Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment.

TitleChronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment.
Publication TypeJournal Article
Year of Publication2014
AuthorsKim-Fuchs C, Le CP, Pimentel MA, Shackleford D, Ferrari D, Angst E, Hollande F, Sloan EK
JournalBrain Behav Immun
Volume40
Pagination40-7
Date Published2014 Aug
ISSN1090-2139
KeywordsAdrenergic beta-Agonists, Adrenergic beta-Antagonists, Animals, Cell Line, Tumor, Chronic Disease, Cyclic AMP, Disease Progression, Humans, Mice, Mice, Inbred BALB C, Pancreas, Pancreatic Neoplasms, Receptors, Adrenergic, beta, Restraint, Physical, Signal Transduction, Stress, Psychological, Sympathetic Nervous System
Abstract

Pancreatic cancer cells intimately interact with a complex microenvironment that influences pancreatic cancer progression. The pancreas is innervated by fibers of the sympathetic nervous system (SNS) and pancreatic cancer cells have receptors for SNS neurotransmitters which suggests that pancreatic cancer may be sensitive to neural signaling. In vitro and non-orthotopic in vivo studies showed that neural signaling modulates tumour cell behavior. However the effect of SNS signaling on tumor progression within the pancreatic microenvironment has not previously been investigated. To address this, we used in vivo optical imaging to non-invasively track growth and dissemination of primary pancreatic cancer using an orthotopic mouse model that replicates the complex interaction between pancreatic tumor cells and their microenvironment. Stress-induced neural activation increased primary tumor growth and tumor cell dissemination to normal adjacent pancreas. These effects were associated with increased expression of invasion genes by tumor cells and pancreatic stromal cells. Pharmacological activation of β-adrenergic signaling induced similar effects to chronic stress, and pharmacological β-blockade reversed the effects of chronic stress on pancreatic cancer progression. These findings indicate that neural β-adrenergic signaling regulates pancreatic cancer progression and suggest β-blockade as a novel strategy to complement existing therapies for pancreatic cancer.

DOI10.1016/j.bbi.2014.02.019
Alternate JournalBrain Behav. Immun.
PubMed ID24650449
PubMed Central IDPMC4102665
Grant ListCA160890 / CA / NCI NIH HHS / United States
R01 CA160890 / CA / NCI NIH HHS / United States