The invariable recurrence of glioblastoma multiforme remains one of the most challenging frontiers in neuro-oncology. The molecular and cellular mechanisms underlying this recurrence have been debated and literature is rife with publications of either astrocytes or neural progenitor cells (NPCs) as the likely candidate for glioma cell of origin/recurrence. These hypotheses have engendered much investigation to uncover the mechanisms underlying both the transformation of normal brain cells, as well as the clonal evolution of tumor cells and the contribution of unique cell types and niches that are drivers of tumor origination, progression, and recurrence. Already debate exists about whether any cell or only a few unique cells (ie, cancer stem cells) comprise the cellular pool for tumor origin and recurrence. Whether a differentiated or progenitor cell acquires the necessary oncogenic changes for transformation, the heterogeneity of glioma cell types is believed to arise from a malignant progenitor cell. Does the astrocyte dedifferentiate? Does a NPC become a malignant cancer stem cell? Rarely, has it been discussed that the cell of origin could be a neuron.
Indeed data presented by the Verma group have shown that not only NSCs residing either in the subventricular zone (SVZ) and hippocampus (HP) (eg, in Nestin-Cre– and Sox2-Cre–injected mice), but also mature neurons can be targets of genetic alterations that can lead to gliomagenesis. In fact, they isolated primary cortical neurons from SynI-Cre mice and transduced them in vitro with shNF1-shp53 virus resulting in expression of oncogenic genes (Figure). The isolated neurons were Map2-positive (a marker of mature neurons), GFAP-negative, doublecortin-negative (a neuronal progenitor marker), and Ki67-negative (a marker for cell proliferation). After transduction the neurons were transplanted into NOD-SCID mice, with the formation of gliomas, tumors demonstrated the same histopathology as those observed with the direct in vivo stereotaxic transductions.
The inclusion of neurons as cells from which gliomas can arise adds obstacles and opportunities in the road ahead for clinical management of patients. Tumors must now be conceptualized as ecosystems in which any and all cellular components can be exploited by the oncogenic process for evolutionary advantage. Clearly, this has been reinforced with the expanding understanding of tumor microenvironment, where stromal cells are fundamental to tumor survival. Similarly, all cells in the neural milieu are candidates and/or contributors for gliomagenesis, suggesting a renewed focus on total cell exhaustion with combinatorial therapies may offer the optimal strategy.