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• W47954908 abstract "Glioblastoma multiforme (GBM) is one of most common and still poorly treatedprimary brain tumors. One of the biggest challenges in brain tumour research is thepossibility of reprogramming cancer cells toward less aggressive phenotypes. To reachthis aim however, a more complete understanding of the biology of GBM cells isneeded, in particular considering the role played by hypoxia as a signaling pathwaysregulator. In search for new therapeutic approaches, Bone Morphogenetic Proteins(BMPs) have been demonstrated to induce astroglial commitment in GBM-derived cellsin vitro. The mTOR pathway represent a controversial link between the pro-stemnesshypoxic pathway and the pro-differentiating BMPs pathway. Indeed, HIF-1α iscontrolled at the transcriptional and translational level by mTOR and, alike BMP, alsomTOR pathway modulates glial differentiation in central nervous system (CNS) stemcells. Here, we investigate the role of mTOR signaling in the regulation of HIF-1αstability in primary GBM-derived cells maintained under hypoxia (2% oxygen). Wefound that GBM cells, when acutely exposed to high oxygen tension, undergoAkt/mTOR pathway activation and that BMP2 acts in an analogous way. Importantly,repression of Akt/mTOR signaling is maintained by HIF-1α through REDD1upregulation. On the other hand, BMP2 counter-acts HIF-1α stability by modulatingintracellular succinate and by controlling proline hydroxylase 2 (PHD2) protein throughinhibition of FKBP38, a PHD2 protein regulator. Despite being encouraging, these datasuggested that hypoxia, which is characteristic of the brain niche where GBM reside,strongly counter-acts BMP effects; so a new therapeutic approaches able to counteracttumour growth also in its hypoxic microenvironment is fundamental. In the second partof this study, we reprogrammed primary GBM-derived cells toward a less oncogenicphenotype by activating Wnt pathway in GBM hypoxic microenvironment, that usuallycorrelates with a malignant behaviour of cancer cells. We demonstrate that exogenousWnt3a ligand mediates neuronal differentiation and proliferation inhibition of GBMcells and that this phenomenon is enhanced under hypoxic conditions by HIF-1α-mediated up-regulation of β-catenin co-factors TCF1 and LEF1. Moreover, we showthat Wnt pathway activation inhibits Notch signalling, thus enhancing the prodifferentiatingeffects exerted by the Wnt activated pro-neuronal genes NEUROD1 and4NEUROG1, and that this occurs mainly in the GBM cancer stem cell subpopulation(CD133+). By using a zebrafish-based protocol for orthotopic xeno-transplantation ofprimary GBM-derived cells, we show that Wnt pathway activation is able to promoteneuronal differentiation of GBM cells by inhibiting Notch signalling also in an in vivosetting.Conclusions: In this study we elucidate the molecular mechanisms by which two prodifferentiatingstimuli, BMP2 and acute high oxygen exposure, control HIF-1α stability.We previously reported that both these stimuli, by inducing astroglial differentiation,affect GBM cells growth. We also found differences in high oxygen and BMP2sensitivity between GBM cells and normal cells that should be further investigated tobetter define tumor cell biology. Moreover, we add more information in the epistaticrelationship between HIF-1α, Wnt and Notch signalling in GBM-derived cells,demonstrating a Wnt-regulated suppression of Notch activity in the hypoxicmicroenvironment of GBM tumours.The third part of my PhD study focused on Medulloblastoma (MDB) which is the mostcommon brain malignancy of childhood. It is currently thought that MDB arises fromaberrantly functioning stem cells in the cerebellum that fail to maintain proper controlof self-renewal. Additionally, it has been reported that MDB cells display higherendogenous Notch signalling activation, known to promote the survival andproliferation of neoplastic neural stem cells and to inhibit their differentiation. Whileinteraction between Hypoxia Inducible Factor-1α (HIF-1α) and Notch signalling isrequired to maintain normal neural precursors in an undifferentiated state, an interactionhas not been identified in MDB. Here, we investigate whether hypoxia, through HIF-1αstabilization, modulates Notch1 signalling in primary MDB-derived cells. Our resultsindicate that MDB-derived precursor cells require hypoxic conditions for in vitroexpansion, whereas acute exposure to 20% oxygen induces tumor cell differentiationand death through inhibition of Notch signaling. Importantly, stimulating Notch1activation with its ligand Dll4 under hypoxic conditions leads to expansion of MDBderivedCD133+ and nestin+ precursors, suggesting a regulatory effect on stem cells. Incontrast, MDB cells undergo neuronal differentiation when treated with γ-secretaseinhibitor, which prevents Notch activation.5Conclusions. These results suggest that hypoxia, by maintaining Notch1 in its activeform, preserves MDB stem cell viability and expansion.Significance: We add new insights in the regulation of brain tumour stem cells andcontribute to clarify the complex relationship between diverse signalling pathways incontrolling GBM cell phenotype." @default.
• W47954908 created "2016-06-24" @default.
• W47954908 creator A5051460984 @default.
• W47954908 date "2012-01-27" @default.
• W47954908 modified "2023-09-27" @default.
• W47954908 title "Analysis of the molecular and phenotypic effects mediated by brain tumour microenvironment on glioblastoma derived cells through in vitro and in vivo models." @default.
• W47954908 hasPublicationYear "2012" @default.
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