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

Caroline P. Le, Cameron J. Nowell, Corina Kim-Fuchs, Edoardo Botteri, Jonathan G. Hiller, Hilmy Ismail, Matthew A. Pimentel, Ming G. Chai, Tara Karnezis, Nicole Rotmensz, Giuseppe Renne, Sara Gandini, Colin W. Pouton, Davide Ferrari, Andreas Möller, Steven A. Stacker and Erica K. Sloan ()
Additional contact information
Caroline P. Le: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University
Cameron J. Nowell: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University
Corina Kim-Fuchs: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University
Edoardo Botteri: European Institute of Oncology
Jonathan G. Hiller: Peter MacCallum Cancer Centre
Hilmy Ismail: Peter MacCallum Cancer Centre
Matthew A. Pimentel: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University
Ming G. Chai: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University
Tara Karnezis: The University of Melbourne
Nicole Rotmensz: European Institute of Oncology
Giuseppe Renne: European Institute of Oncology
Sara Gandini: European Institute of Oncology
Colin W. Pouton: Drug Delivery, Disposition and Dynamics Theme, Monash Institute of Pharmaceutical Sciences, Monash University
Davide Ferrari: The University of Melbourne
Andreas Möller: QIMR Berghofer Medical Research Institute
Steven A. Stacker: The University of Melbourne
Erica K. Sloan: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10634

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