Telomere maintenance in childhood primitive neuroectodermal brain tumors

Introduction: Primitive neuroectodermal tumors (PNET), including medulloblastoma (PNET/MB) and supratentorial PNET (sPNET), are the most common malignant brain tumors of childhood. The stabilization of telomere lengths by telomerase activation is an important step in carcinogenesis and cell immortalization. Epigallocatechin-gallate (EGCG), the major polyphenol in green tea, is a telomerase inhibitor with antiproliferative and anticarcinogenic effects against different types of cancer.

Methods and Results: In this study, we used real time RT-PCR to measure the mRNA expression of the human telomerase reverse transcriptase (hTERT) in 50 primary PNET (43 PNET/MB, 7 sPNET), 14 normal human brain samples and 6 human PNET cell lines. Compared to normal human cerebellum, 38/50 (76%) primary PNET had ≥ 5×upregulated hTERT mRNA expression. While a positive correlation between hTERT mRNA expression and telomerase activity was detected in PNET cell lines, no correlation was found between telomerase activity and telomere length. Treatment of PNET cell lines with EGCG resulted in a dose-dependent inhibition of telomerase activity at µM levels. Although EGCG displayed strong proliferation inhibitory effects against TRAP-positive PNET cell lines, it had no significant effect against TRAP-negative D425 cells.

Conclusions: These results provide evidence for a possible role of telomerase in the pathogenesis of most PNET, and indicate that subsets of PNET maintain telomere length by alternative mechanisms. Inhibition of telomerase function represents a novel experimental therapeutic strategy in childhood PNET that warrants further investigation.

Keywords: brain tumor, medulloblastoma, telomerase