Scientific publications

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

Dec 28, 2021 | Magazine: Cancer Letters

Sergio Ortiz-Espinosa  1 , Xabier Morales  2 , Yaiza Senent  1 , Diego Alignani  3 , Beatriz Tavira  4 , Irati Macaya  5 , Borja Ruiz  5 , Haritz Moreno  5 , Ana Remírez  6 , Cristina Sainz  6 , Alejandro Rodriguez-Pena  2 , Alvaro Oyarbide  2 , Mikel Ariz  2 , Maria P Andueza  7 , Karmele Valencia  8 , Alvaro Teijeira  9 , Kai Hoehlig  10 , Axel Vater  10 , Barbara Rolfe  11 , Trent M Woodruff  11 , Jose Maria Lopez-Picazo  12 , Silvestre Vicent  13 , Grazyna Kochan  14 , David Escors  14 , Ignacio Gil-Bazo  15 , Jose Luis Perez-Gracia  16 , Luis M Montuenga  13 , John D Lambris  17 , Carlos Ortiz de Solorzano  18 , Fernando Lecanda  6 , Daniel Ajona  19 , Ruben Pio  8


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.

CITATION  Cancer Lett. 2022 Mar 31;529:70-84.
doi: 10.1016/j.canlet.2021.12.027. Epub 2021 Dec 28. 

Our authors

Dr. Xabier Morales Urteaga
Research Technician Image Platform
Dr. Yaiza Senent Valero
Diego Alignani
Laboratory technician Cytometry Platform
Dr. Beatriz Tavira Iglesias
Project Researcher Solid Tumor Research Program
Dr. Irati Macaya Erro
Borja Ruiz Fernández de Córdoba
Haritz Moreno Moreno
Dr. Ana Remírez Sanz de Acedo
Laboratory technician Solid Tumor Research Program
Cristina Sainz
Laboratory technician Solid Tumor Research Program
Alejandro Rodríguez Pena
Dr. Daniel Ajona Martínez-Polo