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

120 Scopus citations

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

Keywords

  • Glioblastoma

ASJC Scopus subject areas

  • General

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    Hu, B., Guo, P., Fang, Q., Tao, H. Q., Wang, D., Nagane, M., Huang, H. J. S., Gunji, Y., Nishikawa, R., Alitalo, K., Cavenee, W. K., & Cheng, S. Y. (2003). Angiopoietin-2 induces human glioma invasion through the activation of matrix metalloprotease-2. Proceedings of the National Academy of Sciences of the United States of America, 100(15), 8904-8909. https://doi.org/10.1073/pnas.1533394100