Erythroid-transdifferentiated myeloid cells promote portal vein tumor thrombus in hepatocellular carcinoma.
Erythroid-transdifferentiated myeloid cells promote portal vein tumor thrombus in hepatocellular carcinoma.
复制标题
红系转分化的骨髓细胞促进肝细胞癌中门静脉癌栓的形成。
作者：
Zhu WH;Chen J;Huang RK;Zhang Y;Huang ZX;Pang XQ;Hu B;Yang Y;Li X
原理：肝细胞癌（HCC）的主要特征是血管浸润的发生率高。然而，肝癌门静脉癌栓（PVTT）的具体机制尚不清楚。作为髓系细胞发育停滞的结果，CD 71+红系祖细胞（EPCs）和髓系来源的抑制细胞在HCC中发挥重要作用;然而，它们在PVTT中的作用仍不清楚。研究方法：通过形态学、RNA测序、酶联免疫吸附试验和流式细胞术分析，评价CD 71 + EPCs在HCC肿瘤微环境（TME）中的作用。采用共培养技术检测CD 45 + EPCs的血管内皮功能。此外，还在小鼠模型中体内探索了CD 45 + EPCs的PVTT促进功能。结果如下：HCC组织中的CD 45 +EPCs表现出髓样细胞特征，包括形态学、表面标志物、转化生长因子（TGF）-β生成和基因表达，与循环中的相比增加。因此，大比例的CD 45 + EPC，特别是TME中的那些，包含红系转分化的髓系细胞（EDMC）。此外，C-C趋化因子受体2型（CCR 2）mRNA的表达在TME内的CD 45 +EPCs中上调。来自HCC组织的肿瘤巨噬细胞以剂量依赖性方式诱导CD 45 +EPCs大量迁移。同时，免疫荧光分析的结果显示，这两种细胞类型在TME和循环中呈正相关。也就是说，EDMC主要通过循环中来自CD 45 + EPCs的CCR 2被HCC巨噬细胞化学吸引。此外，FX，FVII，FGB，C4 b，CFB和CFH在TME内的CD 45 +EPCs中的表达与脾脏中的表达相比升高。来自HCC TME的CD 45 +EPCs分别通过TGF-β和FGB促进血管内皮细胞迁移和受损管形成。此外，来自TME的CD 45 +EPCs诱导HCC细胞迁移。HCC巨噬细胞诱导的CD 45 +EPCs表现出更高水平的FX、FVII、FGB和TGF-β。同时，CCAAT/增强子结合蛋白β表达的上调诱导TME中CD 45 +EPCs中FGB和TGF-β的产生。WTAP是一种主要的RNA m6 A编写器，稳定了FX和FVII mRNA，并增强了来自TME的CD 45 +EPCs的核输出。TME中CD 45 +EPCs与PVTT和预后不良呈正相关。脾切除可降低循环和TME中CD 45 +EPCs的水平，以及微血管浸润的发生率。将肝癌组织中的CD 45 +EPCs转移到脾切除的肝癌小鼠后，微血管侵袭的发生率增加。结论：在HCC微环境中富集的CD 45 + EPC是EDMC，其由HCC巨噬细胞诱导从循环迁移到TME。随后，EDMCs通过损害血管内皮、加重凝血和促进HCC细胞迁移来促进PVTT。
Rationale: Hepatocellular carcinoma (HCC) is primarily characterized by a high incidence of vascular invasion. However, the specific mechanism underlying portal vein tumor thrombus (PVTT) in HCC remains unclear. As a consequence of myeloid cell developmental arrest, CD71+ erythroid progenitor cells (EPCs) and myeloid-derived suppressor cells play important roles in HCC; however, their roles in PVTT remain unclear. Methods: The role of CD71+ EPCs in the HCC tumor microenvironment (TME) was evaluated via morphological, RNA-sequencing, enzyme-linked immunosorbent assay, and flow cytometric analyses. Co-culture techniques were employed to assess the CD45+ EPCs and their vascular compromising effect. Additionally, the PVTT-promoting function of CD45+ EPCs was explored in vivo in a murine model. Results: The CD45+EPCs in HCC tissues exhibited increased myeloid cell features, including morphology, surface markers, transforming growth factor (TGF)-β generation, and gene expression, compared with those in circulation. Hence, a large proportion of CD45+EPCs, particularly those in TMEs, comprise erythroid-transdifferentiated myeloid cells (EDMCs). Additionally, the expression of C-C chemokine receptor type 2 (CCR2) mRNA was upregulated in CD45+EPCs within the TME. Tumor macrophages from HCC tissues induced substantial migration of CD45+EPCs in a dose-dependent manner. Meanwhile, results from immunofluorescence analyses revealed that these two cell types are positively associated in the TME and circulation. That is, EDMCs are chemoattracted by HCC macrophages mainly via CCR2 from CD45+ EPCs in the circulation. Additionally, the expressions of FX, FVII, FGB, C4b, CFB, and CFH were elevated in CD45+EPCs within the TME compared with those in the spleen. The CD45+EPCs from the HCC TME promoted vessel endothelial cell migration and compromised tube formation through TGF-β and FGB, respectively. Additionally, CD45+EPCs from the TME induced HCC cell migration. HCC macrophage-induced CD45+EPCs to exhibit higher levels of FX, FVII, FGB, and TGF-β. Meanwhile, upregulation of CCAAT/enhancer binding protein beta expression induced FGB and TGF-β generation in CD45+EPCs in the TME. WTAP, a major RNA m6A writer, stabilized FX and FVII mRNA and enhanced their nuclear export in CD45+EPCs from the TME. CD45+EPCs from the TME were positively associated with PVTT and poor prognosis. Splenectomy reduced the level of CD45+EPCs in the circulation and TME, as well as the incidence of microvascular invasion. The incidence of microvascular invasion increased following the transfer of HCC tissue CD45+EPCs to splenectomized HCC-bearing mice. Conclusions: The CD45+EPCs enriched in the HCC microenvironment are EDMCs, which are induced by HCC macrophages to migrate from the circulation to the TME. Subsequently, EDMCs promote PVTT by compromising the blood vessel endothelium, aggravating coagulation, and promoting HCC cell migration.
登录
查看更多内容
连接 METTL3 和瘤内 CD33( ) MDSC 预测宫颈癌的临床结果
影响因子：
7.4
作者：
Ni HH;Zhang L;Huang H;Dai SQ;Li J
通讯作者：
Li J
DOI：
10.1016/j.trsl.2020.06.012
发表时间：
2020-11
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
--
作者：
Kim AS;Khorana AA;McCrae KR
通讯作者：
McCrae KR
肿瘤诱导的脾成红细胞样 Ter 细胞的产生促进肿瘤进展
影响因子：
64.5
作者：
Han, Yanmei;Liu, Qiuyan;Cao, Xuetao
通讯作者：
Cao, Xuetao
影响因子：
9.7
作者：
Chen, Jie;Qiao, Yi-Dan;Wu, Xiang-Yuan
通讯作者：
Wu, Xiang-Yuan
影响因子：
6.7
作者：
Fish, Richard J.;Neerman-Arbez, Marguerite
通讯作者：
Neerman-Arbez, Marguerite