Inducible expression of stem cell associated intermediate filament nestin reveals an important role in glioblastoma carcinogenesis

Abstract

The intermediate filament nestin is transiently expressed in neural stem/progenitor cells during the development of central nervous system. Recently, increasing evidence has shown that upregulation of nestin is related to malignancy of several cancers, especially glioblastoma. However, the function of nestin in carcinogenesis remains unclear. In this study, we investigated the role of nestin in glioblastoma carcinogenesis by comparing subclones of rat C6 glioblastoma cells that were either high or low for nestin expression. We found that while nestin expression did not influence the in vitro proliferation of glioblastoma cells, subclones characterized by high levels of nestin formed tumors in vivo at significantly faster rates than subclones with low expression. Importantly, C6 subclones that expressed nestin at low levels in vitro were also found to give rise to tumors highly positive for the protein, suggesting that induction of nestin plays an important role in glioblastoma carcinogenesis. Derivation of nestin positive tumors from nestin negative human U87 glioblastoma cells in immunodeficient mice further confirmed that a switch to positive expression of nestin is fundamental to the course of glioblastoma development. Blocking the expression of nestin in glioblastoma tumors via intratumor injection of shRNA significantly slowed tumor growth and volume. These results demonstrated that nestin plays a crucial role in development of glioblastoma and may potentially be targeted for treatment of the disease.