) · Health Psychology · doi:10.1037/hea0000731 · Cited by 77
“…& Chen, 2017; Cuthbert, 2014; Huppertz et al., 2016), questions about biobehavioral mechanisms linking risk factors to medical outcomes (e.g., Cole et al., 2015; Lutgendorf & Andersen, 2015; Miller, Chen, & Parker, 2011; Suls, Green, & Davidson, 2016; Wirtz & von Känel, 2017), and questions…”
BackgroundGillis, R. D., Botteri, E., Chang, A., Ziegler, A. I., Chung, N.-C., Pon, C. K., Shackleford, D. M., Andreassen, B. K., Halls, M. L., Baker, J. G., et al. (2021) · European Journal of Cancer · doi:10.1016/j.ejca.2021.01.029 · Cited by 76
“3 Introduction The sympathetic nervous system is a branch of the autonomic nervous system that has been shown to increase metastasis and enhance cancer progression (1-3).”
BackgroundChronic stress in solid tumor development: from mechanisms to interventions
Yan, J., Chen, Y., Luo, M., Hu, X., Li, H., Liu, Q., & Zou, Z. (2023) · Journal of Biomedical Science · doi:10.1186/s12929-023-00903-9 · Cited by 89
Role of stress in the pathogenesis of cancer (Review)
Lempesis, I. G., Georgakopoulou, V., Papalexis, P., Chrousos, G. P., & Spandidos, D. A. (2023) · International Journal of Oncology · doi:10.3892/ijo.2023.5572 · Cited by 82
Liu, C., Yang, Y., Chen, C., Li, L., Li, J., Wang, X., Chu, Q., Qiu, L., Ba, Q., Li, X., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25967-9 · Cited by 74
Kesler, S. R., Adams, M., Packer, M., Rao, V., Henneghan, A. M., Blayney, D. W., & Palesh, O. (2017) · Brain and Behavior · doi:10.1002/brb3.643 · Cited by 77
“Stress is also associated with disrupted functional dynamics in patients with breast cancer, inflammatory response, and tumor progression (Churchill et al., 2015; Cole et al., 2015).”
BackgroundAdverse childhood experiences (ACEs), cell-mediated immunity, and survival in the context of cancer
Steel, J. L., Antoni, M. H., Pathak, R., Butterfield, L. H., Yoram Vodovotz, B., Savkova, A., Marsh, W., Wang, Y., Jing, H., Grammer, E., et al. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.04.050 · Cited by 75
Role of Anillin in Tumour: From a Prognostic Biomarker to a Novel Target
Nguyen, T. M., & Lee, C. H. (2020) · Cancers · doi:10.3390/cancers12061600 · Cited by 67
Mravec, B., Tibenský, M., Horváthová, Ľ., & Babál, P. (2019) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-19-0346 · Cited by 74
“Preclinical and clinical studies have shown that norepinephrine and epinephrine, via binding to b-adrenergic receptors, potentiate the induction of DNA mutations via induction of oxidative stress that reduces the efficiency of DNA-repair mechanisms (57, 58), activate oncogenes (59, 60), induce tumor-promoting inflamma…”
BackgroundEpinephrine promotes COX-2-dependent immune suppression in myeloid cells and cancer tissues
Muthuswamy, R., Okada, N. J., Jenkins, F. J., McGuire, K. P., McAuliffe, P. F., Zeh, H. J., Bartlett, D. L., Wallace, C. T., Watkins, S. C., Henning, J. D., et al. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.02.008 · Cited by 70
“The mechanisms underlying these effects have yet to be fully elucidated (Cole et al., 2015; Shin et al., 2016).”
InfluentialBrown, L. C., Murphy, A. R., Lalonde, C. S., Subhedar, P. D., Miller, A. H., & Stevens, J. S. (2020) · Cancer · doi:10.1002/cncr.32934 · Cited by 73
“table finding is that activation of the SNS regulates breast cancer metastasis through β-adrenergic signaling, and it is hypothesized that blocking SNS activity may minimize breast cancer metastasis, an effect that may be mediated by SNS effects on the inflammatory response.(57,58)”
BackgroundSympathetic activity in breast cancer and metastasis: partners in crime
Conceição, F., Sousa, D. M., Paredes, J., & Lamghari, M. (2021) · Bone Research · doi:10.1038/s41413-021-00137-1 · Cited by 73
The Emerging Role of Nerves and Glia in Colorectal Cancer
Schonkeren, S. L., Thijssen, M. S., Vaes, N., Boesmans, W., & Melotte, V. (2021) · Cancers · doi:10.3390/cancers13010152 · Cited by 71
“described that the sympathetic nervous system can regulate various processes involved in tumorigenesis, such as proliferation, angiogenesis, and epithelial-mesenchymal transition [93].”
BackgroundRicon, I., Hanalis‐Miller, T., Haldar, R., Jacoby, R., & Ben‐Eliyahu, S. (2019) · Cancer · doi:10.1002/cncr.31594 · Cited by 71
“These pathways promote inflammation, angiogenesis, tumor invasion capacity, and epithelial-to-mesenchymal transition (EMT) by increasing tumors’ secretion of various prometastatic proteins such as IL-6, IL-8, vascular endothelial growth factor, and matrix metallopeptidase 9 (MMP9) as well as the expression of various…”
BackgroundInfluentialNeighborhood Disadvantage and Breast Cancer–Specific Survival
Goel, N., Hernandez, A. E., Thompson, C., Choi, S., Westrick, A. C., Stoler, J. B., Antoni, M. H., Rojas, K. E., Kesmodel, S. B., Figueroa, M. E., et al. (2023) · JAMA Network Open · doi:10.1001/jamanetworkopen.2023.8908 · Cited by 70
Self-citationβ 3 ‐Adrenoceptor as a potential immuno‐suppressor agent in melanoma
Calvani, M., Bruno, G., Monte, M. D., Nassini, R., Fontani, F., Casini, A., Cavallini, L., Becatti, M., Bianchini, F., Logu, F. D., et al. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14660 · Cited by 66
“…immune environment in melanoma, being the only evidence limited to the findings that βadrenergic stimulation recruits and polarizes macrophages, thus promoting tumour progression (Cole et al., 2015), and that β2-AR blockade improves the anti-tumor efficacy of immunotherapy (Kokolus et al., 2017).”
BackgroundObstructive Sleep Apnea and Incident Cancer: A Large Retrospective Multicenter Clinical Cohort Study
Kendzerska, T., Povitz, M., Leung, R. S. T., Boulos, M. I., McIsaac, D. I., Murray, B. J., Bryson, G. L., Talarico, R., Hilton, J. F., Malhotra, A., et al. (2020) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-20-0975 · Cited by 71
“Finally, an increase in sympathetic nervous system activity associated with the acute and long-term carotid body response to intermittent hypoxia may affect tumors and their microenvironments, causing progression and metastatic activity (9, 54).”
BackgroundChronic stress accelerates the development of endometriosis in mouse through adrenergic receptor β2
Long, Q., Liu, X., Qi, Q.-M., & Guo, S. (2016) · Human Reproduction · doi:10.1093/humrep/dew237 · Cited by 68
Jiang, W., Yu, L., Li, Z., Sun, J., Li, J.-W., Wei, W., Li, L., Zhang, C., Huang, C., Yang, S., et al. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.05.031 · Cited by 69
Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens
Nagaraja, A. S., Dood, R. L., Armaiz-Peña, G. N., Kang, Y., Wu, S. Y., Allen, J. K., Jennings, N. B., Mangala, L. S., Pradeep, S., Lyons, Y., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.93076 · Cited by 63
“Prior studies have identified the direct role of NE in driving molecular changes in tumor cells, but influences on stroma have been limited to natural killer cells, macrophage infiltration, and angiogenesis (1).”
BackgroundInfluentialSelf-citationStress, inflammation, and eicosanoids: an emerging perspective
Umamaheswaran, S., Dasari, S. K., Yang, P., Lutgendorf, S. K., & Sood, A. K. (2018) · Cancer and Metastasis Reviews · doi:10.1007/s10555-018-9741-1 · Cited by 65
“followed has shown that stress impacts multiple biological processes, including inflammation, metabolism, and malignant progression [12].”
Self-citationThe Neuroimmune Axis in the Tumor Microenvironment
Shurin, M. R., Shurin, G. V., Zlotnikov, S. B., & Bunimovich, Y. L. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1900828 · Cited by 61
“Neurotransmitters can directly affect carcinogenesis: b-adrenergic signaling can inhibit DNA damage repair, downregulate p53-associated apoptosis, modulate a wide variety of growth and survival pathways, and activate a range of mesenchymal cell types present in tumor stroma (such as fibroblasts, pericytes, mesenchymal…”
BackgroundHijacking of the nervous system in cancer: mechanism and therapeutic targets
Zhang, Y., Liao, Q., Wen, X., Fan, J., Yuan, T., Tong, X., Jia, R., Chai, P., & Fan, X. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02246-5 · Cited by 67
Falcinelli, M., Thaker, P. H., Lutgendorf, S. K., Conzen, S. D., Flaherty, R. L., & Flint, M. S. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-0684 · Cited by 69
Self-citationLinks between inflammation, amygdala reactivity, and social support in breast cancer survivors
Muscatell, K. A., Eisenberger, N. I., Dutcher, J. M., Cole, S. W., & Bower, J. E. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.09.008 · Cited by 60
“Growing evidence indicates that social isolation is associated with activation of inflammatory processes (Cole et al., 2015), and greater social support has been shown to predict survival in women with breast (Kroenke et al., 2006) and ovarian cancer (Lutgendorf et al., 2005; 2012).”
BackgroundSelf-citationLinking Structural Racism and Discrimination and Breast Cancer Outcomes: A Social Genomics Approach
Carlos, R. C., Obeng‐Gyasi, S., Cole, S. W., Zebrack, B., Pisano, E. D., Troester, M. A., Timsina, L., Wagner, L. I., Steingrimsson, J. A., Gareen, I. F., et al. (2022) · Journal of Clinical Oncology · doi:10.1200/jco.21.02004 · Cited by 62
Self-citationThe Risk of Psychological Stress on Cancer Recurrence: A Systematic Review
Oh, H.-M., & Son, C. (2021) · Cancers · doi:10.3390/cancers13225816 · Cited by 67
“In particular, uncontrolled chronic psychological stress could induce unbalanced gene expression and cellular dysfunction, thus increasing the risk of recurrence- or metastasis-favorable tumor microenvironments such as macrophage infiltration, proangiogenesis, epithelial-mesenchymal transition, and tumor invasion [13,…”
Background
Metadata
- Authors
- Cole, S. W., Nagaraja, A. S., Lutgendorf, S. K., Green, P. A., & Sood, A. K.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- University of Iowa (US)
- National Cancer Institute (US)
- Venue
- Nature Reviews Cancer
- Published
- 2015-08-24
- Volume
- 15
- Issue
- 9
- Pages
- 563-572
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- PMC
- PMC4828959
- OpenAlex
- W1959055352
- Cited by
- 576
- References
- 132
- Citations by year
- 2026: 66 · 2025: 53 · 2024: 47 · 2023: 63 · 2022: 66 · 2021: 57 · 2020: 67 · 2019: 57 · 2018: 43 · 2017: 32 · 2016: 22 · 2015: 3
- FWCI
- 4.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (AG017265, R37AG033590, AG033590, R01AG033590, P30AG017265)
- National Cancer Institute (CA 109298, CA177909, P50CA098258, U54CA151668, R01CA177909, CA083639, CA-104825, R01CA109298, CA140933, R01CA116778, R01CA104825, CA151668, CA-116778, R01CA140933, P50CA083639, CA098258, P30CA016672)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Stress, Anesthesia, and Immune Response
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Keywords
- sympathetic nervous system, tumor microenvironment, peripheral autonomic nervous system, beta-adrenergic signaling, physiological stress, metastasis, macrophage infiltration, tumor inflammation, angiogenesis, epithelial-mesenchymal transition, tumor invasion, antitumor immunity, hematologic cancer, cancer stem cells, hematopoietic differentiation
- MeSH terms
- Cell Differentiation, Humans, Neoplasms, Neovascularization, Pathologic, Sympathetic Nervous System, Gene Expression Regulation, Neoplastic, Epithelial-Mesenchymal Transition, Tumor Microenvironment
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