Stemness Marker Detection in the Periphery of Glioblastoma and Ability of Glioblastoma to Generate Glioma Stem Cells: Clinical Correlations.

Background: Recent studies suggested glioma stem cells (GSCs) are key contributors to therapeutic resistance of glioblastoma multiforme (GBM) and are responsible for GBM recurrence.

Methods: We characterized the phenotype of cancer cells in the core and periphery of 20 GBM tumors, correlating clinical outcome to the ability to form GSCs and distinguishing survival based on Ki-67 staining.

Results: Similar levels of methylguanine-deoxyribonucleic acid methyltransferase were found in the core and periphery of GBM tumors, whereas Ki-67 was reduced in the periphery. Similar levels of stemness markers in the periphery and in the core of all GBM cultures were found. Only cells expressing >30% SOX2 levels were able to produce neurospheres. Immunophenotypic analysis showed higher levels of stemness markers in GSC cultures than in all GBM primary cultures. GSC in vitro production and coexpression of Ki-67 >5% negatively correlated with outcome.

Conclusions: Not all GBM cultures can generate GSCs, and this capacity is linked to >30% SOX2 levels. The ability to form spheres negatively correlated to survival, and the detection of >5% Ki-67 levels may be useful to identify patients at risk of disease progression. The presence of GSC-/SOX-2-/Ki-67- cells may be regarded as a new prognostic factor. The presence of stemness markers and methylguanine-deoxyribonucleic acid methyltransferase in the periphery of GBM tumors may be the reason for treatment failure and recurrence. Development of stem cell-targeted therapies and elaboration of more aggressive treatments represent an opportunity to eliminate the GBM source and the nidus of recurrence.