Chaperone-Mediated Autophagy in Pericytes: A Key Target for the Development of New Treatments against Glioblastoma Progression

Abstract

Glioblastoma (GB) cells physically interact with peritumoral pericytes (PCs) present in the brain microvasculature. These interactions facilitate tumor cells to aberrantly increase and benefit from chaperone-mediated autophagy (CMA) in the PC. GB-induced CMA leads to major changes in PC immunomodulatory phenotypes, which, in turn, support cancer progression. In this review, we focus on the consequences of the GB-induced up-regulation of CMA activity in PCs and evaluate how manipulation of this process could offer new strategies to fight glioblastoma, increasing the availability of treatments for this cancer that escapes conventional therapies. We finally discuss the use of modified PCs unable to increase CMA in response to GB as a cell therapy alternative to minimize undesired off-target effects associated with a generalized CMA inhibition.

The Role of Cellular Prion Protein in Glioma Tumorigenesis Could Be through the Autophagic Mechanisms: A Narrative Review

“…It was recently discovered that some human prion peptides induce autophagy flux and autophagic cell death in the neuronal cell [ 23 , 45 , 46 ]. Further, autophagy inhibitors can reduce prion protein-induced autophagic cell death via AMP pathway [ 47 , 48 , 49 ]. An increased calcineurin activity mediated by prion protein-induced neuronal cell damage and provided insight into the fundamental mechanism underlying AMPK and autophagy flux in prion disease [ 47 ].…”

“…So, it was demonstrated that prion protein-calcineurin activation was involved in prion protein-mediated neuronal cell death and AMPK and autophagy signaling pathways [ 49 ]. It regulates metabolic homeostasis by controlling autophagy [ 8 ].…”

“…It regulates metabolic homeostasis by controlling autophagy [ 8 ]. It seems that prion peptide decreased the AMPK activity via dephosphorylation and increases autophagic cell death [ 49 ]. At the same time, prion protein increases calcineurin activity, resulting in decreased AMPK phosphorylation that induces autophagic cell death [ 47 ].…”

“…Recent studies provided the first direct evidence that autophagy induction results in cellular PrPSc degradation. When autophagy is suppressed by pharmacological interference or siRNA gene-silencing of essential members of the autophagic machinery, the capacity of compound-induced autophagy in reducing cellular levels of PrPC is impaired [ 49 , 50 , 51 ] ( Figure 1 ). Because cells in which the PRNP was eliminated are more susceptible to apoptotic cell death by serum deprivation.…”

A selective type of autophagy to maintain glioma stem cell activity

“…Glioblastoma multiforme (GBM) is the most aggressive and abundance primary brain tumor; presenting, unfortunately, very low chances of recovery; among all the cancer types, it is one of those specially complicated in terms of treatment ( 1 ). About three in 100,000 people develop the disease per year; the average age at diagnosis is sixty-four; and it presents an estimate patient survival lower than fifteen months (The 2021 WHO Classification).…”