Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

Neural regulation of pancreatic cancer: Beta-adrenergic signaling increases primary tumor growth and metastasis (#135)

Corina Kim-Fuchs 1 2 , Ming Chai 1 , Eliane Angst 2 , Erica Sloan 1
  1. Monash Institute of Pharmaceutical Science, Monash University, Melbourne, Australia
  2. Department of Visceral Surgery and Medicine, University Hospital, Bern, Switzerland

Pancreatic cancer is the 4th leading cause of cancer death. New therapeutic strategies to treat pancreatic cancer and to prevent recurrence and metastasis are critically needed. The sympathetic nervous system (SNS) innervates the pancreas and key metastatic target organs including lymph nodes and liver, and releases stress neurotransmitters in response to activation. However the impact of SNS signalling on pancreatic cancer progression is currently unknown. To investigate the effect of SNS signalling in an orthotopic mouse model of pancreatic cancer progression we used 2 hr daily restraint stress to physiologically activate the SNS. To track tumor progression, 1 mm3 tumor pieces were derived in vivo from luciferase-tagged PANC-1 pancreatic carcinoma cells and then implanted into the pancreatic tail. Bioluminescence imaging was used to track primary tumour growth, metastasis and tumor recurrence after surgical resection. Physiological SNS activation increased primary tumor size by 19-fold (p = 0.05). Pharmacological SNS activation with the beta-agonist isoprenaline increased primary tumor burden by 4-fold. RT-PCR confirmed expression of beta1- and beta2-adrenergic receptors on PANC-1 cells. However, isoprenaline did not modulate tumor cell proliferation in vitro, suggesting that chronic stress accelerated cancer progression through an indirect mechanism. Stress increased metastasis to liver, local regional lymph nodes and adrenal gland. Consistent with beta-adrenergic regulation of metastasis, isoprenaline increased invasion of PANC-1 cells through matrigel by 7.3-fold (p <0.01). We are now conducting proof-of-principle studies to investigate if blocking beta-adrenergic signalling slows pancreatic cancer progression. These studies will pave the way for new therapeutic interventions that slow or block pancreatic cancer progression by targeting peripheral neural pathways.