Gao Meng, Dong Hang, Jiang Siyi, Chen Fangping, Fu Yunfeng, Luo Yanwei
Department of Blood Transfusion, The Third Xiangya Hospital, Central South University, Changsha, China.
Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, China.
Oncogenesis. 2024 Jun 13;13(1):21. doi: 10.1038/s41389-024-00522-5.
The hypercoagulable state is a hallmark for patients with multiple myeloma (MM) and is associated with disease progression. Activated platelets secrete exosomes and promote solid tumor growth. However, the role of platelet-derived exosomes in MM is not fully clear. We aim to study the underlying mechanism of how platelet-derived exosomes promote MM cell growth. Flow cytometry, Western blot, proteome analysis, co-immunoprecipitation, immunofluorescence staining, and NOD/SCID mouse subcutaneous transplantation model were performed to investigate the role of exosomal LRG1 on multiple myeloma cell growth. Peripheral blood platelets in MM patients were in a highly activated state, and platelet-rich plasma from MM patients significantly promoted cell proliferation and decreased apoptotic cells in U266 and RPMI8226 cells. Leucine-rich-alpha-2-glycoprotein 1 (LRG1) was significantly enriched in MM platelet-derived exosomes. Blocking LRG1 in recipient cells using LRG1 antibody could significantly eliminate the proliferation-promoting effect of platelet-derived exosomes on MM cells. And high exosomal LRG1 was associated with poor prognosis of patients with MM. Mechanistic studies revealed that LRG1 interacted with Olfactomedin 4 (OLFM4) to accelerate MM progression by activating the epithelial-to-mesenchymal transition (EMT) signaling pathway and promoting angiogenesis. Our results revealed that blocking LRG1 is a promising therapeutic strategy for the treatment of MM.
高凝状态是多发性骨髓瘤（MM）患者的一个标志，且与疾病进展相关。活化的血小板分泌外泌体并促进实体瘤生长。然而，血小板源性外泌体在MM中的作用尚不完全清楚。我们旨在研究血小板源性外泌体促进MM细胞生长的潜在机制。采用流式细胞术、蛋白质免疫印迹法、蛋白质组分析、免疫共沉淀、免疫荧光染色以及NOD/SCID小鼠皮下移植模型来研究外泌体富含亮氨酸的α-2-糖蛋白1（LRG1）对多发性骨髓瘤细胞生长的作用。MM患者的外周血血小板处于高度活化状态，MM患者的富血小板血浆显著促进U266和RPMI8226细胞的增殖并减少凋亡细胞。LRG1在MM血小板源性外泌体中显著富集。使用LRG1抗体阻断受体细胞中的LRG1可显著消除血小板源性外泌体对MM细胞的促增殖作用。并且外泌体LRG1水平高与MM患者的不良预后相关。机制研究表明，LRG1与嗅觉介质4（OLFM4）相互作用，通过激活上皮-间质转化（EMT）信号通路和促进血管生成来加速MM进展。我们的结果表明，阻断LRG1是一种有前景的MM治疗策略。
