Stromal-driven and Amyloid β-dependent induction of neutrophil extracellular traps modulates tumor growth
| Autor: | Maximilien Euler, Sarah J. Welsh, James O. Jones, Carla P. Martins, Tobias Janowitz, Hafsa Munir, Jacqueline D. Shields, Markus H. Hoffmann |
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| Přispěvatelé: | Hoffmann, Markus [0000-0001-9698-9922], Shields, Jacqueline D. [0000-0003-2153-9710], Apollo - University of Cambridge Repository, Shields, Jacqueline D [0000-0003-2153-9710] |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Extracellular Traps Carcinogenesis Neutrophils General Physics and Astronomy Cell Communication 96/34 medicine.disease_cause 59 Mice 0302 clinical medicine Cancer-Associated Fibroblasts Protein-Arginine Deiminase Type 4 Bone Marrow Neoplasms Tumor Cells Cultured Tumor Microenvironment 14/19 64 Multidisciplinary CD11b Antigen Chemistry article Prognosis Healthy Volunteers 13/31 Observational Studies as Topic medicine.anatomical_structure 030220 oncology & carcinogenesis Tumour immunology Female 64/60 631/67/327 Cancer microenvironment Stromal cell Amyloid Science Primary Cell Culture Mice Transgenic 13/106 General Biochemistry Genetics and Molecular Biology 631/250/2504/223/1699 03 medical and health sciences Stroma medicine Animals Humans Inflammation Amyloid beta-Peptides 82/58 General Chemistry Neutrophil extracellular traps Disease Models Animal 030104 developmental biology 631/250/256 631/67/580 Cancer cell 14/63 Cancer research Bone marrow Amyloid Precursor Protein Secretases Reactive Oxygen Species |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-16 (2021) |
| Popis: | Tumors consist of cancer cells and a network of non-cancerous stroma. Cancer-associated fibroblasts (CAF) are known to support tumorigenesis, and are emerging as immune modulators. Neutrophils release histone-bound nuclear DNA and cytotoxic granules as extracellular traps (NET). Here we show that CAFs induce NET formation within the tumor and systemically in the blood and bone marrow. These tumor-induced NETs (t-NETs) are driven by a ROS-mediated pathway dependent on CAF-derived Amyloid β, a peptide implicated in both neurodegenerative and inflammatory disorders. Inhibition of NETosis in murine tumors skews neutrophils to an anti-tumor phenotype, preventing tumor growth; reciprocally, t-NETs enhance CAF activation. Mirroring observations in mice, CAFs are detected juxtaposed to NETs in human melanoma and pancreatic adenocarcinoma, and show elevated amyloid and β-Secretase expression which correlates with poor prognosis. In summary, we report that CAFs drive NETosis to support cancer progression, identifying Amyloid β as the protagonist and potential therapeutic target. The tumor microenvironment is composed of many cell types that crosstalk to modulate local immunity. Here the authors show that Amyloid β proteins from cancer-associated fibroblasts (CAF) induce neutrophil extracellular trap (NET) production by neutrophils, while NET feeds back to activate CAF, thereby implicating Amyloid β as a potential therapy target. |
| Databáze: | OpenAIRE |
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