| Literature DB >> 29249692 |
Bernhard W Renz1, Ryota Takahashi2, Takayuki Tanaka2, Marina Macchini3, Yoku Hayakawa4, Zahra Dantes5, H Carlo Maurer2, Xiaowei Chen2, Zhengyu Jiang2, C Benedikt Westphalen6, Matthias Ilmer7, Giovanni Valenti2, Sarajo K Mohanta8, Andreas J R Habenicht8, Moritz Middelhoff2, Timothy Chu2, Karan Nagar2, Yagnesh Tailor2, Riccardo Casadei9, Mariacristina Di Marco10, Axel Kleespies7, Richard A Friedman11, Helen Remotti12, Maximilian Reichert5, Daniel L Worthley13, Jens Neumann14, Jens Werner7, Alina C Iuga12, Kenneth P Olive15, Timothy C Wang16.
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 β-blockers. These findings suggest that catecholamines drive a feedforward loop, whereby upregulation of neurotrophins increases sympathetic innervation and local norepinephrine accumulation.Entities:
Keywords: NGF-BDNF; TRK; adrenergic signaling; neurotrophins; pancreatic cancer; stress; β-blockers
Mesh：
Substances：
Year: 2017 PMID： 29249692 PMCID： PMC5760435 DOI： 10.1016/j.ccell.2017.11.007
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743