Lung Cancer Cells-Controlled Dkk-1 Production in Brain Metastatic Cascade Drive Microglia to Acquire a Pro-tumorigenic Phenotype.
Lung Cancer Cells-Controlled Dkk-1 Production in Brain Metastatic Cascade Drive Microglia to Acquire a Pro-tumorigenic Phenotype.
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脑转移级联中肺癌细胞控制的 Dkk-1 产生驱动小胶质细胞获得促肿瘤表型。
DOI：
10.3389/fcell.2020.591405
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发表时间：
2020
影响因子：
5.5
通讯作者：
Li B
中科院分区：
文献类型：
--
作者：
Gan DX;Wang YB;He MY;Chen ZY;Qin XX;Miao ZW;Chen YH;Li B
向器官性主要由肿瘤来源的外来体决定。迄今为止，肺癌细胞来源的外泌体在转移前小生境形成中的作用尚不清楚。建立肺癌细胞来源的exosomes眼眶后注射和脑室内注射的动物模型。应用细胞因子芯片筛选肺癌细胞来源的exosomes内化后脑内皮细胞释放的细胞因子。建立了模拟小胶质细胞-血管龛的肺癌细胞来源的exosomes细胞共培养体系。采用qRT-PCR、western blot和免疫荧光法检测Dkk-1的表达水平和小胶质细胞的活性。进行高脑转移细胞的体内选择以分析肺癌细胞与小胶质细胞的直接相互作用。动物实验表明，肺癌细胞来源的exosomes内化到脑内皮后，有抑制信号从脑内皮传递到小胶质细胞，这导致M1表型小胶质细胞绝对减少，M2表型小胶质细胞相对增加。进一步的结果表明，肺癌细胞来源的外泌体诱导内源性Dkk-1从脑内皮释放，这使得小胶质细胞在转移前的小生境中获得促肿瘤发生的特征。随后，转移性肺癌细胞中Dkk-1的下降解除了对小胶质细胞的抑制，并增强了转移性小胶质细胞的活化。我们的研究结果揭示了“神经血管单元”中不同细胞对肺癌细胞转移信息的协同反应，并为肺癌脑转移提供了潜在的治疗途径。
Organotropism is primarily determined by tumor-derived exosomes. To date, the role of lung cancer cells-derived exosomes underlying the pre-metastatic niche formation is unclear. The animal models of retro-orbital and intra-ventricular injection were constructed to administrate lung cancer cells-derived exosomes. Cytokine array was used to screen the cytokines released from brain endothelium after internalization of lung cancer cells-derived exosomes. The cellular co-culture system was established to mimic microglia-vascular niche contained lung cancer cells-derived exosomes. The levels of Dkk-1 and the activities of microglia were analyzed by qRT-PCR, western blot and immunofluorescence. In vivo selections of highly brain metastatic cells were performed to analyze the direct interaction of lung cancer cells with microglia. Animal studies demonstrated that there was a suppressive signal transferred from brain endothelium to microglia after internalization of lung cancer cells-derived exosomes into brain endothelium, which caused an absolutely less M1 phenotypic microglia and a relatively more M2 phenotypic microglia. Further results indicated that lung cancer cells-derived exosomes induced a release of endogenous Dkk-1 from brain endothelium, which rendered microglia to acquire a pro-tumorigenic feature in pre-metastatic niche. Subsequently, the declines of Dkk-1 in metastatic lung cancer cells removed the suppression on microglia and enhanced microglial activation in metastatic niche. Our findings shed a new light on the synergistic reaction of the different cells in “neurovascular units” toward the metastatic messages from lung cancer cells and provided a potential therapeutic pathway for lung cancer metastasis to brain.
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DOI：
10.1084/jem.20150950
发表时间：
2016-05-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
D'Amico L;Mahajan S;Capietto AH;Yang Z;Zamani A;Ricci B;Bumpass DB;Meyer M;Su X;Wang-Gillam A;Weilbaecher K;Stewart SA;DeNardo DG;Faccio R
通讯作者：
Faccio R
影响因子：
5.5
作者：
Kinjyo, Ichiko;Bragin, Denis;Wilson, Bridget S.
通讯作者：
Wilson, Bridget S.
影响因子：
6.4
作者：
Lahav, Tzlil Gener;Adler, Omer;Erez, Neta
通讯作者：
Erez, Neta
影响因子：
6.2
作者：
Pukrop, Tobias;Dehghani, Faramarz;Binder, Claudia
通讯作者：
Binder, Claudia
影响因子：
6.2
作者：
Norden DM;Trojanowski PJ;Villanueva E;Navarro E;Godbout JP
通讯作者：
Godbout JP