title: Chronic stress increases experimental pancreatic cancer growth, reduces survival and can be antagonised by beta-adrenergic receptor blockade.
abstract: OBJECTIVE
  Chronic stress could promote tumour growth and reduce survival of pancreatic cancer patients via beta-adrenergic receptors of tumour cells. We have tested the impact of chronic acoustic and restraint stress on tumour development in an orthotopic syngeneic murine model of pancreatic cancer.
  
  
  RESULTS
  Tumour-bearing C57BL/6 mice exposed to chronic stress had 45% (p = 0.0138) higher circulating steroid and 111% (p = 0.0052) higher adrenal tyrosine hydroxylase levels. Their immune response was significantly suppressed: The in vitro LPS response of splenocytes was significantly reduced regarding Th1- and Th2-cytokines including IFN-gamma, IL-6, IL-10 and MCP-1 (0.0011 < p < 0.043). Also, tumours of stressed mice showed a tendency towards fewer total CD4 cells, more regulatory T cells (Treg), less T cell/tumour cell contacts and a reduction of CTLA-4 in CD4 cells (p > 0.05). TGF-beta in vitro was increased by 23.4% using catecholamines (p < 0.012) and in vivo employing chronic stress (p < 0.001). After 5 weeks tumour volumes were 130% (p = 0.0061) larger and median survival reduced by 13.5% (p = 0.0058). Tumours expressed more VEGF (p = 0.0334), had greater microvessel densities (p = 0.047), and an increased MMP-9 expression (p = 0.0456). Beta-catecholamines increased proliferation in tumour cells by 18% (p < 0.0001) and migration by 78% (p = 0.0348) whereas the beta-blocker propranolol reduced these effects by 25% (p < 0.0001) and 53% (p = 0.045), respectively. When stressed tumour-bearing animals were treated with propranolol tumour volumes were reduced by 69% (p = 0.0088) and survival improved by 14% (p < 0.0058).
  
  
  CONCLUSIONS
  The potential treatment with beta-blockers of patients with pancreatic cancer or other malignancies should be further evaluated as an adjuvant anti-neoplastic agent in clinical trials.
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Lars Ivo
authors.initials: LI
authors.lastname: Partecke
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Speerforck
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Käding
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Seubert
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kühn
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Lorenz
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schwandke
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Sendler
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Keßler
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Dung Nguyen
authors.initials: DN
authors.lastname: Trung
authors.affiliation: Institute of Pharmacology, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Oswald
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Frank Ulrich
authors.initials: FU
authors.lastname: Weiss
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Henkel
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Pia
authors.initials: P
authors.lastname: Menges
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Beyer
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Claus-Dieter
authors.initials: CD
authors.lastname: Heidecke
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany. Electronic address: wolfram.bernstorff@uni-greifswald.de.
authors.forename: Wolfram
authors.initials: W
authors.lastname: von Bernstorff
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D011433:Propranolol / Q000494:pharmacology / Q000627:therapeutic use*; D013315:Stress, Psychological / Q000378:metabolism / Q000473:pathology*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000319:Adrenergic beta-Antagonists; D014408:Biomarkers, Tumor; D011433:Propranolol
keywords: Beta blocker; Cancer therapy; Chronic stress; Immunosuppression; Mouse model; Orthotopic pancreatic cancer