title: Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment.
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.
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia; Department of Visceral Surgery and Medicine, University Hospital Bern, Bern, Switzerland.
authors.forename: Corina
authors.initials: C
authors.lastname: Kim-Fuchs
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Caroline P
authors.initials: CP
authors.lastname: Le
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Pimentel
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Shackleford
authors.affiliation: Department of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Davide
authors.initials: D
authors.lastname: Ferrari
authors.affiliation: Department of Visceral Surgery and Medicine, University Hospital Bern, Bern, Switzerland; Clinic of Surgery, Cantonal Hospital, Schaffhausen, Switzerland.
authors.forename: Eliane
authors.initials: E
authors.lastname: Angst
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia; Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Hollande
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia; Department of Cancer Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Cousins Center for PNI, Semel Institute for Neuroscience and Human Behavior, UCLA AIDS Institute and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, USA. Electronic address: erica.sloan@monash.edu.
authors.forename: Erica K
authors.initials: EK
authors.lastname: Sloan
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D002908:Chronic Disease; D000242:Cyclic AMP / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010179:Pancreas / Q000294:innervation*; D010190:Pancreatic Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D012149:Restraint, Physical; D015398:Signal Transduction; D013315:Stress, Psychological / Q000150:complications*; D013564:Sympathetic Nervous System / Q000378:metabolism*
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP
keywords: Beta-adrenergic; Beta-blocker; Chronic stress; Invasion; Pancreatic cancer; Tumor microenvironment