Oncogenic epidermal growth factor receptor up-regulates multiple elements of the tissue factor signaling pathway in human glioma cells

Magnus, Nathalie; Garnier, Delphine; Rak, Janusz

doi:10.1182/blood-2009-10-250639

Cited by 129 publications

(121 citation statements)

References 21 publications

(33 reference statements)

Supporting

Mentioning

110

Contrasting

Unclassified

Order By: Relevance

“…It was recently shown that glioma cells display increased cell migration and invasion under hypoxic conditions, which was associated with enhanced TF/VIIa-mediated PAR-2 activation (32), and that EGFRvIII transformed GBM cells become hypersensitive to TF/PAR-mediated signaling (10), indicating a role of this pathway also in autocrine stimulation of GBM cells. Whereas malignant transformation appears to induce TF as well as PARs (10), we found that hypoxia specifically up-regulates TF, and rather down-regulates PAR-2 expression in GBM cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Experimental models of tumor development, as well as human cancer materials, link TF to the aggressiveness of several malignancies, including gliomas (5)(6)(7). TF induction in cancer cells may be driven by oncogenetic events, e.g., through EGF receptor (EGFR) and its mutant, EGFRvIII, and inactivation of the tumor suppressor PTEN (6,(8)(9)(10). Other reports have suggested that TF may be triggered by hypoxia through the transcription factor Early growth response gene-1 (11).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2–mediated heparin-binding EGF signaling in endothelial cells

Svensson

Kucharzewska

Christianson

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

265

211

View full text Add to dashboard Cite

Highly malignant tumors, such as glioblastomas, are characterized by hypoxia, endothelial cell (EC) hyperplasia, and hypercoagulation. However, how these phenomena of the tumor microenvironment may be linked at the molecular level during tumor development remains ill-defined. Here, we provide evidence that hypoxia up-regulates protease-activated receptor 2 (PAR-2), i.e., a G-protein–coupled receptor of coagulation-dependent signaling, in ECs. Hypoxic induction of PAR-2 was found to elicit an angiogenic EC phenotype and to specifically up-regulate heparin-binding EGF-like growth factor (HB-EGF). Inhibition of HB-EGF by antibody neutralization or heparin treatment efficiently counteracted PAR-2–mediated activation of hypoxic ECs. We show that PAR-2–dependent HB-EGF induction was associated with increased phosphorylation of ERK1/2, and inhibition of ERK1/2 phosphorylation attenuated PAR-2–dependent HB-EGF induction as well as EC activation. Tissue factor (TF), i.e., the major initiator of coagulation-dependent PAR signaling, was substantially induced by hypoxia in several types of cancer cells, including glioblastoma; however, TF was undetectable in ECs even at prolonged hypoxia, which precludes cell-autonomous PAR-2 activation through TF. Interestingly, hypoxic cancer cells were shown to release substantial amounts of TF that was mainly associated with secreted microvesicles with exosome-like characteristics. Vesicles derived from glioblastoma cells were found to trigger TF/VIIa–dependent activation of hypoxic ECs in a paracrine manner. We provide evidence of a hypoxia-induced signaling axis that links coagulation activation in cancer cells to PAR-2–mediated activation of ECs. The identified pathway may constitute an interesting target for the development of additional strategies to treat aggressive brain tumors.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2–mediated heparin-binding EGF signaling in endothelial cells

Svensson

Kucharzewska

Christianson

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

265

211

View full text Add to dashboard Cite

show abstract

“…It is therefore not surprising that activation, amplification or mutation of EGFR (e.g. expression of ligand independent form known as EGFRvIII), as well as overexpression of HER-2 result in the increase of TF production by glioma and carcinoma cells, respectively [61] [56].…”

mentioning

confidence: 99%

“…This may result in abnormally high and/or constitutive expression of TF in transformed cells [8]. Second, oncogenes can trigger coagulation gene expression ectopically [55][56][57], that is in cancer cells originating from tissues that normally do not produce coagulation factors. Third, oncogenic and differentiation pathways may modulate biogenesis of procoagulant extracellular vesicles (EVs), including emission of TFbearing large and small (exosome-like) microparticles that could enter biofluids and general circulation [58].…”

mentioning

confidence: 99%

Oncogenes and the coagulation system – forces that modulate dormant and aggressive states in cancer

Magnus

D’Asti

Meehan

et al. 2014

Thrombosis Research

Self Cite

View full text Add to dashboard Cite

“…Interestingly, recent data showed that as a result of EGFRvIII-dependent transformation, GB cells become hypersensitive to signaling mediated by tissue factor and protease-activated receptors, producing angiogenic factors (e.g., VEGF and IL-8) [151].…”

Section: The Egfrviii Paradigmmentioning

confidence: 99%

Brain cancer immunoediting: novel examples provided by immunotherapy of malignant gliomas

Pellegatta

Cuppini

Finocchiaro

2011

Expert Review of Anticancer Therapy

View full text Add to dashboard Cite

Oncogenic epidermal growth factor receptor up-regulates multiple elements of the tissue factor signaling pathway in human glioma cells

Cited by 129 publications

References 21 publications

Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2–mediated heparin-binding EGF signaling in endothelial cells

Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2–mediated heparin-binding EGF signaling in endothelial cells

Oncogenes and the coagulation system – forces that modulate dormant and aggressive states in cancer

Brain cancer immunoediting: novel examples provided by immunotherapy of malignant gliomas

Contact Info

Product

Resources

About