Department of Immunology, Kanazawa University Graduate School of Medical Sciences, Takara, Kanazawa, Ishikawa, Japan.
Department of Neurosurgery, Kanazawa University Graduate School of Medical Sciences, Takara, Kanazawa, Ishikawa, Japan.
Carcinogenesis. 2020 Sep 24;41(9):1238-1245. doi: 10.1093/carcin/bgaa052.
Glioma persists as one of the most aggressive primary tumors of the central nervous system. Glioma cells are known to communicate with tumor-associated macrophages/microglia via various cytokines to establish the tumor microenvironment. However, how extracellular vesicles (EVs), emerging regulators of cell-cell communication networks, function in this process is still elusive. We report here that glioma-derived EVs promote tumor progression by affecting microglial gene expression in an intracranial implantation glioma model mouse. The gene expression of thrombospondin-1 (Thbs1), a negative regulator of angiogenesis, was commonly downregulated in microglia after the addition of EVs isolated from different glioma cell lines, which endogenously expressed Wilms tumor-1 (WT1). Conversely, WT1-deficiency in the glioma-derived EVs significantly attenuated the Thbs1 downregulation and suppressed the tumor progression. WT1 was highly expressed in EVs obtained from the cerebrospinal fluid of human patients with malignant glioma. Our findings establish a novel model of tumor progression via EV-mediated WT1-Thbs1 intercellular regulatory pathway, which may be a future diagnostic or therapeutic target.
神经胶质瘤是中枢神经系统中最具侵袭性的原发性肿瘤之一。已知神经胶质瘤细胞通过各种细胞因子与肿瘤相关的巨噬细胞/小胶质细胞相互通讯，从而建立肿瘤微环境。然而，细胞间通讯网络的新兴调节因子——细胞外囊泡 (EVs) 在这一过程中是如何发挥作用的，目前仍不清楚。我们在这里报告，在颅内植入神经胶质瘤模型小鼠中，神经胶质瘤来源的 EV 通过影响小胶质细胞的基因表达来促进肿瘤进展。在添加源自不同神经胶质瘤细胞系的 EV 后，血小板反应蛋白-1 (Thbs1) 的基因表达，即血管生成的负调节剂，通常在小胶质细胞中下调，而这些 EV 内源性表达 Wilms 肿瘤-1 (WT1)。相反，WT1 在神经胶质瘤来源的 EV 中的缺失显著减弱了 Thbs1 的下调，并抑制了肿瘤进展。WT1 在来自恶性神经胶质瘤患者脑脊液的 EVs 中高度表达。我们的研究结果建立了一种通过 EV 介导的 WT1-Thbs1 细胞间调节途径促进肿瘤进展的新模型，这可能是未来的诊断或治疗靶点。
