β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer

被引：316

作者：

Renz, Bernhard W. ^{[1
,2
,3
]}

Takahashi, Ryota ^{[2
,3
]}

Tanaka, Takayuki ^{[2
,3
]}

Macchini, Marina ^{[2
,3
,4
]}

Hayakawa, Yoku ^{[2
,3
,5
]}

Dantes, Zahra ^{[6
]}

Maurer, H. Carlo ^{[2
,3
]}

Chen, Xiaowei ^{[2
,3
]}

Jiang, Zhengyu ^{[2
,3
]}

Westphalen, C. Benedikt ^{[2
,3
,7
]}

Ilmer, Matthias ^{[1
]}

Valenti, Giovanni ^{[2
,3
]}

Mohanta, Sarajo K. ^{[8
]}

Habenicht, Andreas J. R. ^{[8
]}

Middelhoff, Moritz ^{[2
,3
]}

Chu, Timothy ^{[2
,3
]}

Nagar, Karan ^{[2
,3
]}

Tailor, Yagnesh ^{[2
,3
]}

Casadei, Riccardo ^{[9
]}

Di Marco, Mariacristina ^{[10
]}

Kleespies, Axel ^{[1
]}

Friedman, Richard A. ^{[11
]}

Remotti, Helen ^{[12
]}

Reichert, Maximilian ^{[6
]}

Worthley, Daniel L. ^{[2
,3
,13
]}

Neumann, Jens ^{[14
]}

Werner, Jens ^{[1
]}

Iuga, Alina C. ^{[12
]}

Olive, Kenneth P. ^{[2
,3
,12
]}

Wang, Timothy C. ^{[2
,3
]}

机构：

[1] Hosp Univ Munich, Dept Gen Visceral & Transplantat Surg, D-81377 Munich, Germany

[2] Columbia Univ, Med Ctr, Dept Digest & Liver Dis, 1130 St Nicholas Ave, New York, NY 10032 USA

[3] Columbia Univ, Med Ctr, Herbert Irving Comprehens Canc Ctr, 1130 St Nicholas Ave, New York, NY 10032 USA

[4] IRCCS, San Raffaele Sci Inst, Dept Oncol, I-20132 Milan, Italy

[5] Univ Tokyo, Grad Sch Med, Dept Gastroenterol, Tokyo 1138655, Japan

[6] Tech Univ Munich, Klinikum Rechts Isar, Dept Med 2, D-81675 Munich, Germany

[7] Hosp Univ Munich, Dept Internal Med 3, D-81377 Munich, Germany

[8] Univ Munich, Inst Cardiovasc Prevent, D-80336 Munich, Germany

[9] Univ Bologna, Alma Mater Studiorum, Dept Internal Med & Surg DIMEC, St Orsola Malpighi Hosp, I-40138 Bologna, Italy

[10] Univ Bologna, St Orsola Malpighi Hosp, Dept Expt Diagnost & Specialty Med, I-40138 Bologna, Italy

[11] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Biomed Informat Shared Resource, Dept Biomed Informat,Med Ctr, New York, NY 10032 USA

[12] Columbia Univ, Med Ctr, Dept Pathol & Cell Biol, New York, NY 10032 USA

[13] Univ Adelaide, Dept Med, Adelaide, SA 5005, Australia

[14] Hosp Univ Munich, Dept Pathol, D-81377 Munich, Germany

来源：

CANCER CELL | 2018年 / 33卷 / 01期

关键词：

DUCTAL ADENOCARCINOMA; TUMOR-GROWTH; PERINEURAL INVASION; NEURAL INVASION; CELLS; EXPRESSION; SURVIVAL; BLOCKERS; NEURONS; NERVE;

D O I：

10.1016/j.ccell.2017.11.007

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：75 / +

页数：23

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