37. Chronic stress promotes lymph node metastasis through beta-adrenergic regulation of lymphangiogenesis

Abstract

Remodelling of tumor lymphatic vasculature facilitates tumor cell metastasis to lymph nodes. However, the physiological pathways that regulate lymphatic remodelling – or lymphangiogenesis – and lymphatic metastasis are yet to be defined. To investigate the impact of beta-adrenergic signaling on lymphangiogenesis and lymphatic metastasis, we explored the effect of restraint stress in an orthotopic xenograft model of triple negative breast cancer. Longitudinal bioluminescence imaging revealed that chronic stress reduced time to lymph node metastasis and increased tumor cell load in draining lymph nodes. Pharmacological activation of beta-adrenergic pathways similarly induced lymphatic remodelling and this effect was blocked with pharmacological beta-blockade. Chronic stress increased the expression of lymphangiogenic growth factor VEGFC and its receptor Vefgr3, and shRNA knock-down of VEGFC reversed the effect of stress on lymph vessel density within primary tumors. We recently found that inflammation increased dilation of lymphatic collector vessels to promote breast cancer metastasis. Consistent with those studies, we found that stress regulated VEGFC by modulating expression of pro-inflammatory COX-2. Treatment with COX-2 inhibitor celecoxib reversed stress-induced lymph vessel dilation and blocked stress-enhanced tumor lymphangiogenesis and lymph node metastasis. These data show that stress acts through a betaAR-inflammation-VEGFC axis to promote lymph node metastasis. Importantly, these studies identify critical opportunities for therapeutic intervention that may help protect women with breast cancer from the adverse effects of stress biology.