O4.10CNS STEM CELL SPECIFIC TUMOURIGENESIS REVEALS LINEAGE RELATIONSHIP BETWEEN EXPERIMENTAL AND HUMAN GLIOMAS AND A DOMINANCE OF GLIAL SIGNATURES DURING TUMOUR PROPAGATION IN VITRO

摘要

BACKGROUND: Brain tumors are thought to originate from stem/progenitor cell populations that acquire specific genetic mutations. Although current preclinical models have relevance to human pathogenesis, many do not recapitulate the histogenesis of the human disease. METHODS: and AIMS: We analysed the spectrum of intrinsic brain tumors arising from the neurogenic zone of the SVZ or from cancer stem cells that were generated and propagated in vitro and introduced into the brain by orthotopic allografting. We analyzed the relationship of the combination of mutations, the morphologic tumor phenotype, and the expression profile. In addition we developed a novel approach to generate brain tumours by inducing locally restricted, stem cell selective gene targeting, by injecting the active compound 4OH-Tamoxifen directly into the ventricles of GLAST cre ER(T); PTENlox/lox;p53lox/lox mice. We validated our model system by correlating expression and phenotype of their human counterparts. RESULTS: The combination of genetic mutations and cellular environment during tumour propagation defined the incidence and phenotype of intrinsic murine tumors. Importantly, in vitro passage of cancer stem cells uniformly promoted a glial expression profile in culture and in brain tumours. Gene expression profiling confirmed that experimental gliomas corresponded to distinct subclasses of human glioblastoma, whereas experimental supratentorial PNET correspond to atypical teratoid/rhabdoid tumour (AT/RT), a rare childhood tumour. CONCLUSION: Our key findings are that the genotype and phenotype can be strongly modified in vitro by growth factors, characterized by a shift toward a stem/transient amplifying phenotype in vitro and that experimental gliomas correlate with the TCGA classical subtype of human glioblastomas. Using a novel method to selectively recombine genetically defined cell populations, B-type SVZ stem cells, we generate gliomas similar to this achieved by targeting a broader population of progenitor cells, indicating that highly selective targeting of specific SVZ stem cell population is not essential to generate an effective model system for brain tumours. This finding has important implications for the development of biologically relevant brain tumour models.