gms | German Medical Science

Objective: Malignant brain tumours contain a distinct sub-population of tumorigenic cells generally termed “brain tumour initiating cells” (BTICs) that possess biological features of adult neural stem cells. The ability to repopulate the entire tumour and confer radio- and chemo-resistance clearly identifies BTICs as the prime cell target for therapy of malignant brain tumours. This study was carried out to show the chromosomal changes that characterize BTICs before and after irradiation.

Methods: TICs were isolated from established GBM primary cultures. Radioresistant cell populations were selected by exposing BTICs cultures to repetitive rounds of clinically relevant doses of ionizing radiation (IR). The tumorigenic potential of the BTICs was confirmed by using an orthotopic glioma mouse model. Six BTIC and their radioresistant cultures were analyzed using comparative genetic hybridization (CGH).

Results: All 12 cell cultures revealed chromosomal changes. Radioresistant BTICs revealed higher mean copy number netto changes than primary BTCIs (17.83 ± 2.89 versus 15.0 ± 2.46). The increase in copy number changes was due to more chromosomal gains (10.83 ± 2.44 versus 7.83 ± 1,64) after irradiation. Chromosomal gains in primary and irradiated BTCIs were seen on whole chromosome 7 (100%) and 1q (83.3%). Gain of 17q was more frequently found in irradiated BTCIs (83.3% vs 50%). Losses in primary and irradiated BTCIs were mainly to 10p (66.7%), 10q (50%) and 9p (50%). Losses on 1p (50% vs 16.7%) were more frequently observed in irradiated BTICs .

Conclusions: BTICs share the common cytogenetic changes observed in high grade gliomas. Higher chromosomal instability mirrors the invasive behaviour and accelerated tumour progression after irradiation. The gain of 17q and loss of 1p might reflect adverse prognostic factors as seen in neuroblastomas of advanced stage.