Glioblastoma cancer stem cells: Basis for a functional hypothesis

GBM Cancer stem cells (CSCs) are responsible for growth, recurrence and resistance to chemo- and radio-therapy. They are supposed to originate from the transformation of Neural stem cells (NSC) of the Sub-ventricular zone (SVZ) or Sub-granular zone (SGZ) of hippocampus. Alternatively, they can be the expression of a functional status of competence or dedifferentiated cells of the tumor re-acquiring stemness properties. The origin of gliomas has been put in relation with the primitive neuroepithelial cells of the SVZ or NSC or progenitors, as showed by the development of experimental tumors in rats by transplacental ethylnitrosourea administration. The demonstration of CSCs in GBM is based on Neurosphere (NS) and Adherent cell (AC) development in culture. NS share the same genetic alterations with primary tumors and express stemness antigens, whereas AC show differentiation antigens. NS are generated by the most malignant areas of GBM. CSCs are considered at the top of a hierarchy of tumor cells of which the most immature are Nestin+/CD133– cells or established on the basis of EGFR amplification or delta-EGFR. NS in serum conditions differentiate and give origin to AC, the real nature of which is still a matter of discussion. Cells in culture could be simply in vitro entities depending on culture methodology. CSCs in GBM could be tumor cells at the end of a dedifferentiation process re-acquiring stemness properties, in an opposite way to what is realized in normal cytogenesis, where stemness is lost progressively with cell differentiation. This interpretation could fit with the origin of the two GBM types, primary and secondary. In primary GBM the tumor originates directly from stem cells or progenitors from SVZ with an accelerated transformation, whereas secondary GBM originates by transformation from astrocytomas arisen through a slow transformation from migrating stem cells and progenitors.