The sympathetic nervous system induces a metastatic switch in primary breast cancer.

TitleThe sympathetic nervous system induces a metastatic switch in primary breast cancer.
Publication TypeJournal Article
Year of Publication2010
AuthorsSloan EK, Priceman SJ, Cox BF, Yu S, Pimentel MA, Tangkanangnukul V, Arevalo JMG, Morizono K, Karanikolas BDW, Wu L, Sood AK, Cole SW
JournalCancer Res
Volume70
Issue18
Pagination7042-52
Date Published2010 Sep 15
ISSN1538-7445
KeywordsAdenocarcinoma, Animals, Cell Line, Tumor, Female, Macrophages, Mammary Neoplasms, Experimental, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasm Metastasis, Stress, Physiological, Sympathetic Nervous System, T-Lymphocytes
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.

DOI10.1158/0008-5472.CAN-10-0522
Alternate JournalCancer Res.
PubMed ID20823155
PubMed Central IDPMC2940980
Grant ListCA109298 / CA / NCI NIH HHS / United States
CA110793 / CA / NCI NIH HHS / United States
CA116778 / CA / NCI NIH HHS / United States
CA138687 / CA / NCI NIH HHS / United States
R01 CA160890 / CA / NCI NIH HHS / United States
R21 CA138687 / CA / NCI NIH HHS / United States
R21 CA138687-01 / CA / NCI NIH HHS / United States