PT  - JOURNAL ARTICLE
AU  - Hu, Bin
AU  - Thirtamara-Rajamani, Keerthi K.
AU  - Sim, Hosung
AU  - Viapiano, Mariano S.
TI  - Fibulin-3 Is Uniquely Upregulated in Malignant Gliomas and Promotes Tumor Cell Motility and Invasion
AID  - 10.1158/1541-7786.MCR-09-0207
DP  - 2009 Nov 01
TA  - Molecular Cancer Research
PG  - 1756--1770
VI  - 7
IP  - 11
4099  - http://mcr.aacrjournals.org/content/7/11/1756.short
4100  - http://mcr.aacrjournals.org/content/7/11/1756.full
SO  - Mol Cancer Res2009 Nov 01; 7
AB  - Malignant gliomas are highly invasive tumors with an almost invariably rapid and lethal outcome. Surgery and chemoradiotherapy fail to remove resistant tumor cells that disperse within normal tissue, which are a major cause for disease progression and therapy failure. Infiltration of the neural parenchyma is a distinctive property of malignant gliomas compared with other solid tumors. Thus, glioma cells are thought to produce unique molecular changes that remodel the neural extracellular matrix and form a microenvironment permissive for their motility. Here, we describe the unique expression and proinvasive role of fibulin-3, a mesenchymal matrix protein specifically upregulated in gliomas. Fibulin-3 is downregulated in peripheral tumors and is thought to inhibit tumor growth. However, we found fibulin-3 highly upregulated in gliomas and cultured glioma cells, although the protein was undetectable in normal brain or cultured astrocytes. Overexpression and knockdown experiments revealed that fibulin-3 did not seem to affect glioma cell morphology or proliferation, but enhanced substrate-specific cell adhesion and promoted cell motility and dispersion in organotypic cultures. Moreover, orthotopic implantation of fibulin-3–overexpressing glioma cells resulted in diffuse tumors with increased volume and rostrocaudal extension compared with controls. Tumors and cultured cells overexpressing fibulin-3 also showed elevated expression and activity of matrix metalloproteases, such as MMP-2/MMP-9 and ADAMTS-5. Taken together, our results suggest that fibulin-3 has a unique expression and protumoral role in gliomas, and could be a potential target against tumor progression. Strategies against this glioma-specific matrix component could disrupt invasive mechanisms and restrict the dissemination of these tumors. (Mol Cancer Res 2009;7(11):1756–70)© 2009 American Association for Cancer Research.