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β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer

2017; Cell Press; Volume: 33; Issue: 1 Linguagem: Inglês

10.1016/j.ccell.2017.11.007

1878-3686

Bernhard W. Renz, Ryota Takahashi, Takayuki Tanaka, Marina Macchini, Yoku Hayakawa, Zahra Dantes, H. Carlo Maurer, Xiaowei Chen, Zhengyu Jiang, C. Benedikt Westphalen, Matthias Ilmer, Giovanni Valenti, Sarajo K. Mohanta, Andreas J. R. Habenicht, Moritz Middelhoff, Timothy Chu, Karan Nagar, Yagnesh Tailor, Riccardo Casadei, Mariacristina Di Marco, Axel Kleespies, Richard A. Friedman, Helen Remotti, Maximilian Reichert, Daniel L. Worthley, Jens Neumann, Jens Werner, Alina C. Iuga, Kenneth P. Olive, Timothy C. Wang,

Neuropeptides and Animal Physiology

Summary Catecholamines stimulate epithelial proliferation, but the role of sympathetic nerve signaling in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Catecholamines promoted ADRB2-dependent PDAC development, nerve growth factor (NGF) secretion, and pancreatic nerve density. Pancreatic Ngf overexpression accelerated tumor development in LSL- Kras +/G12D ; Pdx1 -Cre (KC) mice. ADRB2 blockade together with gemcitabine reduced NGF expression and nerve density, and increased survival of LSL- Kras +/G12D ;LSL- Trp53 +/R172H ; Pdx1 -Cre (KPC) mice. Therapy with a Trk inhibitor together with gemcitabine also increased survival of KPC mice. Analysis of PDAC patient cohorts revealed a correlation between brain-derived neurotrophic factor (BDNF) expression, nerve density, and increased survival of patients on nonselective β-blockers. These findings suggest that catecholamines drive a feedforward loop, whereby upregulation of neurotrophins increases sympathetic innervation and local norepinephrine accumulation.