Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, China.
Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China.
Cell Oncol (Dordr). 2023 Aug;46(4):987-1000. doi: 10.1007/s13402-023-00790-0. Epub 2023 Mar 14.
Stromal interaction molecule 1 (STIM1)-mediated Ca signaling regulates tumor angiogenesis in nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-related human malignancy. However, the mechanism by which STIM1 modulates endothelial functional phenotypes contributing to tumor angiogenesis remains elusive.
NPC cell-derived exosomes were isolated via differential centrifugation and observed using transmission electron microscopy. Exosome particle sizes were assessed by nanoparticle tracking analysis (NTA). Uptake of exosomes by recipient ECs was detected by fluorescent labeling of the exosomes with PKH26. Tumor angiogenesis-associated profiles were characterized by determining cell proliferation, migration, tubulogenesis and permeability in human umbilical vein endothelial cells (HUVECs). Activation of the Akt/ERK pathway was assessed by detecting the phosphorylation levels using Western blotting. A chick embryo chorioallantoic membrane (CAM) xenograft model was employed to study tumor-associated neovascularization in vivo.
We found that NPC cell-derived exosomes harboring EBV-encoded latent membrane protein 1 (LMP1) promoted proliferation, migration, tubulogenesis and permeability by activating the Akt/ERK pathway in ECs. STIM1 silencing reduced LMP1 enrichment in NPC cell-derived exosomes, thereby reversing its pro-oncogenic effects in an Akt/ERK pathway-dependent manner. Furthermore, STIM1 knockdown in NPC cells blunted tumor-induced vascular network formation and inhibited intra-tumor neovascularization in the chorioallantoic membrane (CAM) xenograft model.
STIM1 regulates tumor angiogenesis by controlling exosomal EBV-LMP1 delivery to ECs in the NPC tumor microenvironment. Blocking exosome-mediated cell-to-cell horizontal transfer of EBV-associated oncogenic signaling molecules may be an effective therapeutic strategy for NPC.
基质相互作用分子 1（STIM1）介导的 Ca 信号调节鼻咽癌（NPC）中的肿瘤血管生成，NPC 是一种与 EBV 相关的人类恶性肿瘤。然而，STIM1 调节内皮细胞功能表型从而促进肿瘤血管生成的机制仍不清楚。
通过差速离心分离 NPC 细胞衍生的外泌体，并通过透射电子显微镜观察。通过纳米颗粒跟踪分析（NTA）评估外泌体颗粒大小。通过用 PKH26 荧光标记外泌体来检测外泌体被受体 EC 摄取。通过测定人脐静脉内皮细胞（HUVEC）中的细胞增殖、迁移、小管形成和通透性来表征与肿瘤血管生成相关的表型。通过 Western blot 检测磷酸化水平来评估 Akt/ERK 通路的激活。采用鸡胚绒毛尿囊膜（CAM）异种移植模型在体内研究与肿瘤相关的新生血管形成。
我们发现 NPC 细胞衍生的携带 EBV 编码的潜伏膜蛋白 1（LMP1）的外泌体通过激活 ECs 中的 Akt/ERK 通路促进增殖、迁移、小管形成和通透性。STIM1 沉默减少了 NPC 细胞衍生的外泌体中 LMP1 的富集，从而以 Akt/ERK 通路依赖的方式逆转其致癌作用。此外，NPC 细胞中的 STIM1 敲低减弱了肿瘤诱导的血管网络形成，并抑制了绒毛尿囊膜（CAM）异种移植模型中的肿瘤内新生血管形成。
STIM1 通过控制 NPC 肿瘤微环境中外泌体 EBV-LMP1 向 EC 的传递来调节肿瘤血管生成。阻断外泌体介导的 EBV 相关致癌信号分子的细胞间横向转移可能是 NPC 的一种有效治疗策略。
