Abstract
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.
Highlights
Gliomas are the most prevalent and lethal intracranial tumors in adults, accounting for approximately 36% of primary brain tumors [1]
As it occurs in different hematopoietic and solid-tumors, Glioblastoma multiforme (GBM) harbors a fraction of cancer stem cells known as glioma stem cells (GSCs), which are endowed with key features of normal neural stem cells (NSCs) of the adult brain, such as sustained self-renewal and proliferation [33]
MTOR inhibition downregulates both mRNA, protein levels, and the activity of the matrix metalloproteinases, MMP-9 and MMP-2, which promote tumor invasion through extracellular matrix degradation. These findings suggest that mammalian Target Of Rapamycin (mTOR) inhibition coupled with radio- and/or chemo-therapy might hold great potential in hindering GBM progression
Summary
Gliomas are the most prevalent and lethal intracranial tumors in adults, accounting for approximately 36% of primary brain tumors [1]. MTOR hyper-activation and autophagy suppression are both implicated in a crucial standpoint of GBM pathophysiology, that is, maintaining the oncogenic properties of malignant glioma by promoting the growth and maintenance of glioma stem-like cells (GSCs) As it occurs in different hematopoietic and solid-tumors, GBM harbors a fraction of cancer stem cells known as GSCs, which are endowed with key features of normal neural stem cells (NSCs) of the adult brain, such as sustained self-renewal and proliferation [33]. MTOR inhibition and autophagy induction contribute to reducing stem cell-like properties, promoting differentiation, and restraining cell migration and invasion potential of GSCs [32,49,55,56] In this scenario, dysregulations of mTOR and autophagy machinery do intermingle with a myriad of molecular pathways to sustain GSCs proliferation, GBM aggressiveness, and treatment resistance. Sci. 2019, 20, 3824 the mechanisms by which autophagy impairment may sustain GSCs self-renewal, proliferation, and resistance to therapies might provide novel insights into the neurobiology of GBM, and hopefully, contribute to the development of new therapeutic strategies
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