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The Sympathetic Nervous System Induces a Metastatic Switch in Primary Breast Cancer
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Abstract
Metastasis to distant tissues is the chief driver of breast cancer–related mortality, but little is known about the systemic physiologic dynamics that regulate this process. To investigate the role of neuroendocrine activation in cancer progression, we used in vivo bioluminescence imaging to track the development of metastasis in an orthotopic mouse model of breast cancer. Stress-induced neuroendocrine activation had a negligible effect on growth of the primary tumor but induced a 30-fold increase in metastasis to distant tissues including the lymph nodes and lung. These effects were mediated by β-adrenergic signaling, which increased the infiltration of CD11b+F4/80+ macrophages into primary tumor parenchyma and thereby induced a prometastatic gene expression signature accompanied by indications of M2 macrophage differentiation. Pharmacologic activation of β-adrenergic signaling induced similar effects, and treatment of stressed animals with the β-antagonist propranolol reversed the stress-induced macrophage infiltration and inhibited tumor spread to distant tissues. The effects of stress on distant metastasis were also inhibited by in vivo macrophage suppression using the CSF-1 receptor kinase inhibitor GW2580. These findings identify activation of the sympathetic nervous system as a novel neural regulator of breast cancer metastasis and suggest new strategies for antimetastatic therapies that target the β-adrenergic induction of prometastatic gene expression in primary breast cancers. Cancer Res; 70(18); 7042–52. ©2010 AACR.
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“In the context of metastatic breast cancer, for example, stress effects on tumor metastasis are mediated by β-adrenergic up-regulation of monocytes and macrophages within the tumor microenvironment [44] (i.e., the same dynamic that drives the CTRA transcriptome shift in circulating blood [9]).”
From Human Social Genomics (2014) · cites this paper as [44]
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“Furthermore, Sloan et al. found that both stress-induced and pharmacological β-adrenergic stimulation promoted macrophage migration into tumor tissue in a mouse model of breast cancer. These macrophages then adopted an immunosuppressive M2 phenotype, leading to increased production of TGF-β, VEGF, and MMP-9, which in turn promoted angiogenesis and metastasis.322”
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“Parallel findings in animal and in vitro models support these data [11, 16–22].”
From Living Well: Protocol for a web-based program to improve quality of life in rural and urban ovarian cancer survivors (2024) · cites this paper as [20]
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“Parallel effects have been observed in experimental animal models of cancer, and those analyses again identify a prominent role for SNS activation of β-adrenergic signaling [43], [44].”
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Metadata
- Authors
- Sloan, E. K., Priceman, S. J., Cox, B. F., Yu, S., Pimentel, M. A., Tangkanangnukul, V., Arevalo, J. M. G., Morizono, K., Karanikolas, B. D. W., Wu, L., Sood, A. K., & Cole, S. W.
- Affiliations
- University of California, Los Angeles (US)
- Authors' Affiliations: 1UCLA Norman Cousins Center at the Semel Institute for Neuroscience and Human Behavior, Department of Medicine, 2Division of Hematology-Oncology, UCLA School of Medicine, UCLA AIDS Institute, 3Jonsson Comprehensive Cancer Center, 4UCLA Department of Molecular and Medical Pharmacology, and 5UCLA Molecular Biology Institute, Los Angeles, California; and 6Departments of Gynecologic Oncology and Cancer Biology, M.D. Anderson Comprehensive Cancer Center, Houston, Texas
- Corresponding author
- Sloan, Erica K.
- ORCID
- Venue
- Cancer Research
- Published
- 2010-09-14
- Volume
- 70
- Issue
- 18
- Pages
- 7042-7052
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2940980
- OpenAlex
- W2107567947
- Cited by
- 930
- References
- 53
- Citations by year
- 2026: 97 · 2025: 76 · 2024: 72 · 2023: 63 · 2022: 78 · 2021: 94 · 2020: 59 · 2019: 65 · 2018: 42 · 2017: 40 · 2016: 45 · 2015: 50 · 2014: 38 · 2013: 49 · 2012: 32
- FWCI
- 23.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA 109298, R01CA110793, CA 110793, R01CA109298, R01CA116778, CA-116778, R21CA138687, CA138687, R01CA160890)
- 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
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- breast cancer metastasis, sympathetic nervous system, neuroendocrine activation, stress, beta-adrenergic signaling, tumor-associated macrophages, M2 macrophage polarization, propranolol, GW2580, lymph node metastasis, lung metastasis, orthotopic mouse model, anti-metastatic therapy
- MeSH terms
- Adenocarcinoma, Animals, Female, Macrophages, Mammary Neoplasms, Experimental, Mice, Inbred BALB C, Mice, Nude, Neoplasm Metastasis, Stress, Physiological, Sympathetic Nervous System, T-Lymphocytes, Cell Line, Tumor, Mice
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