Combinations of genetic mutations in the adult neural stem cell compartment determine brain tumour phenotypes

Abstract

It has been suggested that intrinsic brain tumours originate from a neural stem/progenitor cell population in the subventricular zone of the post-natal brain. However, the influence of the initial genetic mutation on the phenotype as well as the contribution of mature astrocytes to the formation of brain tumours is still not understood. We deleted Rb/p53, Rb/p53/PTEN or PTEN/p53 in adult subventricular stem cells; in ectopically neurografted stem cells; in mature parenchymal astrocytes and in transplanted astrocytes. We found that only stem cells, but not astrocytes, gave rise to brain tumours, independent of their location. This suggests a cell autonomous mechanism that enables stem cells to generate brain tumours, whereas mature astrocytes do not form brain tumours in adults. Recombination of PTEN/p53 gave rise to gliomas whereas deletion of Rb/p53 or Rb/p53/PTEN generated primitive neuroectodermal tumours (PNET), indicating an important role of an initial Rb loss in driving the PNET phenotype. Our study underlines an important role of stem cells and the relevance of initial genetic mutations in the pathogenesis and phenotype of brain tumours.

Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

“…S7). Furthermore, in accordance with the reported role of p53 in suppressing transformation of NPCs (18)(19)(20)(21)(22), ETCimpaired/p53-deficient NPCs grow faster upon oncogenic activation and are capable of forming brain tumors in a subset of orthotopically transplanted animals. The incomplete penetrance observed in these experiments may be due to the fact that other cooperative oncogenic events may have to be acquired, as previously suggested (21), and indeed these might be favored by ROS increase as well as by p53 loss.…”

“…We studied the effect of oxidative metabolism inhibition in NPCs derived from the subventricular zone (SVZ), one of the two main postnatal neurogenic niches involved in brain tumorigenesis (20,23). To this end, we inhibited the ETC by knocking down the Significance Brain cancer is one of the deadliest human tumors and is characterized by several genetic changes leading to impairment of tumor suppressive pathways and oncogene activation.…”

“…Finally, p53, which has emerged as an important regulator of mitochondrial metabolism and cellular redox control (15)(16)(17), is often found mutated or functionally inactivated in HGG. Its inactivation in neural progenitor/stem cells (NPCs), which act as HGG cells of origin, contributes to gliomagenesis (18)(19)(20)(21)(22). In particular, deletion of a significant portion of the p53 DNA binding domain induces the accumulation of cooperative oncogenic events, thus leading to HGG (21).…”

Conditional Activation of Bmi1 Expression Regulates Self-renewal, Apoptosis, and Differentiation of Neural Stem/Progenitor Cells In Vitro and In Vivo

“…We induced Bmi1 overexpression in adult mice by means of intraventricular injection of AdenoCre in STOPFloxBmi1 mice. This is a highly efficient method to obtain recombination of LoxP alleles in cells of the SVZ, as reported in the literature [26] and as we have seen in our experiments in R26R mice (Supporting Information Fig. S5A, S5B).…”

Cancer Stem Cells as a Result of a Reprogramming-Like Mechanism

“…But, what are the mechanisms of tumor relapse by which tumors evolve to escape oncogene dependence? Several recent studies of the effect of oncogenes in stem cells in cancer development (Barker et al, 2009;Perez-Caro et al, 2009;Zhu et al, 2009;Bussard et al, 2010;Jacques et al, 2010;Nakagawa et al, 2010;Saring et al, 2010;Zhang et al, 2010) implicate that tumor reprogramming (where the maintenance of oncogene expression is not critical for the generation of differentiated tumor cells) might represent a potentially important mechanism of tumour development for many types of cancer and that, if this is the case, the oncogenes that initiate tumor formation might be dispensable for tumor progression and/or maintenance. The practical implications that this new point of view has for the therapy of cancer are obviously enormous (Castellanos et al, 2010).…”