A Key Pathway to Cancer Resilience: The Role of Autophagy in Glioblastomas

Abstract

There are no effective strategies for the successful treatment of glioblastomas (GBM). Current therapeutic modalities effectively target bulk tumor cells but leave behind marginal GBM cells that escape from the surgical margins and radiotherapy field, exhibiting high migratory phenotype and resistance to all available anti-glioma therapies. Drug resistance is mostly driven by tumor cell plasticity: a concept associated with reactivating transcriptional programs in response to adverse and dynamic conditions from the tumor microenvironment. Autophagy, or “self-eating”, pathway is an emerging target for cancer therapy and has been regarded as one of the key drivers of cell plasticity in response to energy demanding stress conditions. Many studies shed light on the importance of autophagy as an adaptive mechanism, protecting GBM cells from unfavorable conditions, while others recognize that autophagy can kill those cells by triggering a non-apoptotic cell death program, called ‘autophagy cell death’ (ACD). In this review, we carefully analyzed literature data and conclude that there is no clear evidence indicating the presence of ACD under pathophysiological settings in GBM disease. It seems to be exclusively induced by excessive (supra-physiological) stress signals, mostly from in vitro cell culture studies. Instead, pre-clinical and clinical data indicate that autophagy is an emblematic example of the ‘dark-side’ of a rescue pathway that contributes profoundly to a pro-tumoral adaptive response. From a standpoint of treating the real human disease, only combinatorial therapy targeting autophagy with cytotoxic drugs in the adjuvant setting for GBM patients, associated with the development of less toxic and more specific autophagy inhibitors, may inhibit adaptive response and enhance the sensibility of glioma cells to conventional therapies.

Galectins in Glioma: Current Roles in Cancer Progression and Future Directions for Improving Treatment

“…Autophagy plays a central role in cancer progression [ 93 ]. In glioma, autophagy is believed to be an adaptive MoA used by glioma cells to protect them from unfavorable conditions [ 94 ].…”

New Salicylanilide Derivatives and Their Peptide Conjugates as Anticancer Compounds: Synthesis, Characterization, and In Vitro Effect on Glioblastoma

“…Despite the progress in cancer treatments, almost no advancement in the therapy of gliomas has been introduced; those brain tumors display stemness signatures, and new strategies against the highly proliferative activity of glioma cells have been studied and new compounds acting against them are needed. , These new agents need to penetrate the blood–brain barrier, then also penetrate through the tissue of the whole brain, and selectively eliminate cancer cells without harming the normal brain tissue. , The malignant glioma resistance to chemotherapy , suggests that cancer therapy should include agents that target residual cells to prevent the regrowth of neoplastic cells . Numerous molecular and cellular targets are described as a possibility in GBM treatment, , and modulation of the autophagic flux is one of them. − …”

BCL6 is a context-dependent mediator of the glioblastoma therapy response

“…A recent review concluded that most of the studies indicating autophagic cell death in response to treatment were in vitro studies using high doses, whereas clinical and pre-clinical studies indicated that autophagy was a protective mechanism. 132 Therefore, they hypothesised that autophagy is a protective mechanism in GBM therapy response, but very high levels of stress can over-activate autophagy, leading to cell death. 132 Similarly, the authors of a review paper suggested that the level of ER stress may determine the role of autophagy.…”

“…132 Therefore, they hypothesised that autophagy is a protective mechanism in GBM therapy response, but very high levels of stress can over-activate autophagy, leading to cell death. 132 Similarly, the authors of a review paper suggested that the level of ER stress may determine the role of autophagy. 133 They suggested that up to moderate levels of stress, the ER unfolded protein response (UPR) pathway led to initiation of autophagy to remove damaged cellular components and thereby protect cells from apoptosis.…”

“…418 Autophagy is a known mechanism of therapy resistance in GBM and was induced by 48 hours after acute IR. 132,423 Furthermore, mitochondrial dysfunction and ER stress are two conditions that initiate the ISR. 419 Crosstalk between these two organelles is important in the regulation of reactive oxygen species (ROS) such as those produced by IR, so it is not surprising that the acute treatments, particularly IR, upregulated proteins involved in trafficking across mitochondrial and ER membranes.…”