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.

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
  • Mice, Transgenic
  • Nerve Growth Factors / metabolism*
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology

Substances

  • Adrenergic Agents
  • Catecholamines
  • Nerve Growth Factors
  • Deoxycytidine
  • gemcitabine

Supplementary concepts

  • Pancreatic Carcinoma