早期胃癌（GC）淋巴结（LN）转移的具体机制尚未阐明。贫血是GC的重要临床特征，其在LN转移中的作用也不清楚。由于慢性贫血导致红系祖细胞（EPC）数量的增加，所以我们研究了其与GC LN转移的关联。我们采用流式细胞术和免疫荧光分析来筛选和研究I至III期GC患者循环和肿瘤中的EPC，并确定其对T和B细胞的激活以及淋巴内皮细胞（LECs）功能的影响，并利用基于两株人腺癌GC细胞系的裸鼠足跖-膝关节淋巴结转移模型评估其促进LN转移的能力。还分析了EPCs的预后价值。CD45- EPCs在LN转移阳性（N+）和LN转移阴性（N0）GC患者的单个核细胞、肿瘤和LN中的比例较高。在N+患者中，转移性LN中CD45- EPCs比非转移性LN更丰富。瘤内淋巴管内皮透明质酸受体1的免疫反应显示，CD45- EPCs与淋巴结分期和淋巴管密度呈正相关。此外，CD45- EPCs通过其S100A8/A9异源二聚体诱导的混合上皮/间质（E/M）状态增加了LEC扩增和迁移，但对LEC的侵袭和血管生成以及T和B细胞扩增无影响。CD45- EPCs在体内促进了LN转移，S100A8/A9异源二聚体模仿了这种现象。最后，CD45- EPCs预测了全期和无病生存。I至III期GC患者在根治切除后。CD45- EPCs在GC组织和转移性LN中积累，并通过S100A8/9诱导的LEC混合E/M状态促进LN转移，这是GC早期期间LN转移的特定机制。©2023 作者独家许可给国际胃癌学会和日本胃癌学会。

Specific mechanisms of lymph node (LN) metastasis in early-stage gastric cancer (GC) have not been elucidated. The role of anemia, a vital clinical feature of GC, in LN metastasis is also unclear. Since the number of erythroid progenitor cells (EPCs) is increased in chronic anemia, we investigated its association with LN metastasis in GC.Flow cytometry and immunofluorescence analyses were performed to sort and study EPCs from the circulation and tumors of patients with stage I-III GC. The effect of these EPCs on the activation of T and B cells and on the functions of lymphatic endothelial cells (LECs) was determined, and their ability to promote LN metastasis was evaluated using a footpad-popliteal LN metastasis model based on two human adenocarcinoma GC cell lines in nude mice. The prognostic value of EPCs was also analyzed.The proportion of CD45- EPCs was higher in the mononuclear cells in the circulation, tumors, and LNs of GC patients with LN metastasis (N+) than in those of GC patients without LN metastasis (N0). In N+ patients, CD45- EPCs were more abundant in metastatic LNs than in non-metastatic LNs. Lymphatic vessel endothelial hyaluronan receptor 1 immunoreactivity in tumors revealed that CD45- EPCs were positively associated with nodal stages and lymph vessel density. Furthermore, CD45- EPCs increased LEC proliferation and migration through their S100A8/A9 heterodimer-induced hybrid epithelial/mesenchymal (E/M) state; however, they did not influence the invasion and tubulogenesis of LECs or T and B cell proliferation. CD45- EPCs promoted LN metastasis in vivo; the S100A8/A9 heterodimer mimicked this phenomenon. Finally, CD45- EPCs predicted the overall and disease-free survival of stage I-III GC patients after radical resection.The CD45- EPCs accumulated in GC tissues and metastatic LNs and promoted LN metastasis via the S100A8/9-induced hybrid E/M state of LECs, which was the specific mechanism of LN metastasis in the early stages of GC.© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.