Glioma cell of origin: Reprogramming and Cancer Stem cells

Glioblastomas are the most common and lethal form of intracranial tumors. In the last century we have accumulated tremendous amounts of data on this type of cancer, but we have achieved very little improvement in its treatment. This inadequate progress led us to reexamine the gliomagenesis theory and reconsider the cell of origin of this deadly disease. We recently developed a mouse glioma model using Cre-inducible lentiviral vectors that faithfully recapitulate the pathophysiology of human glioblastoma multiforme (GBM). Injection of a single lentiviral vector expressing either HRasV12-shp53 or shNF1-shp53 into the brain of GFAP-Cre or Nestin-Cre mice led to tumor formation after 6-8 weeks of injection. Tumors were also obtained when the virus was injected either in the cortex or the stratium in the GFAP-Cre mice, suggesting that astrocytes can also serve as the glioma cell of origin. We made sections of these brains at various time points following injection of the lentiviral vector and, using high resolution large-scale mosaic imaging, we examined the expression of different markers. Notably, tumors start out to be GFAP+, but by eight weeks are largely Nestin+ and Sox2+. We believe that astrocytes can be reprogrammed by the introduction of oncogenes/tumor suppressors to form cancer iPS-like stem cells that can give rise to all the cell lineages and heterogeneity observed in GBM. To further explore this hypothesis, we transduced primary cortical astrocytes obtained from GFAP-Cre mice. Only when both H-Ras and shp53 were in the viral vector were the cells able to reprogram and give rise to neurospheres, a property ascribed to neural stem cells. We were also able to obtain tumors when we aimed to transduce neurons by injecting our lentiviral vector in Syn-Cre mice, suggesting that the reprogramming process is not restricted to glial cells.

Together, our results suggest that any cell in the brain, whether terminally differentiated or neural stem cell, can be the glioma cell of origin and the biological behavior of these tumors depends on the dysregulation of specific genetic elements.