Cancer cells co-opt nociceptive nerves to thrive in nutrient-poor environments and upon nutrient-starvation therapies
Cancer cells co-opt nociceptive nerves to thrive in nutrient-poor environments and upon nutrient-starvation therapies
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癌细胞利用伤害性神经在营养贫乏的环境和营养饥饿疗法中茁壮成长
DOI：
10.1016/j.cmet.2022.10.012
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发表时间：
2022
期刊：
影响因子：
29
通讯作者：
Tong Ji
中科院分区：
文献类型：
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作者：
Yu Zhang;Chengzhong Lin;Zheqi Liu;Yiting Sun;Mingtao Chen;Yibo Guo;Wei Liu;Chenping Zhang;Wantao Chen;Jian Sun;Ronghui Xia;Yuhua Hu;Xi Yang;Jiang Li;Zhiyuan Zhang;Wei Cao;Shuyang Sun;Xu Wang;Tong Ji
尽管营养饥饿疗法可以在多种癌症中引发强烈的抗肿瘤作用，但已经令人信服地证明，癌细胞利用肿瘤微环境在营养不良的环境中茁壮成长。在这里，我们揭示了癌细胞可以利用伤害神经在营养不良的环境中茁壮成长。通过对口腔黏膜癌低糖环境的初步研究，我们发现癌细胞通过ros触发的c-Jun激活来分泌神经生长因子（NGF），从而使伤害神经产生降钙素基因相关肽（CGRP）。神经源性CGRP随后通过rap1介导的mTOR-Raptor相互作用的破坏在癌细胞中诱导细胞保护性自噬。抗糖酵解和基于抗血管生成的营养饥饿疗法都加剧了癌细胞和伤害神经的恶性循环，并且在治疗上受益于用fda批准的抗偏头痛药物阻断神经源性CGRP。我们的研究揭示了在营养不良的环境和营养饥饿疗法中，伤害神经作为癌症进展的微环境帮凶的作用。
Although nutrient-starvation therapies can elicit strong anti-tumor effects in multiple carcinomas, it has been convincingly demonstrated that cancer cells exploit the tumor microenvironment to thrive in nutrient-poor environments. Here, we reveal that cancer cells can co-opt nociceptive nerves to thrive in nutrient-poor environments. Initially examining the low-glucose environment of oral mucosa carcinomas, we discovered that cancer cells employ ROS-triggered activation of c-Jun to secrete nerve growth factor (NGF), which conditions nociceptive nerves for calcitonin gene-related peptide (CGRP) production. The neurogenic CGRP subsequently induces cytoprotective autophagy in cancer cells through Rap1-mediated disruption of the mTOR-Raptor interaction. Both anti-glycolysis and anti-angiogenesis-based nutrient-starvation therapies aggravate the vicious cycle of cancer cells and nociceptive nerves and therapeutically benefit from blocking neurogenic CGRP with an FDA-approved antimigraine drug. Our study sheds light on the role of the nociceptive nerve as a microenvironmental accomplice of cancer progression in nutrient-poor environments and upon nutrient-starvation therapies.