Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression
| Autor: | Charles S. Specht, Miaolu Tang, Zhijun Liu, Michael Glantz, Hong Gang Wang, Megan M. Young, Benjamin Anderson, Dawit Aregawi, Wei Li, Tong Lu, Soo Yeon Kim, Brad E. Zacharia, Cynthia Lawson, Krishnamoorthy Thamburaj, Yiju Wei, Patricia P. Yee, Stephen Y. Chih |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Necrosis Neutrophils Cell General Physics and Astronomy Mice 0302 clinical medicine Medicine lcsh:Science Cancer Multidisciplinary biology medicine.anatomical_structure 030220 oncology & carcinogenesis Myeloperoxidase Disease Progression Female Tumor necrosis factor alpha medicine.symptom Cancer microenvironment Cell death Cell biology Programmed cell death Iron Science Ischemia Mice Nude Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Cell Line Tumor Coenzyme A Ligases Animals Ferroptosis Humans business.industry General Chemistry Phospholipid Hydroperoxide Glutathione Peroxidase medicine.disease CNS cancer 030104 developmental biology Cell culture Tumor progression Cancer research biology.protein lcsh:Q Glioblastoma business |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-22 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Tumor necrosis commonly exists and predicts poor prognoses in many cancers. Although it is thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscure. Here, we show that necrosis in glioblastoma (GBM) involves neutrophil-triggered ferroptosis. In a hyperactivated transcriptional coactivator with PDZ-binding motif-driven GBM mouse model, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse brain tumors kill cocultured tumor cells. Mechanistically, neutrophils induce iron-dependent accumulation of lipid peroxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibition or depletion of myeloperoxidase suppresses neutrophil-induced tumor cell cytotoxicity. Intratumoral glutathione peroxidase 4 overexpression or acyl-CoA synthetase long chain family member 4 depletion diminishes necrosis and aggressiveness of tumors. Furthermore, analyses of human GBMs support that neutrophils and ferroptosis are associated with necrosis and predict poor survival. Thus, our study identifies ferroptosis as the underlying nature of necrosis in GBMs and reveals a pro-tumorigenic role of ferroptosis. Together, we propose that certain tumor damage(s) occurring during early tumor progression (i.e. ischemia) recruits neutrophils to the site of tissue damage and thereby results in a positive feedback loop, amplifying GBM necrosis development to its fullest extent. Tumour necrosis is associated with tumour aggressiveness and poor outcomes in patients with glioblastomas, but the underlying mechanisms remain poorly understood. Here, the authors show that in a xenograft mouse model of glioblastoma, tumour-infiltrating neutrophils amplify necrosis by promoting myeloperoxidase-induced tumour cell ferroptosis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|