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01 08, 2018;33 (1): 75-90.e7.

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
Author Information
  1. Bernhard W Renz: 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. Ryota Takahashi: 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. Takayuki Tanaka: 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.
  4. Marina Macchini: 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.
  5. Yoku Hayakawa: 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.
  6. Zahra Dantes: Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
  7. H Carlo Maurer: 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.
  8. Xiaowei Chen: 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.
  9. Zhengyu Jiang: 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.
  10. C Benedikt Westphalen: 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.
  11. Matthias Ilmer: Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, 81377 Munich, Germany.
  12. Giovanni Valenti: 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.
  13. Sarajo K Mohanta: Institute for Cardiovascular Prevention, University of Munich, 80336 Munich, Germany.
  14. Andreas J R Habenicht: Institute for Cardiovascular Prevention, University of Munich, 80336 Munich, Germany.
  15. Moritz Middelhoff: 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.
  16. Timothy Chu: 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.
  17. Karan Nagar: 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.
  18. Yagnesh Tailor: 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.
  19. Riccardo Casadei: Department of Internal Medicine and Surgery (DIMEC), Alma Mater Studiorum, University of Bologna, Sant'Orsola-Malpighi Hospital, 40138 Bologna, Italy.
  20. Mariacristina Di Marco: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Sant'Orsola-Malpighi Hospital, 40138 Bologna, Italy.
  21. Axel Kleespies: Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, 81377 Munich, Germany.
  22. Richard A Friedman: Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center, Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA.
  23. Helen Remotti: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
  24. Maximilian Reichert: Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
  25. Daniel L Worthley: 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.
  26. Jens Neumann: Department of Pathology, Hospital of the University of Munich, 81377 Munich, Germany.
  27. Jens Werner: Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, 81377 Munich, Germany.
  28. Alina C Iuga: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
  29. Kenneth P Olive: 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.
  30. Timothy C Wang: 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.
PMID: 29249692 DOI: 10.1016/j.ccell.2017.11.007

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;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 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

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Grants

  1. P30 CA013696/NCI NIH HHS
  2. R35 CA210088/NCI NIH HHS
  3. S10 RR025686/NCRR NIH HHS

MeSH Term

Adrenergic Agents
Animals
Carcinoma in Situ
Catecholamines
Cell Line, Tumor
Deoxycytidine
Mice, Transgenic
Nerve Growth Factors
Pancreatic Neoplasms
Gemcitabine
Pancreatic Neoplasms

Chemicals

Adrenergic Agents
Catecholamines
Nerve Growth Factors
Deoxycytidine
Gemcitabine
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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