β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer
Renz, B. W., Takahashi, R., Tanaka, T., Macchini, M., Hayakawa, Y., Dantes, Z., Maurer, H. C., Chen, X., Jiang, Z., Westphalen, C. B., Ilmer, M., Valenti, G., Mohanta, S. K., Habenicht, A. J. R., Middelhoff, M., Chu, T., Nagar, K., Tailor, Y., Casadei, R., Di Marco, M., Kleespies, A., Friedman, R. A., Remotti, H., Reichert, M., Worthley, D. L., Neumann, J., Werner, J., Iuga, A. C., Olive, K. P., and Wang, T. C. (2018). Cancer Cell 33, 75-90 e77. doi: 10.1016/j.ccell.2017.11.007
Catecholamines stimulate epithelial proliferation, but the role of sympathetic nerve signaling in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Catecholamines promoted ADRB2-dependent PDAC development, nerve growth factor (NGF) secretion, and pancreatic nerve density. Pancreatic Ngf overexpression accelerated tumor development in LSL-Kras+/G12D;Pdx1-Cre (KC) mice. ADRB2 blockade together with gemcitabine reduced NGF expression and nerve density, and increased survival of LSL-Kras+/G12D;LSL-Trp53+/R172H;Pdx1-Cre (KPC) mice. Therapy with a Trk inhibitor together with gemcitabine also increased survival of KPC mice. Analysis of PDAC patient cohorts revealed a correlation between brain-derived neurotrophic factor (BDNF) expression, nerve density, and increased survival of patients on nonselective β-blockers. These findings suggest that catecholamines drive a feedforward loop, whereby upregulation of neurotrophins increases sympathetic innervation and local norepinephrine accumulation.