Molecular and cellular intratumoral heterogeneity in primary glioblastoma: clinical and translational implications

Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is associated with significant morbidity and mortality despite maximal safe resection followed by chemo- and radiotherapy. GBMs contain self-renewing, tumorigenic glioma stem cells that contribute to tumor initiation, heterogeneity, therapeutic resistance, and recurrence. Intratumoral heterogeneity (ITH) of GBMs is also a major contributing factor to poor clinical outcomes associated with these high-grade glial tumors. Herein, the authors summarize recent discoveries and advances in the molecular and phenotypic characterization of GBMs with particular focus on ITH. In so doing, they attempt to highlight recent advances in molecular signatures/properties and metabolic alterations in an effort to clarify translational implications that may ultimately improve clinical outcomes.