β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer.
β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer.
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DOI：
10.1016/j.ccell.2018.10.010
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发表时间：
2018-11-12
期刊：
影响因子：
50.3
通讯作者：
Wang TC
中科院分区：
文献类型：
--
作者：
Renz BW;Takahashi R;Tanaka T;Macchini M;Hayakawa Y;Dantes Z;Maurer HC;Chen X;Jiang Z;Westphalen CB;Ilmer M;Valenti G;Mohanta SK;Habenicht AJR;Middelhoff M;Chu T;Nagar K;Tailor Y;Casadei R;Di Marco M;Kleespies A;Friedman RA;Remotti H;Reichert M;Worthley DL;Neumann J;Werner J;Iuga AC;Olive KP;Wang TC
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ADRB 2依赖的PDAC的发展，神经生长因子（NGF）的分泌，和胰腺神经密度。胰腺Ngf过表达加速LSL-Kras+/G12 D; Pdx 1-Cre（KC）小鼠的肿瘤发展。ADRB 2阻断剂与吉西他滨联合使用可降低NGF表达和神经密度，并增加LSL-Kras+/G12 D; LSL-Trp 53 +/R172 H; Pdx 1-Cre（KPC）小鼠的存活率。用Trk抑制剂与吉西他滨一起治疗也增加了KPC小鼠的存活率。对PDAC患者队列的分析揭示了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率增加之间的相关性。这些发现表明，儿茶酚胺驱动前馈回路，从而上调神经营养因子增加交感神经支配和局部去甲肾上腺素积累。
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. PancreaticNgfoverexpression 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.
影响因子：
50.3
作者：
Renz BW;Takahashi R;Tanaka T;Macchini M;Hayakawa Y;Dantes Z;Maurer HC;Chen X;Jiang Z;Westphalen CB;Ilmer M;Valenti G;Mohanta SK;Habenicht AJR;Middelhoff M;Chu T;Nagar K;Tailor Y;Casadei R;Di Marco M;Kleespies A;Friedman RA;Remotti H;Reichert M;Worthley DL;Neumann J;Werner J;Iuga AC;Olive KP;Wang TC
通讯作者：
Wang TC