A Radial Glia Gene Marker, Fatty Acid Binding Protein 7 (FABP7), Is Involved in Proliferation and Invasion of Glioblastoma Cells

Antonella De Rosa,Annette Bakker,Elisa Mori,Vincenzo Miragliotta,Patrizia Tunici,Gaetano Finocchiaro,Serena Pellegatta,Federico Malusa,Letizia Magnoni,Marco Rossi,Maria Carmela Speranza,Svetlana Kotliarova

doi:10.1371/journal.pone.0052113

Antonella De Rosa, Annette Bakker + Show 10 more

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https://doi.org/10.1371/journal.pone.0052113

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Abstract

Glioblastoma multiforme (GBM) is among the most deadly cancers. A number of studies suggest that a fraction of tumor cells with stem cell features (Glioma Stem-like Cells, GSC) might be responsible for GBM recurrence and aggressiveness. GSC similarly to normal neural stem cells, can form neurospheres (NS) in vitro, and seem to mirror the genetic features of the original tumor better than glioma cells growing adherently in the presence of serum. Using cDNA microarray analysis we identified a number of relevant genes for glioma biology that are differentially expressed in adherent cells and neurospheres derived from the same tumor. Fatty acid-binding protein 7 (FABP7) was identified as one of the most highly expressed genes in NS compared to their adherent counterpart. We found that down-regulation of FABP7 expression in NS by small interfering RNAs significantly reduced cell proliferation and migration. We also evaluated the potential involvement of FABP7 in response to radiotherapy, as this treatment may cause increased tumor infiltration. Migration of irradiated NS was associated to increased expression of FABP7. In agreement with this, in vivo reduced tumorigenicity of GBM cells with down-regulated expression of FABP7 was associated to decreased expression of the migration marker doublecortin. Notably, we observed that PPAR antagonists affect FABP7 expression and decrease the migration capability of NS after irradiation. As a whole, the data emphasize the role of FABP7 expression in GBM migration and provide translational hints on the timing of treatment with anti-FABP7 agents like PPAR antagonists during GBM evolution.

Highlights

Gliomas are the most common primary malignancy in the central nervous system (CNS)
Primary and recurrent glioblastoma neurospheres were positive for Fatty acid-binding protein 7 (FABP7) expression whereas in the adherent cells no (Ct $40) or significantly lower FABP7 expression was observed: normal human astrocytes and normal human neural progenitors were used as controls (Figure 2A)
We identified for the first time that FABP7 is almost exclusively expressed in neurospheres and not in the adherent cells, derived from the same glioblastoma tumor

Summary

Introduction

Gliomas are the most common primary malignancy in the central nervous system (CNS) These tumors exhibit histological resemblance to glial cells. It has been suggested that many tumors contain a subpopulation of cancer cells possessing stem cell properties These ‘‘cancer stem-like cells’’ were reported to contribute to invasion and chemoresistance of glioblastoma tumors [3,4]. There is no unanimity around the exact role and nature of cancer stem cells, many studies converge in showing that under specific culture conditions GBM cells tend to form spheres that contain stemlike cells [6,7,8]. In the current study we find that neurospheres, display typical characteristics (invasion, migration, proliferation) of the clinically relevant GBM much better than their adherent counterpart

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