Angiopoietin-2 induces human glioma invasion through the activation of matrix metalloprotease-2

Bo Hu*, Ping Guo, Quan Fang, Huo Quan Tao, Degui Wang, Motoo Nagane, Hui Jein Su Huang, Yuji Gunji, Ryo Nishikawa, Kari Alitalo, Webster K. Cavenee, Shi Yuan Cheng

*Corresponding author for this work

Research output: Contribution to journalArticle

118 Citations (Scopus)

Abstract

A hallmark of highly malignant human gliomas is their infiltration of the brain. We analyzed a large number of primary human glioma biopsies and found high levels of expression of an angiogenic regulator, angiopoietin-2 (Ang2), in the invasive areas, but not in the central regions, of those tumors. In the invasive regions where Ang2 was overexpressed, increased levels of matrix metalloprotease-2 (MMP-2) were also apparent. Consonant with these features, intracranial xenografts of glioma cells engineered to express Ang2 were highly invasive into adjacent brain parenchyma compared with isogenic control tumors. In regions of the Ang2-expressing tumors that were actively invading the brain, high levels of expression of MMP-2 and increased angiogenesis were also evident. A link between these two features was apparent, because stable expression of Ang2 by U87MG cells or treatment of several glioma cell lines with recombinant Ang2 in vitro caused activation of MMP-2 and acquisition of increased invasiveness. Conversely, MMP inhibitors suppressed Ang2-stimulated activation of MMP-2 and Ang2-induced cell invasion. These results suggest that Ang2 plays a critical role in inducing tumor cell infiltration, and that this invasive phenotype is caused by activation of MMP-2.

Original languageEnglish (US)
Pages (from-to)8904-8909
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number15
DOIs
StatePublished - Jul 22 2003

Fingerprint

Angiopoietin-2
Metalloproteases
Glioma
Neoplasms
Brain
human ANGPT2 protein
Matrix Metalloproteinase Inhibitors
Heterografts
Phenotype
Biopsy
Cell Line

Keywords

  • Glioblastoma

ASJC Scopus subject areas

  • General

Cite this

Hu, Bo ; Guo, Ping ; Fang, Quan ; Tao, Huo Quan ; Wang, Degui ; Nagane, Motoo ; Huang, Hui Jein Su ; Gunji, Yuji ; Nishikawa, Ryo ; Alitalo, Kari ; Cavenee, Webster K. ; Cheng, Shi Yuan. / Angiopoietin-2 induces human glioma invasion through the activation of matrix metalloprotease-2. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 15. pp. 8904-8909.
@article{0f573574a9194c87a870f42e356addcd,
title = "Angiopoietin-2 induces human glioma invasion through the activation of matrix metalloprotease-2",
abstract = "A hallmark of highly malignant human gliomas is their infiltration of the brain. We analyzed a large number of primary human glioma biopsies and found high levels of expression of an angiogenic regulator, angiopoietin-2 (Ang2), in the invasive areas, but not in the central regions, of those tumors. In the invasive regions where Ang2 was overexpressed, increased levels of matrix metalloprotease-2 (MMP-2) were also apparent. Consonant with these features, intracranial xenografts of glioma cells engineered to express Ang2 were highly invasive into adjacent brain parenchyma compared with isogenic control tumors. In regions of the Ang2-expressing tumors that were actively invading the brain, high levels of expression of MMP-2 and increased angiogenesis were also evident. A link between these two features was apparent, because stable expression of Ang2 by U87MG cells or treatment of several glioma cell lines with recombinant Ang2 in vitro caused activation of MMP-2 and acquisition of increased invasiveness. Conversely, MMP inhibitors suppressed Ang2-stimulated activation of MMP-2 and Ang2-induced cell invasion. These results suggest that Ang2 plays a critical role in inducing tumor cell infiltration, and that this invasive phenotype is caused by activation of MMP-2.",
keywords = "Glioblastoma",
author = "Bo Hu and Ping Guo and Quan Fang and Tao, {Huo Quan} and Degui Wang and Motoo Nagane and Huang, {Hui Jein Su} and Yuji Gunji and Ryo Nishikawa and Kari Alitalo and Cavenee, {Webster K.} and Cheng, {Shi Yuan}",
year = "2003",
month = "7",
day = "22",
doi = "10.1073/pnas.1533394100",
language = "English (US)",
volume = "100",
pages = "8904--8909",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "15",

}

Angiopoietin-2 induces human glioma invasion through the activation of matrix metalloprotease-2. / Hu, Bo; Guo, Ping; Fang, Quan; Tao, Huo Quan; Wang, Degui; Nagane, Motoo; Huang, Hui Jein Su; Gunji, Yuji; Nishikawa, Ryo; Alitalo, Kari; Cavenee, Webster K.; Cheng, Shi Yuan.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 15, 22.07.2003, p. 8904-8909.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Angiopoietin-2 induces human glioma invasion through the activation of matrix metalloprotease-2

AU - Hu, Bo

AU - Guo, Ping

AU - Fang, Quan

AU - Tao, Huo Quan

AU - Wang, Degui

AU - Nagane, Motoo

AU - Huang, Hui Jein Su

AU - Gunji, Yuji

AU - Nishikawa, Ryo

AU - Alitalo, Kari

AU - Cavenee, Webster K.

AU - Cheng, Shi Yuan

PY - 2003/7/22

Y1 - 2003/7/22

N2 - A hallmark of highly malignant human gliomas is their infiltration of the brain. We analyzed a large number of primary human glioma biopsies and found high levels of expression of an angiogenic regulator, angiopoietin-2 (Ang2), in the invasive areas, but not in the central regions, of those tumors. In the invasive regions where Ang2 was overexpressed, increased levels of matrix metalloprotease-2 (MMP-2) were also apparent. Consonant with these features, intracranial xenografts of glioma cells engineered to express Ang2 were highly invasive into adjacent brain parenchyma compared with isogenic control tumors. In regions of the Ang2-expressing tumors that were actively invading the brain, high levels of expression of MMP-2 and increased angiogenesis were also evident. A link between these two features was apparent, because stable expression of Ang2 by U87MG cells or treatment of several glioma cell lines with recombinant Ang2 in vitro caused activation of MMP-2 and acquisition of increased invasiveness. Conversely, MMP inhibitors suppressed Ang2-stimulated activation of MMP-2 and Ang2-induced cell invasion. These results suggest that Ang2 plays a critical role in inducing tumor cell infiltration, and that this invasive phenotype is caused by activation of MMP-2.

AB - A hallmark of highly malignant human gliomas is their infiltration of the brain. We analyzed a large number of primary human glioma biopsies and found high levels of expression of an angiogenic regulator, angiopoietin-2 (Ang2), in the invasive areas, but not in the central regions, of those tumors. In the invasive regions where Ang2 was overexpressed, increased levels of matrix metalloprotease-2 (MMP-2) were also apparent. Consonant with these features, intracranial xenografts of glioma cells engineered to express Ang2 were highly invasive into adjacent brain parenchyma compared with isogenic control tumors. In regions of the Ang2-expressing tumors that were actively invading the brain, high levels of expression of MMP-2 and increased angiogenesis were also evident. A link between these two features was apparent, because stable expression of Ang2 by U87MG cells or treatment of several glioma cell lines with recombinant Ang2 in vitro caused activation of MMP-2 and acquisition of increased invasiveness. Conversely, MMP inhibitors suppressed Ang2-stimulated activation of MMP-2 and Ang2-induced cell invasion. These results suggest that Ang2 plays a critical role in inducing tumor cell infiltration, and that this invasive phenotype is caused by activation of MMP-2.

KW - Glioblastoma

UR - http://www.scopus.com/inward/record.url?scp=0041806539&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0041806539&partnerID=8YFLogxK

U2 - 10.1073/pnas.1533394100

DO - 10.1073/pnas.1533394100

M3 - Article

C2 - 12861074

AN - SCOPUS:0041806539

VL - 100

SP - 8904

EP - 8909

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 15

ER -