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

TLDR

Chronic stress activates sympathetic nervous system signaling, promoting cancer progression, yet the mechanisms of tumor cell dissemination remain unclear. We demonstrate that chronic stress remodels tumor‑associated lymphatics through VEGFC and COX2‑mediated macrophage inflammation, and that blocking SNS signaling prevents this remodeling and reduces lymphatic metastasis, indicating that targeting SNS could curb tumor spread.

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.