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

TitleChronic stress in mice remodels lymph vasculature to promote tumour cell dissemination.
Publication TypeJournal Article
Year of Publication2016
AuthorsLe CP, Nowell CJ, Kim-Fuchs C, Botteri E, Hiller JG, Ismail H, Pimentel MA, Chai MG, Karnezis T, Rotmensz N, Renne G, Gandini S, Pouton CW, Ferrari D, Möller A, Stacker SA, Sloan EK
JournalNat Commun
Date Published2016
KeywordsAnimals, Breast Neoplasms, Cell Line, Chronic Disease, Cyclooxygenase 2, Female, Gene Expression Regulation, Neoplastic, Humans, Lymphatic System, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasms, Neoplasms, Experimental, Signal Transduction, Stress, Physiological, Vascular Endothelial Growth Factor C

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.

Alternate JournalNat Commun
PubMed ID26925549
PubMed Central IDPMC4773495
Grant ListCA160890 / CA / NCI NIH HHS / United States