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The Autophagy Status of Cancer Stem Cells in Gliobastoma Multiforme: From Cancer Promotion to Therapeutic Strategies

1
Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Roma 55, 56126 Pisa, Italy
2
I.R.C.C.S. Neuromed, via Atinense 18, 86077 Pozzilli (IS), Italy
3
Department of Neuroscience, Mental Health and Sense Organs NESMOS, Sapienza University of Rome, 00185 Roma, Italy
*
Author to whom correspondence should be addressed.
These authors equally contributed to the present work.
Int. J. Mol. Sci. 2019, 20(15), 3824; https://doi.org/10.3390/ijms20153824
Received: 10 July 2019 / Revised: 26 July 2019 / Accepted: 3 August 2019 / Published: 5 August 2019
(This article belongs to the Special Issue Molecular Biology of Brain Tumors)
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor featuring rapid cell proliferation, treatment resistance, and tumor relapse. This is largely due to the coexistence of heterogeneous tumor cell populations with different grades of differentiation, and in particular, to a small subset of tumor cells displaying stem cell-like properties. This is the case of glioma stem cells (GSCs), which possess a powerful self-renewal capacity, low differentiation, along with radio- and chemo-resistance. Molecular pathways that contribute to GBM stemness of GSCs include mTOR, Notch, Hedgehog, and Wnt/β-catenin. Remarkably, among the common biochemical effects that arise from alterations in these pathways, autophagy suppression may be key in promoting GSCs self-renewal, proliferation, and pluripotency maintenance. In fact, besides being a well-known downstream event of mTOR hyper-activation, autophagy downregulation is also bound to the effects of aberrantly activated Notch, Hedgehog, and Wnt/β-catenin pathways in GBM. As a major orchestrator of protein degradation and turnover, autophagy modulates proliferation and differentiation of normal neuronal stem cells (NSCs) as well as NSCs niche maintenance, while its failure may contribute to GSCs expansion and maintenance. Thus, in the present review we discuss the role of autophagy in GSCs metabolism and phenotype in relationship with dysregulations of a variety of NSCs controlling pathways, which may provide novel insights into GBM neurobiology. View Full-Text
Keywords: rapamycin; glioma stem cells; stemness; differentiation; mTOR; Notch; Hedgehog; Wnt/β-catenin rapamycin; glioma stem cells; stemness; differentiation; mTOR; Notch; Hedgehog; Wnt/β-catenin
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Ryskalin, L.; Gaglione, A.; Limanaqi, F.; Biagioni, F.; Familiari, P.; Frati, A.; Esposito, V.; Fornai, F. The Autophagy Status of Cancer Stem Cells in Gliobastoma Multiforme: From Cancer Promotion to Therapeutic Strategies. Int. J. Mol. Sci. 2019, 20, 3824.

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