Department of Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Xiangya Hospital, Central South University, Changsha, China; Cancer Research Institute, School of Basic Medicine Science, Central South University, Changsha, China.
Institute of Molecular Medicine and Oncology, College of Biology, Hunan University, Changsha, China.
Cancer Lett. 2020 May 28;478:93-106. doi: 10.1016/j.canlet.2020.03.004. Epub 2020 Mar 8.
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-κB 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-κB 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.
已有多项报告表明，Epstein-Barr 病毒（EBV）编码的潜伏膜蛋白 1（LMP1）可通过细胞外囊泡（EVs）或外泌体进行转移，从而促进癌症进展。然而，其具体机制尚不完全清楚。本研究发现，EV 包裹的 LMP1 可将正常成纤维细胞（NFs）激活为癌相关成纤维细胞（CAFs）。在鼻咽癌（NPC）中，NF-κB p65 通路是促进 NFs 向 CAFs 激活的关键信号。在激活的 CAFs 中，有氧糖酵解和自噬增加。此外，肿瘤细胞中的葡萄糖摄取和乳酸生成减少，线粒体活性增强，这支持了反向沃伯格效应（RWE）。在此过程中，观察到 CAFs 中 MCT4 的上调和肿瘤细胞中 MCT1 的上调。NF-κB p65 通路在调节 MCT4 方面也发挥着重要作用。此外，与 CAFs 共培养可促进 NPC 细胞的增殖、迁移和辐射抗性。并且，EV 包裹的 LMP1 通过激活体内 CAFs 促进了肿瘤的增殖和前转移龛的形成。我们的研究结果表明，EV 包裹的 LMP1 激活的 CAFs 通过自噬和基质-肿瘤代谢偶联促进肿瘤进展。
