Beta-adrenergic regulation of pancreatic cancer progression

Abstract

Cancer is one of the leading causes of death, with 8.2 million deaths worldwide and 14.1 million new cases in 2012. Pancreatic cancer (PaCa) is the fourth leading causes of cancer death worldwide, with around 280,000 new cases per year. The overall five-year survival rate is less than 5%, and effective therapies and tools to improve an early diagnosis are critically needed. Cure from PaCa depends on successful surgical resection of the primary tumour and improved 5-year survival rates over 20-30% have been reported in specialised centres following surgical resection. However, the majority of patients are diagnosed with advanced stage PaCa which prohibits surgical treatments. Even with tumour-free resection margins (R0 resection) recurrence rates are high and most patients eventually die of local tumour recurrence and metastatic disease. Current standard chemotherapeutic treatment in locally advanced and metastatic PaCa patients involves gemcitabine, but the overall prolongation of survival is disappointingly small (5-6 weeks). New and improved therapeutic strategies to treat PaCa and to prevent recurrence and metastasis require a more detailed understanding of the physiological regulators of PaCa progression and their mechanistic molecular and cellular mediators. There is accumulating evidence from human clinical studies and animal models that sympathetic nervous system (SNS) signalling through beta-adrenergic pathways promotes cancer progression. Adrenergic activation via hypertension or chronic stress induces systemic and local release of catecholamines. Catecholamines bind on β-adrenergic receptors (βAR) on tumour and stromal cells and induce a down stream signalling by activation of G-proteins resulting in the activation of adenyl cyclase and cyclic AMP accumulation, followed by the activation of protein kinase A (PKA). PKA activates transcription factors which may regulate cell proliferation. The impact of adrenergic signalling pathways on PaCa growth or metastasis in vivo (orthotopic model) has not been investigated. Nerve fibres from the SNS innervate the pancreas. From clinical results we know, that this perineural invasion by pancreatic cancer cells is one of the important routes of pancreatic cancer cell dissemination and therefore very important for the prognosis of patients with pancreatic cancer. Because of this relationship between pancreatic tumour cells and nerve fibres we think that pancreatic cancer cells may be sensitive to SNS regulation. We studied the effect of chronic stress on pancreatic cancer progression in an orthotopic mouse model. To track tumour progression and metastasis over time we used bioluminescence imaging. We found an increased tumour burden in chronic stressed animals. To confirm the importance of β-adrenergic signalling on cancer progression we performed pharmacological studies in vitro and in vivo. The effect of chronic stress on tumour progression could be blocked in vivo by a treatment with beta blockers. In vitro studies confirmed these results with an increased invasion and proliferation of cells treated with isoprenaline. These results supported our in vivo findings that beta blockers may reduce cancer progression