?2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer.

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

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

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; Pdx1-Cre (KC) mice. ADRB2 blockade together with gemcitabine reduced NGF expression and nerve density, and increased survival of LSL-Kras; LSL-Trp53; 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 ?-blockers. These findings suggest that catecholamines drive a feedforward loop, whereby upregulation of neurotrophins increases sympathetic innervation and local norepinephrine accumulation.     «

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; Pdx1-Cre (KC) mice. ADRB2 blockade together with gemcitabine reduced NGF expression and nerve density, and increased survival of LSL-Kras; LSL...     »