β2 肾上腺素能-神经营养因子前馈回路促进胰腺癌。
β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer.
机构信息
Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, 81377 Munich, Germany; Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA.
Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA.
出版信息
Cancer Cell. 2018 Jan 8;33(1):75-90.e7. doi: 10.1016/j.ccell.2017.11.007. Epub 2017 Dec 14.
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.
儿茶酚胺刺激上皮细胞增殖，但交感神经信号在胰腺导管腺癌（PDAC）中的作用知之甚少。儿茶酚胺促进 ADRB2 依赖性 PDAC 发展、神经生长因子（NGF）分泌和胰腺神经密度。胰腺 Ngf 过表达加速 LSL-Kras;Pdx1-Cre (KC) 小鼠的肿瘤发展。ADRB2 阻断联合吉西他滨减少 NGF 表达和神经密度，并增加 LSL-Kras;LSL-Trp53;Pdx1-Cre (KPC) 小鼠的存活。与吉西他滨联合使用 Trk 抑制剂也增加了 KPC 小鼠的存活。对 PDAC 患者队列的分析表明，脑源性神经营养因子 (BDNF) 表达、神经密度与非选择性β受体阻滞剂患者生存时间延长之间存在相关性。这些发现表明，儿茶酚胺驱动正反馈环，其中神经营养因子的上调增加了交感神经支配和局部去甲肾上腺素的积累。
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