Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction.
Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction.
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DOI：
10.1158/0008-5472.can-16-1701
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发表时间：
2018-06-15
期刊：
影响因子：
11.2
通讯作者：
Sood AK
中科院分区：
文献类型：
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作者：
Allen JK;Armaiz-Pena GN;Nagaraja AS;Sadaoui NC;Ortiz T;Dood R;Ozcan M;Herder DM;Haemmerle M;Gharpure KM;Rupaimoole R;Previs RA;Wu SY;Pradeep S;Xu X;Han HD;Zand B;Dalton HJ;Taylor M;Hu W;Bottsford-Miller J;Moreno-Smith M;Kang Y;Mangala LS;Rodriguez-Aguayo C;Sehgal V;Spaeth EL;Ram PT;Wong STC;Marini FC;Lopez-Berestein G;Cole SW;Lutgendorf SK;De Biasi M;Sood AK
越来越多的临床和临床前证据支持肿瘤微环境中持续的肾上腺素能信号传导作为肿瘤生长和进展的驱动因素的关键作用。然而，肾上腺素能神经递质传递到肿瘤微环境的机制还不清楚。在这里，我们提出了一个前馈回路，肾上腺素能信号导致增加肿瘤神经支配的证据。肿瘤细胞对儿茶酚胺的反应是以ADRB 3/cAMP/Epac/JNK依赖的方式产生脑源性神经营养因子（BDNF）。肿瘤微环境中BDNF水平升高通过宿主神经营养受体酪氨酸激酶2（TrkB）受体的信号传导增加神经支配。在癌症患者中，高肿瘤神经计数与BDNF和去甲肾上腺素水平增加和总生存率降低显著相关。总的来说，这些数据描述了一种新的肿瘤神经支配的途径，产生的生物学和临床意义。
Mounting clinical and preclinical evidence supports a key role for sustained adrenergic signaling in the tumor microenvironment as a driver of tumor growth and progression. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. Here we present evidence for a feedforward loop whereby adrenergic signaling leads to increased tumoral innervation. In response to catecholamines, tumor cells produced brain-derived neurotrophic factor (BDNF) in an ADRB3/cAMP/Epac/JNK-dependent manner. Elevated BDNF levels in the tumor microenvironment increased innervation by signaling through host neurotrophic receptor tyrosine kinase 2 (TrkB) receptors. In cancer patients, high tumor nerve counts were significantly associated with increased BDNF and norepinephrine levels and decreased overall survival. Collectively, these data describe a novel pathway for tumor innervation with resultant biological and clinical implications.