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Nat Commun. 2016 Mar 1;7:10634. doi: 10.1038/ncomms10634.

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

Author information

1
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
2
Department of Visceral Surgery and Medicine, University Hospital Bern, 3010 Bern, Switzerland.
3
Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan 20141, Italy.
4
Department of Cancer Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
5
Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia.
6
Tumor Angiogenesis Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
7
Division of Pathology and Laboratory Medicine, European Institute of Oncology, Milan 20141, Italy.
8
Drug Delivery, Disposition and Dynamics Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
9
Department of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria 3010, Australia.
10
Cancer Division, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
11
Cousins Center for PNI, University of California Los Angeles, Los Angeles, CA 90095, USA.
12
UCLA Semel Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
13
Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA.
14
UCLA AIDS Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.

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.

PMID:
26925549
PMCID:
PMC4773495
DOI:
10.1038/ncomms10634
[Indexed for MEDLINE]
Free PMC Article

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