Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction.
Mounting clinical and preclinical evidence supports a key role for sustained adrenergic signaling in the tumor microenvironment as a driver of tumor growth and progression. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. Here we present evidence for a feed-forward loop whereby adrenergic signaling leads to increased tumoral innervation. In response to catecholamines, tumor cells produced brain-derived neurotrophic factor (BDNF) in an ADRB3/cAMP/Epac/JNK-dependent manner. Elevated BDNF levels in the tumor microenvironment increased innervation by signaling through host neurotrophic receptor tyrosine kinase 2 receptors. In patients with cancer, high tumor nerve counts were significantly associated with increased BDNF and norepinephrine levels and decreased overall survival. Collectively, these data describe a novel pathway for tumor innervation, with resultant biological and clinical implications.Significance: Sustained adrenergic signaling promotes tumor growth and metastasis through BDNF-mediated tumoral innervation. Cancer Res; 78(12); 3233-42. ©2018 AACR.
Allen, JK; Armaiz-Pena, GN; Nagaraja, AS; Sadaoui, NC; Ortiz, T; Dood, R; Ozcan, M; Herder, DM; Haemmerle, M; Gharpure, KM; Rupaimoole, R; Previs, RA; Wu, SY; Pradeep, S; Xu, X; Han, HD; Zand, B; Dalton, HJ; Taylor, M; Hu, W; Bottsford-Miller, J; Moreno-Smith, M; Kang, Y; Mangala, LS; Rodriguez-Aguayo, C; Sehgal, V; Spaeth, EL; Ram, PT; Wong, STC; Marini, FC; Lopez-Berestein, G; Cole, SW; Lutgendorf, SK; De Biasi, M; Sood, AK
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