Soluble Urokinase Receptor Is Released Selectively by Glioblastoma Cells That Express Epidermal Growth Factor Receptor Variant III and Promotes Tumor Cell Migration and Invasion

Andrew S Gilder; Karra A Jones; Jingjing Hu; Lei Wang; Clark C Chen; Bob S Carter; Steven L Gonias

doi:10.1074/jbc.M115.637488

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Soluble Urokinase Receptor Is Released Selectively by Glioblastoma Cells That Express Epidermal Growth Factor Receptor Variant III and Promotes Tumor Cell Migration and Invasion

Journal article

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Peer reviewed

Soluble Urokinase Receptor Is Released Selectively by Glioblastoma Cells That Express Epidermal Growth Factor Receptor Variant III and Promotes Tumor Cell Migration and Invasion

Andrew S Gilder, Karra A Jones, Jingjing Hu, Lei Wang, Clark C Chen, Bob S Carter and Steven L Gonias

The Journal of biological chemistry, Vol.290(24), pp.14798-14809

06/12/2015

DOI: 10.1074/jbc.M115.637488

PMCID: PMC4463428

PMID: 25837250

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Abstract

Genomic heterogeneity is characteristic of glioblastoma (GBM). In many GBMs, the EGF receptor gene (EGFR) is amplified and may be truncated to generate a constitutively active form of the receptor called EGFRvIII. EGFR gene amplification and EGFRvIII are associated with GBM progression, even when only a small fraction of the tumor cells express EGFRvIII. In this study, we show that EGFRvIII-positive GBM cells express significantly increased levels of cellular urokinase receptor (uPAR) and release increased amounts of soluble uPAR (suPAR). When mice were xenografted with human EGFRvIII-expressing GBM cells, tumor-derived suPAR was detected in the plasma, and the level was significantly increased compared with that detected in plasma samples from control mice xenografted with EGFRvIII-negative GBM cells. suPAR also was increased in plasma from patients with EGFRvIII-positive GBMs. Purified suPAR was biologically active when added to cultures of EGFRvIII-negative GBM cells, activating cell signaling and promoting cell migration and invasion. suPAR did not significantly stimulate cell signaling or migration of EGFRvIII-positive cells, probably because cell signaling was already substantially activated in these cells. The activities of suPAR were replicated by conditioned medium (CM) from EGFRvIII-positive GBM cells. When the CM was preincubated with uPAR-neutralizing antibody or when uPAR gene expression was silenced in cells used to prepare CM, the activity of the CM was significantly attenuated. These results suggest that suPAR may function as an important paracrine signaling factor in EGFRvIII-positive GBMs, inducing an aggressive phenotype in tumor cells that are EGFRvIII-negative.

ErbB Receptors - metabolism

Neoplasm Invasiveness

Humans

Brain Neoplasms - pathology

Mice, SCID

Brain Neoplasms - metabolism

Receptors, Urokinase Plasminogen Activator - metabolism

Neoplasm Metastasis

Animals

Heterografts

Glioblastoma - pathology

Polymerase Chain Reaction

Cell Line, Tumor

Glioblastoma - metabolism

Mice

Details

Title: Subtitle: Soluble Urokinase Receptor Is Released Selectively by Glioblastoma Cells That Express Epidermal Growth Factor Receptor Variant III and Promotes Tumor Cell Migration and Invasion
Creators: Andrew S Gilder - From the Departments of Pathology and
Karra A Jones - From the Departments of Pathology and
Jingjing Hu - From the Departments of Pathology and
Lei Wang - From the Departments of Pathology and
Clark C Chen - Surgery, Division of Neurosurgery, University of California at San Diego, La Jolla, California 92093
Bob S Carter - Surgery, Division of Neurosurgery, University of California at San Diego, La Jolla, California 92093
Steven L Gonias - From the Departments of Pathology and sgonias@ucsd.edu
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.290(24), pp.14798-14809
DOI: 10.1074/jbc.M115.637488
PMID: 25837250
PMCID: PMC4463428
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: R01 CA169096 / NCI NIH HHS UH2 TR000931 / NCATS NIH HHS UH2TR000931 / NCATS NIH HHS P01 CA069246 / NCI NIH HHS 2P01CA069246-15A / NCI NIH HHS
Language: English
Date published: 06/12/2015
Academic Unit: Pathology
Record Identifier: 9984047875002771

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