Extracellular vesicle packaged LMP1-activated fibroblasts promote tumor progression via autophagy and stroma-tumor metabolism coupling
Extracellular vesicle packaged LMP1-activated fibroblasts promote tumor progression via autophagy and stroma-tumor metabolism coupling
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细胞外囊泡包装的 LMP1 激活的成纤维细胞通过自噬和基质-肿瘤代谢耦合促进肿瘤进展。
DOI：
10.1016/j.canlet.2020.03.004
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发表时间：
2020-05-28
期刊：
影响因子：
9.7
通讯作者：
Yang, Lifang
中科院分区：
文献类型：
--
作者：
Wu, Xia;Zhou, Zhuan;Yang, Lifang
一些报道表明，eb病毒（EBV）编码的潜伏膜蛋白1 （LMP1）通过细胞外囊泡（ev）或外泌体转移，可以促进癌症的进展。然而，其机制仍未完全了解。在本研究中，我们证明了EV包装的LMP1可以将正常成纤维细胞（NFs）激活为癌症相关成纤维细胞（CAFs）。NF-kappa B p65通路是鼻咽癌（NPC）中促进nf对CAFs活化的关键信号。在活化的CAFs中，有氧糖酵解和自噬增加。此外，肿瘤细胞的葡萄糖摄取和乳酸生成减少，线粒体活性增强，支持反向Warburg效应（RWE）。在此过程中，我们观察到CAFs中MCT4和肿瘤细胞中MCT1的上调。NF-kappa B p65通路在MCT4的调控中也起着重要作用。此外，与CAFs共培养可促进鼻咽癌细胞的增殖、迁移和抗辐射能力。EV包装的LMP1在体内通过激活CAFs促进肿瘤增殖和转移前生态位的形成。我们的研究结果表明，EV包装的lmp1激活的cas通过自噬和基质-肿瘤代谢耦合促进肿瘤进展。
Several reports have demonstrated that Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP1), which is transferred by extracellular vesicles (EVs) or exosomes, can promote cancer progression. However, its mechanism is still not fully understood. In the present study, we demonstrated that EV packaged LMP1 can activate normal fibroblasts (NFs) into cancer-associated fibroblasts (CAFs). The NF-kappa B p65 pathway is the key signal that promotes the activation of NFs to CAFs in nasopharyngeal carcinoma (NPC). In activated CAFs, aerobic glycolysis and autophagy were increased. Moreover, glucose uptake and lactate production were decreased, and mitochondrial activity in tumor cells was enhanced, which supported the Reverse Warburg Effect (RWE). During this process, upregulation of MCT4 in CAFs and MCT1 in tumor cells was observed. The NF-kappa B p65 pathway also plays an important role in the regulation of MCT4. Furthermore, co-culture with CAFs promoted the proliferation, migration and radiation resistance of NPC cells. And EV packaged LMP1 promoted tumor proliferation and pre-metastatic niche formation by activating CAFs in vivo. Our findings indicate that EV packaged LMP1-activated CAFs promote tumor progression via autophagy and stroma-tumor metabolism coupling.