β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer

Abstract

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;Pdx1-Cre (KC) mice. ADRB2 blockade together with gemcitabine reduced NGF expression and nerve density, and increased survival of LSL-Kras;LSL-Trp53;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.

Perineural invasion in pancreatic cancer: proteomic analysis and in vitro modelling

“…Moreover, neuroplastic changes are seen in early development of PDAC with ablation of sensory neurons leading to slower development of PanINs (pancreatic intraepithelial neoplasia) (Saloman et al, 2016), while in contrast, subdiaphragmatic vagotomy in LSL-Kras+/G12D; Pdx1-Cre (KC) mice accelerated PDAC development (Renz et al, 2018a). Furthermore, antibody targeting of NGF (nerve growth factor) or small molecule blocking of NGF-Trk pathway led to inhibition of cancer progression and increased overall mice survival in LSL-Kras+/G12D; LSL-Trp53+/R172H; Pdx1-Cre (KPC) mouse model (Renz et al, 2018b;Saloman et al, 2018). These findings confirm the important and active role of the nervous system in both PDAC development and progression as well as its potential for therapeutic targeting (Demir et al, 2012b;Jobling et al, 2015;Mancino et al, 2011;Pour et al, 2003;Saloman et al, 2016;Stopczynski et al, 2014).…”

Stress, inflammation, and eicosanoids: an emerging perspective

“…In addition to enhanced tumor angiogenesis, tumor innervation might further enhance tumorigenesis by enriching the tumor microenvironment with catecholamines released by the newly formed nerve endings. We and others have found that in response to catecholamines, tumor cells release neurotrophins (BDNF/NGF), which leads to increased tumor innervation and growth in restraint stress tumor models [59, 60]. There is evidence to show that behavioral stress contributes to an increase in catecholaminergic nerve fibers within lymphoid organs in primates, an indication of a long-term regulatory influence of stress on immune responses [61].…”

Sympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer

“…The role of the sympathetic nervous system in PDAC has been studied in terms of tumor response to stress and has shown context-dependent effects. Experimental sympathectomy or blockade of badrenergic signaling in mouse models of PDAC abolishes the pro-tumor effect of chronic restraint stress, but also inhibits the anti-tumor effect of "eustress" (positive stress) induced by enriched housing conditions [8][9][10] . How the reactivity of the sympathetic nervous system to stressors can have opposing actions on tumor development is not clear, but it may involve differential regulation of immune cell functions (eustress) or direct effects on tumor cell growth (distress).…”