Platelets and MMP‑9 contribute to esophageal cancer invasion via CD40‑CD154 interactions

Umemoto,Kazufumi; Nakamura,Toru; Sasaki,Katsunori; Sato,Osamu; Suzuki,Tomohiro; Hirano,Satoshi

doi:10.3892/or.2025.8912

Platelets and MMP‑9 contribute to esophageal cancer invasion via CD40‑CD154 interactions

Authors:
- Kazufumi Umemoto
- Toru Nakamura
- Katsunori Sasaki
- Osamu Sato
- Tomohiro Suzuki
- Satoshi Hirano
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Affiliations: Department of Gastroenterological Surgery II, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060‑8638, Japan, Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido 060‑8638, Japan
Published online on: May 9, 2025 https://doi.org/10.3892/or.2025.8912
Article Number: 79
Copyright: © Umemoto et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

CD40 expression in esophageal cancer (EC) is linked to poor prognosis, although its molecular role remains unclear. The present study explored the function of CD40 in EC progression and metastasis, focusing on its interaction with CD154 and the upregulation of MMP‑9. CD40 expression was confirmed in EC cell lines using quantitative PCR, western blotting, flow cytometry and immunocytochemistry. Functional assays showed that recombinant soluble CD154 stimulation enhanced the migration and invasion of CD40‑overexpressing EC cells without affecting viability. Co‑culture experiments with platelets demonstrated that platelet‑derived CD154 acted on CD40‑overexpressing esophageal cancer cells, leading to upregulation of MMP‑9 secretion, potentially driving tumor invasiveness. Serum analysis of patients who underwent esophagectomy revealed that low MMP‑9 levels were associated with longer survival in pathological Stage I, whereas the opposite trend was observed in stages II‑IV. These findings indicated that CD40 activation enhanced tumor cell invasiveness through MMP‑9 upregulation. This dual role of CD40, enhancing antitumor immunity via its expression on antigen‑presenting cells, while promoting tumor invasiveness through MMP‑9 secretion when expressed on esophageal cancer cells, may complicate immunotherapeutic strategies targeting CD40, as such interventions could inadvertently promote malignancy within the tumor microenvironment.

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