p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation

Abstract

Glioblastoma (GBM) is a highly lethal brain tumor presenting as one of two subtypes with distinct clinical histories and molecular profiles. The primary GBM subtype presents acutely as high-grade disease that typically harbors EGFR, Pten and Ink4a/Arf mutations, and the secondary GBM subtype evolves from the slow progression of low-grade disease that classically possesses PDGF and p53 events1–3. Here, we show that concomitant CNS-specific deletion of p53 and Pten in the mouse CNS generates a penetrant acute-onset high-grade malignant glioma phenotype with striking clinical, pathological and molecular resemblance to primary GBM in humans. This genetic observation prompted p53 and Pten mutational analysis in human primary GBM, demonstrating unexpectedly frequent inactivating mutations of p53 as well the expected Pten mutations. Integrated transcriptomic profiling, in silico promoter analysis and functional studies of murine neural stem cells (NSCs) established that dual, but not singular, inactivation of p53 and Pten promotes an undifferentiated state with high renewal potential and drives elevated c-Myc levels and its associated signature. Functional studies validated increased c-Myc activity as a potent contributor to the impaired differentiation and enhanced renewal of p53-Pten null NSCs as well as tumor neurospheres (TNSs) derived from this model. c-Myc also serves to maintain robust tumorigenic potential of p53-Pten null TNSs. These murine modeling studies, together with confirmatory transcriptomic/promoter studies in human primary GBM, validate a pathogenetic role of a common tumor suppressor mutation profile in human primary GBM and establish c-Myc as a key target for cooperative actions of p53 and Pten in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal and tumorigenic potential.

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

“…Conditional overexpression of c-Myc in mouse astroglia leads to brain tumors that resemble human malignant gliomas (Jensen et al, 2003). In addition, c-Myc prevents cell differentiation and promotes self-renewal of tumor cells derived from the pten/p53 double null mouse model (Zheng et al, 2008a). Taken together, these studies support an important role of c-Myc in GSC maintenance.…”

“…Recent studies demonstrated that inactivation of PTEN (a well-known tumor suppressor) promotes undifferentiated state of GSCs (Zheng et al, 2008a, b), suggesting PTEN may promote GSC differentiation. PTEN is a phosphatase with dual-specificity for both protein and lipid and is often mutated in GBMs (Fan et al, 2002;Zheng et al, 2008a). It has been well known that PTEN deletion or functional loss is linked to progression and/or immunoresistance of malignant gliomas (Parsa et al, 2007).…”

Endothelial cells promote neural stem cell proliferation and differentiation associated with VEGF activated Notch and Pten signaling

“…Conditional knockout of Pten in neural stem cells revealed that Pten is indispensable for proper control of neural stem cell proliferation and self-renewal in the developing brain (Groszer et al, 2001). Double knockout of p53 and Pten led to compromised differentiation potential and sustained self-renewal of neural stem cells by means of elevated Myc expression (Zheng et al, 2008). Moreover, conditional deletion of Pten in a subpopulation of adult neural stem cells in the subventricular zone resulted in enhanced neural stem cell self-renewal.…”

Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas

“…Despite recent insights into molecular pathways involved in GBM pathogenesis, gained through comprehensive genetic analysis during the pilot project of 'The Cancer Genome Atlas' initiative (The Cancer Genome Atlas Research Network, 2008) and other studies (Furnari et al, 2007;Zheng et al, 2008), better understanding of the molecular basis and biology of gliomas is needed to validate the emerging, and design new, targeted therapies. Rampant genomic instability and resistance to genotoxic treatment modalities including ionizing radiation and chemotherapy are among the hallmarks of GBM (Furnari et al, 2007), implicating the cellular DNA damage response (DDR) machinery (Jackson and Luo et al, 2009) as an important factor in both pathogenesis and treatment response.…”