title: Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination.
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.
authors.affiliation: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Caroline P
authors.initials: CP
authors.lastname: Le
authors.affiliation: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Nowell
authors.affiliation: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.|Department of Visceral Surgery and Medicine, University Hospital Bern, 3010 Bern, Switzerland.
authors.forename: Corina
authors.initials: C
authors.lastname: Kim-Fuchs
authors.affiliation: Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan 20141, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Botteri
authors.affiliation: Department of Cancer Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Hiller
authors.affiliation: Department of Cancer Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Hilmy
authors.initials: H
authors.lastname: Ismail
authors.affiliation: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Pimentel
authors.affiliation: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Ming G
authors.initials: MG
authors.lastname: Chai
authors.affiliation: Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia.|Tumor Angiogenesis Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Tara
authors.initials: T
authors.lastname: Karnezis
authors.affiliation: Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan 20141, Italy.
authors.forename: Nicole
authors.initials: N
authors.lastname: Rotmensz
authors.affiliation: Division of Pathology and Laboratory Medicine, European Institute of Oncology, Milan 20141, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Renne
authors.affiliation: Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan 20141, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Gandini
authors.affiliation: Drug Delivery, Disposition and Dynamics Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Colin W
authors.initials: CW
authors.lastname: Pouton
authors.affiliation: Department of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Davide
authors.initials: D
authors.lastname: Ferrari
authors.affiliation: Cancer Division, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Möller
authors.affiliation: Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia.|Tumor Angiogenesis Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Stacker
authors.affiliation: Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.|Department of Cancer Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.|Cousins Center for PNI, University of California Los Angeles, Los Angeles, CA 90095, USA.|UCLA Semel Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.|Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA.|UCLA AIDS Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Erica K
authors.initials: EK
authors.lastname: Sloan
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002908:Chronic Disease; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008208:Lymphatic System / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D009374:Neoplasms, Experimental; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism
chemical_list: D042582:Vascular Endothelial Growth Factor C; C467483:vascular endothelial growth factor C, mouse; D051546:Cyclooxygenase 2