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Ortiz-Espinosa S, Morales X, Senent Y, et al. Complement C5a induces the formation of neutrophil extracellular traps by myeloid-derived suppressor cells to promote metastasis. Cancer Lett. 2021;doi: 10.1016/j.canlet.2021.12.027.
Ortiz-Espinosa, S., Morales, X., Senent, Y., Alignani, D., Tavira, B., Macaya, I., Ruiz, B., Moreno, H., Remírez, A., Sainz, C., Rodriguez-Pena, A., Oyarbide, A., Ariz, M., Andueza, M. P., Valencia, K., Teijeira, A., Hoehlig, K., Vater, A., Rolfe, B., Woodruff, T. M., Lopez-Picazo, J. M., Vicent, S., Kochan, G., Escors, D., Gil-Bazo, I., Perez-Gracia, J. L., Montuenga, L. M., Lambris, J. D., Ortiz de Solorzano, C., Lecanda, F., Ajona, D., & Pio, R. (2021). Complement C5a induces the formation of neutrophil extracellular traps by myeloid-derived suppressor cells to promote metastasis. Cancer letters, . https://doi.org/10.1016/j.canlet.2021.12.027
Ortiz-Espinosa, Sergio, et al. "Complement C5a induces the formation of neutrophil extracellular traps by myeloid-derived suppressor cells to promote metastasis." Cancer letters vol. (2021). doi: https://doi.org/10.1016/j.canlet.2021.12.027
Ortiz-Espinosa S, Morales X, Senent Y, Alignani D, Tavira B, Macaya I, Ruiz B, Moreno H, Remírez A, Sainz C, Rodriguez-Pena A, Oyarbide A, Ariz M, Andueza MP, Valencia K, Teijeira A, Hoehlig K, Vater A, Rolfe B, Woodruff TM, Lopez-Picazo JM, Vicent S, Kochan G, Escors D, Gil-Bazo I, Perez-Gracia JL, Montuenga LM, Lambris JD, Ortiz de Solorzano C, Lecanda F, Ajona D, Pio R. Complement C5a induces the formation of neutrophil extracellular traps by myeloid-derived suppressor cells to promote metastasis. Cancer Lett. 2021 Dec 28; doi: 10.1016/j.canlet.2021.12.027. Epub 2021 Dec 28. PMID: 34971753.
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Cancer Lett. 2021 Dec 28; doi: 10.1016/j.canlet.2021.12.027. Epub 2021 Dec 28.

Complement C5a induces the formation of neutrophil extracellular traps by myeloid-derived suppressor cells to promote metastasis.

Cancer letters

Sergio Ortiz-Espinosa, Xabier Morales, Yaiza Senent, Diego Alignani, Beatriz Tavira, Irati Macaya, Borja Ruiz, Haritz Moreno, Ana Remírez, Cristina Sainz, Alejandro Rodriguez-Pena, Alvaro Oyarbide, Mikel Ariz, Maria P Andueza, Karmele Valencia, Alvaro Teijeira, Kai Hoehlig, Axel Vater, Barbara Rolfe, Trent M Woodruff, Jose Maria Lopez-Picazo, Silvestre Vicent, Grazyna Kochan, David Escors, Ignacio Gil-Bazo, Jose Luis Perez-Gracia, Luis M Montuenga, John D Lambris, Carlos Ortiz de Solorzano, Fernando Lecanda, Daniel Ajona, Ruben Pio

Affiliations

  1. Program in Solid Tumors, Cima-University of Navarra, Pamplona, Spain; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain; Navarra's Health Research Institute (IDISNA), Pamplona, Spain.
  2. Program in Solid Tumors, Cima-University of Navarra, Pamplona, Spain; Navarra's Health Research Institute (IDISNA), Pamplona, Spain; Imaging Platform, CIMA, Pamplona, Spain.
  3. Navarra's Health Research Institute (IDISNA), Pamplona, Spain; Cytometry Unit, Cima-University of Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain.
  4. Program in Solid Tumors, Cima-University of Navarra, Pamplona, Spain; Navarra's Health Research Institute (IDISNA), Pamplona, Spain.
  5. Program in Solid Tumors, Cima-University of Navarra, Pamplona, Spain.
  6. Program in Solid Tumors, Cima-University of Navarra, Pamplona, Spain; Navarra's Health Research Institute (IDISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain.
  7. Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain.
  8. Program in Solid Tumors, Cima-University of Navarra, Pamplona, Spain; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain; Navarra's Health Research Institute (IDISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain.
  9. Program in Immunology and Immunotherapy, Cima-University of Navarra, Pamplona, Spain.
  10. Aptarion Biotech, Berlin, Germany.
  11. School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Queensland, Australia.
  12. Navarra's Health Research Institute (IDISNA), Pamplona, Spain; Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain.
  13. Program in Solid Tumors, Cima-University of Navarra, Pamplona, Spain; Navarra's Health Research Institute (IDISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain; Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain.
  14. Navarra's Health Research Institute (IDISNA), Pamplona, Spain; Immunomodulation Group, Navarrabiomed-Biomedical Research Center, Pamplona, Spain.
  15. Program in Solid Tumors, Cima-University of Navarra, Pamplona, Spain; Navarra's Health Research Institute (IDISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain; Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain.
  16. Navarra's Health Research Institute (IDISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain; Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain.
  17. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  18. Program in Solid Tumors, Cima-University of Navarra, Pamplona, Spain; Navarra's Health Research Institute (IDISNA), Pamplona, Spain; Imaging Platform, CIMA, Pamplona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain.
  19. Program in Solid Tumors, Cima-University of Navarra, Pamplona, Spain; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain; Navarra's Health Research Institute (IDISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain. Electronic address: [email protected].

PMID: 34971753 DOI: 10.1016/j.canlet.2021.12.027

Abstract

Myeloid-derived suppressor cells (MDSCs) play a major role in cancer progression. In this study, we investigated the mechanisms by which complement C5a increases the capacity of polymorphonuclear MDSCs (PMN-MDSCs) to promote tumor growth and metastatic spread. Stimulation of PMN-MDSCs with C5a favored the invasion of cancer cells via a process dependent on the formation of neutrophil extracellular traps (NETs). NETosis was dependent on the production of high mobility group box 1 (HMGB1) by cancer cells. Moreover, C5a induced the surface expression of the HMGB1 receptors TLR4 and RAGE in PMN-MDSCs. In a mouse lung metastasis model, inhibition of C5a, C5a receptor-1 (C5aR1) or NETosis reduced the number of circulating-tumor cells (CTCs) and the metastatic burden. In support of the translational relevance of these findings, C5a was able to stimulate migration and NETosis in PMN-MDSCs obtained from lung cancer patients. Furthermore, myeloperoxidase (MPO)-DNA complexes, as markers of NETosis, were elevated in lung cancer patients and significantly correlated with C5a levels. In conclusion, C5a induces the formation of NETs from PMN-MDSCs in the presence of cancer cells, which may facilitate cancer cell dissemination and metastasis.

Copyright © 2021. Published by Elsevier B.V.

Keywords: C5a/C5aR1; HMGB1; Lung metastasis; Myeloid-derived suppressor cells; NETosis

Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: K. Hoehlig and A. Vater are aut

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