High-pressure oxygen rewires glucose metabolism of patient-derived glioblastoma cells and fuels inflammasome response
Arienti, C. et al. (2021) High-pressure oxygen rewires glucose metabolism of patient-derived glioblastoma cells and fuels inflammasome response. Cancer Lett. 506, 152–66. DOI: j.canlet.2021.02.019
Glioblastoma (GBM) is an aggressive malignant brain tumor and has a median survival of 15 months, making it one of the deadliest cancers. Poor outcomes are attributed to intratumoral heterogeneity, the highly invasive nature of tumor cells, and the presence of cancer stem cells. The current therapeutic approach for GBM patients is a maximal safe surgical resection followed by 6 weeks of external beam irradiation and daily use of temozolomide, an alkylating agent that causes DNA damage and cell death. Hypoxia is a feature of GBM and is associated with tumor aggressiveness and resistance to radiation and chemotherapy. Earlier research showed the hypoxic tumor microenvironment is responsible for activating hypoxia-sensitive factors (HIF-1 and HIF-2) and proinflammatory transcription factors (NF-κB), contributing to the GBM aggressiveness and affecting both immune cell composition and glucose metabolism. Previous work also found that the immune cell function surrounding GBM tissue is severely impaired.
The current study investigated the radiosensitizing effects of hyperbaric oxygen therapy (HBOT) when used preceding radiation therapy (RT). Samples were collected from 10 patients, two of whom had recurrent GBM. They maintained patient-derived GBM and transformed human microglial cells (CHME-5) under hypoxic conditions in both monolayer cell culture and 3D spheroids. They performed HBOT by gradually increasing the pressure in a hyperbaric chamber to 1.9 or 2.5 atmospheres absolute (ATA) and maintained the pressure for 1 hour. Within 30 minutes of HBOT, cells were irradiated in doses of 5 and 7.5 Gray . They performed assays to determine effects of HBOT on glucose metabolism and DNA damage, and evaluated inflammasome activation to characterize immune response. This experiment revealed that HBOT inhibited the glioma cell proliferation, downregulated HIF-1 expression and significantly decreased expression of the stemness markers CD44, Nestin and Slug. Results showed HBOT of GMB spheroids led to a decrease in the expression of glucose transporter (GLUT1) and reduced glucose uptake and lactate production in glioma cells. Researchers found that HBOT had a radiosensitizing effect on patient-derived GBM cells and a radioprotective effect on microglia cells. This study also showed evidence of crosstalk between glioma cells and microglia, and that HBOT affects microglia polarization. These results provide new understanding of microglia immunology and how to potentially treat recurrent GBM in humans.
Keywords: Glioblastoma, hypoxia, inflammation, radioresistance, preclinical studies
