Introduction: Chronic activation of sympathetic neurons can lead to increased noradrenaline levels in TME in PDAC. Conclusion: These studies suggest that increased catecholamines can engender a feed ...forward loop, whereby upregulation of NGF can lead to increased innervation and local NE accumulation, thereby enhancing tumor growth.
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 BDNF expression, nerve density, and increased survival of patients on non-selective β-blockers. These findings suggest that catecholamines drive a feed-forward loop, whereby upregulation of neurotrophins increases sympathetic innervation and local norepinephrine accumulation.
Renz et al. show that norepinephrine (NE) promotes ADRB2-dependent pancreatic ductal adenocarcinoma development and secretion of neurotrophins (NT), which in turn promote tumor innervation leading to increased NE and tumor growth. Blockade of ADRB2 or NT receptors improves gemcitabine’s therapeutic effect.
Consistently, immunohistochemistry of both primary tumors and metastasis was strongly positive for vimentin. ...in vitro IL-1β treatment decreased p53 protein expression and his downstream target ...PUMA.
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