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Cited by 354Lymphatic System and DiseasesCancer, Stress, Anesthesia, and Immune ResponseVagus Nerve Stimulation Research

Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination

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Le, Caroline P., Nowell, Cameron J., Kim-Fuchs, Corina, Botteri, Edoardo, Hiller, Jonathan G., Ismail, Hilmy, Pimentel, Matthew A., Chai, Ming G. +9 more·2016·Nature Communications
DOI 10.1038/ncomms10634PMC PMC4773495
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Abstract

Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes.

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  • Drugs that limit HPA axis and downstream SNS signaling, such as β-adrenergic receptor antagonists, COX2 inhibitors, anti-VEGFC therapeutics, or dopamine, have been shown in animal experiments to improve anxiety-like behavior, inhibit chronic tumor-promoting tumor growth, and block stress-induced increase in angiogenesis and lymphatic metastasis.

    “These drugs have been shown in animal experiments to not only significantly improve anxiety-like behavior (47, 48), and inhibit chronic tumor-promoting tumor growth, but also to block a stress-induced increase in angiogenesis and lymphatic metastasis (60).”

    From Chronic Stress Promotes Cancer Development (2020) · cites this paper as [60]

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Authors
Le, C. P., Nowell, C. J., Kim-Fuchs, C., Botteri, E., Hiller, J. G., Ismail, H., Pimentel, M. A., Chai, M. G., Karnezis, T., Rotmensz, N., Renne, G., Gandini, S., Pouton, C. W., Ferrari, D., Möller, A., Stacker, S. A., & Sloan, E. K.
Affiliations
  • Monash University (AU)
  • University Hospital of Bern (CH)
  • European Institute of Oncology (IT)
  • Peter MacCallum Cancer Centre (AU)
  • The University of Melbourne (AU)
  • QIMR Berghofer Medical Research Institute (AU)
  • University of California, Los Angeles (US)
Corresponding author
Sloan, Erica K.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2016-03-01
Volume
7
Issue
1
Pages
10634-10634
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms10634
PMC
PMC4773495
OpenAlex
W2289888151
Cited by
354
References
73
Citations by year
2026: 43 · 2025: 32 · 2024: 30 · 2023: 34 · 2022: 39 · 2021: 45 · 2020: 39 · 2019: 29 · 2018: 26 · 2017: 24 · 2016: 12
FWCI
16.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Monash University Research Portal (Monash University) (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
  • Open Research (University of Surrey) (submittedVersion)
  • Open Access CRIS of the University of Bern
Funders
  • National Breast Cancer Foundation (1008865)
  • Australian and New Zealand College of Anaesthetists
  • Medical Research Council
  • Australian Research Council (LE110100125)
  • National Health and Medical Research Council (1053535, 1008865)
  • National Cancer Institute (CA160890, R01CA160890)
Topics
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
  • Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
  • Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
Keywords
chronic stress, tumour cell dissemination, lymph node metastasis, VEGF-C, cyclooxygenase-2, macrophages, sympathetic nervous system, stress-induced inflammation, breast cancer, tumor progression
MeSH terms
Animals, Breast Neoplasms, Cell Line, Chronic Disease, Female, Humans, Lymphatic System, Mice, Inbred BALB C, Mice, Nude, Neoplasms, Neoplasms, Experimental, Stress, Physiological, Signal Transduction, Gene Expression Regulation, Neoplastic, Vascular Endothelial Growth Factor C, Mice, Cyclooxygenase 2

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