作者
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 Pilar Andueza,Karmele Valencia,Álvaro Teijeira,Kai Hoehlig,Axel Vater,Barbara E. Rolfe,Trent M. Woodruff,José M. López-Picazo,Silvestre Vicent,Grazyna Kochan,David Escors,Ignacio Gil‐Bazo,Jose Luis Pérez‐Gracia,Luis M. Montuenga,John D. Lambris,Carlos Ortiz de Solόrzano,Fernando Lecanda,Daniel Ajona,Rubén Pı́o
摘要
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.