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CD45− erythroid progenitor cells promote lymph node metastasis in gastric cancer by inducing a hybrid epithelial/mesenchymal state in lymphatic endothelial cells

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Abstract

Background and aims

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.

Methods

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.

Results

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.

Conclusions

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.

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Data availability

Data are available in a public, open-access repository. All data relevant to the study are included in the article or uploaded as supplementary information. Data are available in public, open-access repositories, directly included in the article, uploaded as supplementary information from first or last authors.

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Acknowledgements

We are grateful to the central laboratory of the Third Affiliated Hospital of Sun Yat-sen University for providing labs and technical guidance.

Funding

This study was supported by Guangdong Basic and Applied Basic Research Foundation (No. 2021A1515011022, 2023A1515012544, 2022A1515010547 and 2023A1515011803), Tip-top Scientific and Technical Innovative Youth Talents of the Third Affiliated Hospital of Sun Yat-sen University, and National Natural Science Foundation of China (82073397, 81972677, 82103331) and Science Foundation of Guang dong Provincial Bureau of traditional Chinese Medicine (20211090).

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Author notes

  1. Jing-Yun Wen, Xing Li, Jian-Ning Chen have contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, Guangdong, China

    Jing-Yun Wen, Jian-Ning Chen, Jing-Yue Zhang, Yu Du, Ri-Hong Yang & Chun-Kui Shao

  2. Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, China

    Jing-Yun Wen, Xing Li, Jie Chen, Wei-Hang Zhu & Yong-Jian Chen

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Contributions

W-J Y, J-N C and W-H Z acquired the animal data. W-J Y, J C, J-Y Z and Y D performed the in vitro cell experiments. W-J Y, Y-J C and J C acquired the RNA seq data. R-H Y, J-N C, J-Y Z and Y D did the pathologic analysis. X L designed the study, analyzed the data, and wrote the manuscript. C-K S supervised the study and revised the manuscript.

Corresponding author

Correspondence to Chun-Kui Shao.

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No conflicts needed to be declared.

Ethics approval and consent to participate

This study of patient samples was approved by the Clinical Ethics Review Board of the Third Affiliated Hospital of Sun Yat-sen University ([2019]02-387-01). A written informed consent was obtained from all the patients at the time of admission. The animal experiments were carried out under the approval of the Institutional Animal Care and Use Committee of the Third Affiliated Hospital of Sun Yat‐sen University ([2020]02-311).

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Wen, JY., Li, X., Chen, JN. et al. CD45− erythroid progenitor cells promote lymph node metastasis in gastric cancer by inducing a hybrid epithelial/mesenchymal state in lymphatic endothelial cells. Gastric Cancer 26, 918–933 (2023). https://doi.org/10.1007/s10120-023-01425-x

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