Abstract 975: Glioma cell of origin: Reprogramming and cancer stem cells

Abstract

Abstract 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) (1). Injection of a single lentiviral vector expressing H-RasV12 and si_p53 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 (2), 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 P2 mice. Only when both H-Ras and si_p53 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. So far we have used H-Ras as surrogate for EGFR amplification and loss of NF1 observed in patients, but recently we have generated a lenti vector that combines both tumor suppressor genes si_NF1 and si_p53, and the preliminary results confirmed our findings using H-Ras-si_p53 lentivector. 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. (1) Marumoto T, Tashiro A, Friedmann-Morvinski D, Scadeng M, Soda Y, Gage FH, Verma IM. Development of a novel mouse glioma model using lentiviral vectors. Nat Med 15 (1), 110-116 (2009). (2) Price DL, Chow SK, Maclean NA, Hakozaki H, Peltier S, Martone ME, Ellisman MH. High-resolution large-scale mosaic imaging using multiphoton microscopy to characterize transgenic mouse models of human neurological disorders. Neuroinformatics. 2006 Winter;4(1):65-80. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 975. doi:10.1158/1538-7445.AM2011-975