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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. (2018): beta 2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer. In: Cancer Cell, Vol. 33, No. 1: pp. 75-90
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Abstract

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 beta-blockers. These findings suggest that catecholamines drive a feedforward loop, whereby upregulation of neurotrophins increases sympathetic innervation and local norepinephrine accumulation.