Mitochondria’s Role in the Maintenance of Cancer Stem Cells in Glioblastoma

Abstract

Glioblastoma (GBM), one of the deadliest primary brain malignancies, is characterized by a high recurrence rate due to its limited response to existing therapeutic strategies such as chemotherapy, radiation therapy, and surgery. Several mechanisms and pathways have been identified to be responsible for GBM therapeutic resistance. Glioblastoma stem cells (GSCs) are known culprits of GBM resistance to therapy. GSCs are characterized by their unique self-renewal, differentiating capacity, and proliferative potential. They form a heterogeneous population of cancer stem cells within the tumor and are further divided into different subpopulations. Their distinct molecular, genetic, dynamic, and metabolic features distinguish them from neural stem cells (NSCs) and differentiated GBM cells. Novel therapeutic strategies targeting GSCs could effectively reduce the tumor-initiating potential, hence, a thorough understanding of mechanisms involved in maintaining GSCs’ stemness cannot be overemphasized. The mitochondrion, a regulator of cellular physiological processes such as autophagy, cellular respiration, reactive oxygen species (ROS) generation, apoptosis, DNA repair, and cell cycle control, has been implicated in various malignancies (for instance, breast, lung, and prostate cancer). Besides, the role of mitochondria in GBM has been extensively studied. For example, when stressors, such as irradiation and hypoxia are present, GSCs utilize specific cytoprotective mechanisms like the activation of mitochondrial stress pathways to survive the harsh environment. Proliferating GBM cells exhibit increased cytoplasmic glycolysis in comparison to terminally differentiated GBM cells and quiescent GSCs that rely more on oxidative phosphorylation (OXPHOS). Furthermore, the Warburg effect, which is characterized by increased tumor cell glycolysis and decreased mitochondrial metabolism in the presence of oxygen, has been observed in GBM. Herein, we highlight the importance of mitochondria in the maintenance of GSCs.

The polarity protein Par3 coordinates positively self-renewal and negatively invasiveness in glioblastoma

“…5 ). This finding bridges the function of Par3 with a relatively well-established field of GBM metabolism, which has been shown to depend on mitochondrial action, glucose oxidation, and glycolysis at least in mice bearing GBM tumors [ 43 ], and in various studies of human GBM [ 44 ]. Furthermore, human GBMs with stem-like characteristics appear to generate their ATP via mitochondrial oxidative phosphorylation in parallel to the generation of ROS [ 45 ].…”

Targeted Anti-mitochondrial Therapy: The Future of Oncology

“…It has been evidenced that CSCs activate mitochondrial stress pathways in response to stressors such as radiation, chemotherapy, or hypoxia. This contribution is multidimensional by regulating stemness, quiescence, and treatment resistance 85 . Recent studies on glioblastoma stem cells (GSCs) demonstrated the pivotal role of mitochondria in GSCs biology.…”

Extracellular citrate and metabolic adaptations of cancer cells

“…CSCs are often quiescent with the ability for self-renewal and proliferative potential. They also show a high capacity to switch quickly between glycolysis and OXPHOS [22]. Although some of the CSCs such as breast, ovarian cancers or glioblastoma [23][24][25] rely on glycolysis as the predominant metabolic pathway, it is now more widely accepted that most CSCs use OXPHOS as their preferred mechanism of energy acquisition.…”