scholarly journals TAMI-23. NEUTROPHIL-TRIGGERED FERROPTOSIS PROMOTES TUMOR NECROSIS IN GLIOBLASTOMA PROGRESSION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii218-ii218
Author(s):  
Patricia Yee ◽  
Yiju Wei ◽  
Soo Yeon Kim ◽  
Tong Lu ◽  
Cynthia Lawson ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Tumor Necrosis ◽  
Treatment Resistance ◽  
Binding Motif ◽  
Lipid Hydroperoxides ◽  
Orthotopic Mouse Model ◽  
Mouse Tumors ◽  
Downstream Effector ◽  
Human Gbm ◽  
Early Tumor

Abstract Tumor necrosis indicates poor prognoses in many cancers, including glioblastomas (GBMs). Although thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscured by lack of animal models recapitulating the extent of necrosis in human GBMs. The molecular and clinical heterogeneity of GBMs adds further complexity. Not all GBMs contain necrosis. Mesenchymal (MES)-GBM, the subtype correlated with worst prognosis and highest treatment resistance, is most closely associated with necrosis. MES-GBM exhibits hyperactivity of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo tumor suppressive pathway effector whose expression in human GBMs predicts short survival. To elucidate mechanisms driving GBM necrosis, we devised a novel orthotopic mouse model recapitulating human MES-GBM phenotypically and histopathologically by expressing a constitutively-active TAZ mutant (TAZ4SA) in three human GBM cell lines (LN229, U87, and LN18) lacking MES signatures (GBM4SA). GBM4SA mice lived significantly shorter than mice implanted with GBMvector or mutant TAZ unable to bind its downstream effector, TEAD (GBM4SA-S51A). Extensive (≥30% of tumor volume) necrosis was present in GBM4SA mice but not GBMvector or GBM4SA-S51A. In GBM4SA tumors, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse tumors killed co-cultured tumor cells. Neutrophils induce iron-dependent accumulation of lipid hydroperoxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibiting myeloperoxidase suppresses neutrophil-induced tumor cytotoxicity. Intratumoral glutathione peroxidase 4 (GPX4) overexpression or acyl-CoA synthetase 4 (ACSL4) depletion diminishes necrosis and aggressiveness of tumors. Human GBM analysis indicates neutrophils and ferroptosis are associated with necrosis and predict poor survival. Together, we propose that certain tumor damage(s) during early tumor progression (i.e. ischemia) recruits neutrophils to damaged tissue and results in a positive feedback loop, amplifying GBM necrosis development. We show GBM necrosis involves neutrophil-triggered ferroptosis and reveal an unprecedented pro-tumorigenic role of ferroptosis.

scholarly journals Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Patricia P. Yee ◽  
Yiju Wei ◽  
Soo-Yeon Kim ◽  
Tong Lu ◽  
Stephen Y. Chih ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Tumor Necrosis ◽  
Feedback Loop ◽  
Lipid Peroxides ◽  
Binding Motif ◽  
Transcriptional Coactivator ◽  
Chronic Ischemia ◽  
Neutrophil Depletion ◽  
Early Tumor

Abstract 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.

scholarly journals Abstract 3751: A mode of treatment resistance of metastatic tumor cells: Propagation exceeds elimination in number

2019 ◽  
Author(s):  
Chie Kudo-Saito ◽  
Yukinori Ozaki ◽  
Keiichi Kinowaki ◽  
Hidetaka Kawabata ◽  
Yamato Ogiwara
Keyword(s):  
Tumor Cells ◽  
Treatment Resistance ◽  
Metastatic Tumor

scholarly journals Syndecan-4 Promotes Epithelial Tumor Cells Spreading and Regulates the Turnover of PKCα Activity under Mechanical Stimulation on the Elastomeric Substrates

2015 ◽  
Vol 36 (4) ◽  
pp. 1291-1304 ◽  
Author(s):  
Chun-Ping Huang ◽  
Chao-Min Cheng ◽  
Hong-Lin Su ◽  
Yi-Wen Lin
Keyword(s):  
Mechanical Stress ◽  
Tumor Cells ◽  
Focal Adhesion ◽  
Mechanical Stimulation ◽  
Binding Motif ◽  
Epithelial Tumor ◽  
Cell Contractility ◽  
Myosin Light Chain 2 ◽  
Epithelial Tumor Cells ◽  
Time Courses

Background: Heparan sulfate proteoglycans (HSPGs) at the cell surface play an important role in cell adhesion, spreading, formation of focal adhesion complexes (FACs), and sensing mechanical stress. Syndecans are members of the HSPGs family and are highly expressed in various tumor cells. Syndecan-4 (SDC4) is a unique member of syndecans that activates protein kinase C alpha (PKCα). However, syndecan-4 in tumor cells development is not clear when receiving mechanical stress. Aims: Here we investigate the role of syndecan-4 in tumor cells spreading and its downstream kinases under mechanical stimulation. Methods: Epithelial tumor cells were seeded onto elastomeric polydimethylsiloxane (PDMS) membranes coated with poly-L-lysine (Pl), fibronectin (Fn), or anti-SDC4 antibody and stretched with a modified pressure-driven cell-stretching (PreCS) device. Results: When cells received mechanical stimulation, engagement of syndecan-4 promoted the phosphorylation of focal adhesion kinase (FAK) at tyrosine 397 and PKCα at serine 657. Furthermore, we analyzed the cell contractility marker—myosin light chain 2 (MLC2) in 30 min time courses. The levels of phosphorylated MLC2 at serine19 were augmented through ligations of syndecan-4 but not integrin binding motif (RGD) at 10 min mechanical stimulation and were suppressed at 30 min and this phenomenon was associated with the activity of PKCα. Conclusion: Our data demonstrate that syndecan-4 is essential for transmitting the mechanotransduction signals via activation of PKCα and is important for tumor cells spreading, assembly of actin cytoskeleton and cell contractility.

Platelet Interaction with Tumor Cells

1975 ◽  
Author(s):  
G. Gasic ◽  
T. Gasic ◽  
B. Hsu ◽  
P. Koch ◽  
S. Niewiarowski
Keyword(s):  
Tumor Cells ◽  
Gamma Globulin ◽  
Wilms Tumor ◽  
Preliminary Evidence ◽  
Human Tumors ◽  
Research Support ◽  
Mouse Tumors ◽  
Adp Release ◽  
Colonic Adenocarcinomas ◽  
Mammary Adenocarcinomas

Previous investigations demonstrated that mouse tumors cause platelet aggregation (PA) and increase platelet turnover. Depletion of platelets by neuraminidase and inhibition of PA by aspirin reduced the munber of metastases (Gasic et al., Int. J. Cancer 11, 704, 1973). The purpose of this investigation was to study further interaction of cells from various mouse and human tumors with platelets. Cells of 7 mouse tumors (1 mammary adenocarcinomas, 5 sarcomas, I melanoma) and 14 human tumors (8 breast, 3 colonic adenocarcinomas, 1 cancer of the ureter, 1 Wilms tumor, and 1 neuroblastoma) aggregated homologous platelets suspended in heparinized plasma. Three mouse tumors (2 mammary and 1 sarcoma) and 5 human tumors (2 breast, 1 sarcoma, 1 Wilms, and 1 neuroblastoma) did not. PA was accompanied by the release of radio-activity from 14C-serotonin labeled platelets (range 15–90%). PA activity was not correlated with fibrinolytic or procoagulant activity. The contribution of plasminogen activators, thrombin, and tumor immune complexes has been excluded. However, gamma globulin of tumor bearing mice contained a “blocking factor” which delayed PA. Since enzymatic removal of ADP reduced PA it is possible that the ADP release either by tumors or by platelets played a contributory role. The pattern of PA by tumor cells rossembled that induced by collagen. Indeed preliminary evidence suggests that collagen-like material associated with tumor cells might be involved in platelet adherence to these cells and subsequent aggregation.(Supported by NIH Grants CA-15728, HL 14217. HL 15226, and by a Univ. of Penna.’s General Research Support Grant.)

scholarly journals A Novel Human Phosphatidylethanolamine-binding Protein Resists Tumor Necrosis Factor α-induced Apoptosis by Inhibiting Mitogen-activated Protein Kinase Pathway Activation and Phosphatidylethanolamine Externalization

2004 ◽  
Vol 279 (44) ◽  
pp. 45855-45864 ◽  
Author(s):  
Xiaojian Wang ◽  
Nan Li ◽  
Bin Liu ◽  
Hongying Sun ◽  
Taoyong Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Necrosis Factor ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Breast Cancer Cells ◽  
Tumor Necrosis ◽  
Induced Apoptosis ◽  
Phosphatidylethanolamine Binding Protein ◽  
Necrosis Factor ◽  
Mcf 7

The phosphatidylethanolamine (PE)-binding proteins (PEBPs) are an evolutionarily conserved family of proteins with pivotal biological functions. Here we describe the cloning and functional characterization of a novel family member, human phosphatidylethanolamine-binding protein 4 (hPEBP4). hPEBP4 is expressed in most human tissues and highly expressed in tumor cells. Its expression in tumor cells is further enhanced upon tumor necrosis factor (TNF) α treatment, whereas hPEBP4 normally co-localizes with lysosomes, TNFα stimulation triggers its transfer to the cell membrane, where it binds to Raf-1 and MEK1. L929 cells overexpressing hPEBP4 are resistant to both TNFα-induced ERK1/2, MEK1, and JNK activation and TNFα-mediated apoptosis. Co-precipitation andin vitroprotein binding assay demonstrated that hPEBP4 interacts with Raf-1 and MEK1. A truncated form of hPEBP4, lacking the PE-binding domain, maintains lysosomal co-localization but has no effect on cellular responses to TNFα. Given that MCF-7 breast cancer cells expressed hPEBP4 at a high level, small interfering RNA was used to silence the expression of hPEBP4. We demonstrated that down-regulation of hPEBP4 expression sensitizes MCF-7 breast cancer cells to TNFα-induced apoptosis. hPEBP4 appears to promote cellular resistance to TNF-induced apoptosis by inhibiting activation of the Raf-1/MEK/ERK pathway, JNK, and PE externalization, and the conserved region of PE-binding domain appears to play a vital role in this biological activity of hPEBP4.

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