Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Oncology Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1021-335X Online ISSN: 1791-2431
Journal Cover
July-2025 Volume 54 Issue 1

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
July-2025 Volume 54 Issue 1

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML

  • Supplementary Files
    • Supplementary_Data1.pdf
    • Supplementary_Data2.pdf
Article Open Access

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
  • View Affiliations / Copyright

    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
    Copyright: © Umemoto et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 79
    |
    Published online on: May 9, 2025
       https://doi.org/10.3892/or.2025.8912
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



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.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

View References

1 

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Pennathur A, Gibson MK, Jobe BA and Luketich JD: Oesophageal carcinoma. Lancet. 381:400–412. 2013. View Article : Google Scholar : PubMed/NCBI

3 

van Kooten C and Banchereau J: CD40-CD40 ligand. J Leukoc Biol. 67:2–17. 2000. View Article : Google Scholar : PubMed/NCBI

4 

Schonbeck U and Libby P: The CD40/CD154 receptor/ligand dyad. Cell Mol Life Sci. 58:4–43. 2001. View Article : Google Scholar : PubMed/NCBI

5 

Richards DM, Sefrin JP, Gieffers C, Hill O and Merz C: Concepts for agonistic targeting of CD40 in immuno-oncology. Hum Vaccin Immunother. 16:377–387. 2020. View Article : Google Scholar : PubMed/NCBI

6 

Xu W, Li Y, Yuan WW, Yin Y, Song WW, Wang Y, Huang QQ, Zhao WH and Wu JQ: Membrane-bound CD40L promotes senescence and initiates senescence-associated secretory phenotype via NF-κB activation in lung adenocarcinoma. Cell Physiol Biochem. 48:1793–1803. 2018. View Article : Google Scholar : PubMed/NCBI

7 

Lim CY, Chang JH, Lee WS, Kim J and Park IY: CD40 agonists alter the pancreatic cancer microenvironment by shifting the macrophage phenotype toward M1 and suppress human pancreatic cancer in organotypic slice cultures. Gut and Liver. 16:645–659. 2022. View Article : Google Scholar : PubMed/NCBI

8 

Bishop GA, Moore CR, Xie P, Stunz LL and Kraus ZJ: TRAF proteins in CD40 signaling. Adv Exp Med Biol. 597:131–151. 2007. View Article : Google Scholar : PubMed/NCBI

9 

van den Oord JJ, Maes A, Stas M, Nuyts J, Battocchio S, Kasran A, Garmyn M, De Wever I and De Wolf-Peeters C: CD40 is a prognostic marker in primary cutaneous malignant melanoma. Am J Pathol. 149:1953–1961. 1996.PubMed/NCBI

10 

Sabel MS, Yamada M, Kawaguchi Y, Chen FA, Takita H and Bankert RB: CD40 expression on human lung cancer correlates with metastatic spread. Cancer Immunol Immunother. 49:101–108. 2000. View Article : Google Scholar : PubMed/NCBI

11 

Li R, Chen WC, Pang XQ, Hua C, Li L and Zhang XG: Expression of CD40 and CD40L in gastric cancer tissue and its clinical significance. Int J Mol Sci. 10:3900–3917. 2009. View Article : Google Scholar : PubMed/NCBI

12 

Ishikawa K, Miyamoto M, Yoshioka T, Kato T, Kaji M, Ohbuchi T, Hirano S, Itoh T, Dosaka-Akita H and Kondo S: Up-regulation of CD40 with juxtacrine activity in human nonsmall lung cancer cells correlates with poor prognosis. Cancer. 113:530–541. 2008. View Article : Google Scholar : PubMed/NCBI

13 

Cooke PW, James ND, Ganesan R, Wallace M, Burton A and Young LS: CD40 expression in bladder cancer. J Pathol. 188:38–43. 1999. View Article : Google Scholar : PubMed/NCBI

14 

Shoji Y, Miyamoto M, Ishikawa K, Yoshioka T, Mishra R, Ichinokawa K, Matsumura Y, Itoh T, Shinohara T, Hirano S and Kondo S: The CD40-CD154 interaction would correlate with proliferation and immune escape in pancreatic ductal adenocarcinoma. J Surg Oncol. 103:230–238. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Matsumura Y, Hiraoka K, Ishikawa K, Shoji Y, Noji T, Hontani K, Itoh T, Nakamura T, Tsuchikawa T, Shichinohe T and Hirano S: CD40 expression in human esophageal squamous cell Carcinoma is associated with tumor progression and lymph node metastasis. Anticancer Res. 36:4467–4475. 2016. View Article : Google Scholar : PubMed/NCBI

16 

Davidson B, Reich R, Risberg B and Nesland JM: The biological role and regulation of matrix metalloproteinases (MMP) in cancer. Arkh Patol. 64:47–53. 2002.PubMed/NCBI

17 

Rhee JS and Coussens LM: RECKing MMP function: Implications for cancer development. Trends Cell Biol. 12:209–211. 2002. View Article : Google Scholar : PubMed/NCBI

18 

Egeblad M and Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2:161–174. 2002. View Article : Google Scholar : PubMed/NCBI

19 

Dagouassat M, Suffee N, Hlawaty H, Haddad O, Charni F, Laguillier C, Vassy R, Martin L, Schischmanoff PO, Gattegno L, et al: Monocyte chemoattractant protein-1 (MCP-1)/CCL2 secreted by hepatic myofibroblasts promotes migration and invasion of human hepatoma cells. Int J Cancer. 126:1095–1108. 2010. View Article : Google Scholar : PubMed/NCBI

20 

Nakamura T, Kuwai T, Kim JS, Fan D, Kim SJ and Fidler IJ: Stromal metalloproteinase-9 is essential to angiogenesis and progressive growth of orthotopic human pancreatic cancer in parabiont nude mice. Neoplasia. 9:979–986. 2007. View Article : Google Scholar : PubMed/NCBI

21 

Rigothier C, Daculsi R, Lepreux S, Auguste P, Villeneuve J, Dewitte A, Doudnikoff E, Saleem M, Bourget C, Combe C and Ripoche J: CD154 induces matrix metalloproteinase-9 secretion in human podocytes. J Cell Biochem. 117:2737–2747. 2016. View Article : Google Scholar : PubMed/NCBI

22 

Takeuchi S, Baghdadi M, Tsuchikawa T, Wada H, Nakamura T, Abe H, Nakanishi S, Usui Y, Higuchi K, Takahashi M, et al: Chemotherapy-derived inflammatory responses accelerate the formation of immunosuppressive myeloid cells in the tissue microenvironment of human pancreatic cancer. Cancer Res. 75:2629–2640. 2015. View Article : Google Scholar : PubMed/NCBI

23 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C (T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

24 

Brierley JD, Gospodarowicz MK and Wittekind C, RBrierley JD, Gospodarowicz MK and Wittekind C: TNM Classification of Malignant Tumours. 8th ed. Oxford: Wiley-Blackwell; 2017

25 

Tone M, Tone Y, Fairchild PJ, Wykes M and Waldmann H: Regulation of CD40 function by its isoforms generated through alternative splicing. Proc Natl Acad Sci USA. 98:1751–1756. 2001. View Article : Google Scholar : PubMed/NCBI

26 

Schlesinger M: Role of platelets and platelet receptors in cancer metastasis. J Hematol Oncol. 11:1252018. View Article : Google Scholar : PubMed/NCBI

27 

Haemmerle M, Stone RL, Menter DG, Afshar-Kharghan V and Sood AK: The platelet lifeline to cancer: Challenges and opportunities. Cancer Cell. 33:965–983. 2018. View Article : Google Scholar : PubMed/NCBI

28 

Gay LJ and Feldin-Habermann B: Contribution of platelets to tumour metastasis. Nat Rev Cancer. 11:123–134. 2011. View Article : Google Scholar : PubMed/NCBI

29 

Goubran H, Sabry W, Kotb R, Seghatchian J and Burnouf T: Platelet microparticles and cancer: An intimate cross-talk. Transfus Apher Sci. 53:168–172. 2015. View Article : Google Scholar : PubMed/NCBI

30 

Blair TA and Frelinger AL: 3rd: Platelet surface marker analysis by mass cytometry. Platelets. 31:633–640. 2020. View Article : Google Scholar : PubMed/NCBI

31 

Chatzigeorgiou A, Lyberi M, Chatzilymperis G, Nezos A and Kamper E: CD40/CD40L signaling and its implication in health and disease. Biofactors. 35:474–483. 2009. View Article : Google Scholar : PubMed/NCBI

32 

Bussolati B, Russo S, Deambrosis I, Cantaluppi V, Volpe A, Ferrando U and Camussi G: Expression of CD154 on renal cell carcinomas and effect on cell proliferation, motility and platelet-activating factor synthesis. Int J Cancer. 100:654–661. 2002. View Article : Google Scholar : PubMed/NCBI

33 

Grazia GA, Bastos DR and Villa LL: CD40/CD40L expression and its prognostic value in cervical cancer. Braz J Med Biol Res. 56:e130472023. View Article : Google Scholar : PubMed/NCBI

34 

Pantel K and Brakenhoff RH: Dissecting the metastatic cascade. Nat Rev Cancer. 4:448–456. 2004. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Umemoto K, Nakamura T, Sasaki K, Sato O, Suzuki T and Hirano S: Platelets and MMP‑9 contribute to esophageal cancer invasion via CD40‑CD154 interactions. Oncol Rep 54: 79, 2025.
APA
Umemoto, K., Nakamura, T., Sasaki, K., Sato, O., Suzuki, T., & Hirano, S. (2025). Platelets and MMP‑9 contribute to esophageal cancer invasion via CD40‑CD154 interactions. Oncology Reports, 54, 79. https://doi.org/10.3892/or.2025.8912
MLA
Umemoto, K., Nakamura, T., Sasaki, K., Sato, O., Suzuki, T., Hirano, S."Platelets and MMP‑9 contribute to esophageal cancer invasion via CD40‑CD154 interactions". Oncology Reports 54.1 (2025): 79.
Chicago
Umemoto, K., Nakamura, T., Sasaki, K., Sato, O., Suzuki, T., Hirano, S."Platelets and MMP‑9 contribute to esophageal cancer invasion via CD40‑CD154 interactions". Oncology Reports 54, no. 1 (2025): 79. https://doi.org/10.3892/or.2025.8912
Copy and paste a formatted citation
x
Spandidos Publications style
Umemoto K, Nakamura T, Sasaki K, Sato O, Suzuki T and Hirano S: Platelets and MMP‑9 contribute to esophageal cancer invasion via CD40‑CD154 interactions. Oncol Rep 54: 79, 2025.
APA
Umemoto, K., Nakamura, T., Sasaki, K., Sato, O., Suzuki, T., & Hirano, S. (2025). Platelets and MMP‑9 contribute to esophageal cancer invasion via CD40‑CD154 interactions. Oncology Reports, 54, 79. https://doi.org/10.3892/or.2025.8912
MLA
Umemoto, K., Nakamura, T., Sasaki, K., Sato, O., Suzuki, T., Hirano, S."Platelets and MMP‑9 contribute to esophageal cancer invasion via CD40‑CD154 interactions". Oncology Reports 54.1 (2025): 79.
Chicago
Umemoto, K., Nakamura, T., Sasaki, K., Sato, O., Suzuki, T., Hirano, S."Platelets and MMP‑9 contribute to esophageal cancer invasion via CD40‑CD154 interactions". Oncology Reports 54, no. 1 (2025): 79. https://doi.org/10.3892/or.2025.8912
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team