β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer

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

doi:10.1016/j.ccell.2017.11.007

β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer

Cancer Cell. 2018 Jan 8;33(1):75-90.e7. doi: 10.1016/j.ccell.2017.11.007. Epub 2017 Dec 14.

Authors

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

Affiliations

¹ Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, 81377 Munich, Germany; Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA.
² Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA.
³ Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
⁴ Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
⁵ Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
⁶ Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Internal Medicine III, Hospital of the University of Munich, 81377 Munich, Germany.
⁷ Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, 81377 Munich, Germany.
⁸ Institute for Cardiovascular Prevention, University of Munich, 80336 Munich, Germany.
⁹ Department of Internal Medicine and Surgery (DIMEC), Alma Mater Studiorum, University of Bologna, Sant'Orsola-Malpighi Hospital, 40138 Bologna, Italy.
¹⁰ Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Sant'Orsola-Malpighi Hospital, 40138 Bologna, Italy.
¹¹ Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center, Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA.
¹² Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
¹³ Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Medicine, University of Adelaide, Adelaide, SA 5005, Australia.
¹⁴ Department of Pathology, Hospital of the University of Munich, 81377 Munich, Germany.
¹⁵ Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
¹⁶ Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA. Electronic address: tcw21@columbia.edu.

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.

Keywords: NGF-BDNF; TRK; adrenergic signaling; neurotrophins; pancreatic cancer; stress; β-blockers.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adrenergic Agents / pharmacology
Animals
Carcinoma in Situ / metabolism
Catecholamines / pharmacology*
Cell Line, Tumor
Deoxycytidine / analogs & derivatives
Deoxycytidine / pharmacology
Gemcitabine
Mice, Transgenic
Nerve Growth Factors / metabolism*
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / pathology

Substances

Adrenergic Agents
Catecholamines
Nerve Growth Factors
Deoxycytidine
Gemcitabine

Abstract

Publication types

MeSH terms

Substances

Grants and funding