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.