Abstract A36: Fibronectin promotes glioma progression by modulating survivin expression and regulatory T cell infiltration

Abstract

Abstract Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor. Current therapies include surgery, radiation and chemotherapy which only modestly improve patient survival. Glioma progression depends upon exponential growth of the tumor cells accompanied by an increase in acute immunosuppression due to tumor infiltration by regulatory T cells (CD4+CD25+FoxP3+, Tregs). Although several markers responsible for glioma progression have been described, none have been identified as key elements responsible for both glioma growth and immunosuppression. In this study we characterize the role of fibronectin, a high-molecular weight extracellular matrix glycoprotein secreted by tumor cells, in controlling glioma progression and mediating immunosuppression. Fibronectin binds to membrane-spanning receptor proteins called integrins and plays an important role in cell signaling and defining cellular shape, mobility, and regulate the cell cycle. Inhibition of fibronectin expression in glioma cells using RNA-silencing delayed cell division in vitro. Analysis of the mechanism for this delayed cell division showed reduced phosphorylation of Src kinase and STAT-3 (Tyr705) resulting in inhibition of survivin, an important marker for glioma progression. In an animal model of glioma, the mean survival of experimental animals increased from 30 days for wild-type tumors to 53 days in fibronectin knockdown tumors. In vitro expression of Treg-recruiting chemokines was reduced in fibronectin knockdown tumor cells. Moreover, brain samples of animals bearing fibronectin knockdown tumors showed delayed infiltration of Tregs. Collectively, we propose that fibronectin is a key marker for glioma progression, as it enhances both tumor progression and immunosuppression. Citation Information: Cancer Res 2009;69(23 Suppl):A36.