Publicaciones científicas

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

28-dic-2021 | Revista: 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


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.

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