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

• Published in: International journal of molecular sciences Vol. 20; no. 15; p. 3824
• Main Authors: Ryskalin, Larisa, Gaglione, Anderson, Limanaqi, Fiona, Biagioni, Francesca, Familiari, Pietro, Frati, Alessandro, Esposito, Vincenzo, Fornai, Francesco
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 05.08.2019; MDPI
• Subjects: Adults; Amino acids; Animals; Antigens; Autophagy; Biomarkers; Brain cancer; Brain Neoplasms - diagnosis; Brain Neoplasms - etiology; Brain Neoplasms - metabolism; Brain Neoplasms - therapy; Brain research; Cancer therapies; Cell adhesion & migration; Cell Differentiation; Cell growth; Cell Transformation, Neoplastic - metabolism; Disease Management; Glioblastoma - diagnosis; Glioblastoma - etiology; Glioblastoma - metabolism; Glioblastoma - therapy; Glioma; Humans; Kinases; Medical prognosis; Metabolism; Molecular Targeted Therapy; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Neurosciences; Protein synthesis; Proteins; Review; Signal Transduction; Stem cells; TOR Serine-Threonine Kinases - metabolism; Tumors; Hedgehog; differentiation; Wnt/β-catenin; Notch; stemness; mTOR; glioma stem cells; rapamycin
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20153824

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.